This article isThis article by protected copyright. All rights reserved. 10.1111/imm.12972doi: differences to lead between the of this version c and Version Record.Please copyediting, paginationbeen throughthe andproofreadingtypesetting, process,may which Accepted This article acceptedhas been for publication andundergone fullpeer review buthasnot Key words: Tel: [email protected] 2RD, UK NG7 Nottingham, Park, *Correspondence: ofNottingham, University Pharmacy, of School Article M Anna Tomlin, Hannah T title: Short pathogens to microbial response immune innate the and matrix the extracellular between interplay A complex :Review Article type :0000 ID (Orcid MARIA PICCININI DR. ANNA +44 (0) 115

extracellular matrix, infection, immunity immunity matrix,infection, extracellular he extracellular matrix matrix extracellular he 82 32274 82 Anna Maria Piccinini, Pharmacy School Building, East Drive, University University EastDrive, Building, School Pharmacy Piccinini, Maria Anna

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ite thisarticle as This article isThis article by protected copyright. All rights reserved. host the within substrates of Accepted variety a defence multiply tissues, underlying invade host, the to adhere bacteria most pathogenic disease, aninfectious establish successfully To Introduction networks, of inflammatory regulation populati leukocyte phagocytosis, activation, macrophage recognition, microbial activities, antimicrobial encompassing thatimplicates data recent pathogens the between interplay close The ECM local the forefront ofinfection. the on impact profound have a Article andthree composition and cell behaviour thatdirect cytokines responses can proteins (MSCRAMM) molecules ECM. contextofthe the in occur immune and cells host tissues pathogens, invading between interactions complex the However, neglected. be to tends matrix infection (ECM) in extracellular thehost of role The Summary also

s

in order to effectively establish an infection an establish effectively order to in hijack or misuse host proteolytic systems proteolytic host misuse hijack or

(1) , including , including

or ultimately affects the outcomeof the affects ultimately .

process biologically active molecules molecules active biologically process The underlying host underlying The enzymes, degrading tissue and by synthesizing ECM glycoproteins, proteoglycans and collagen molecules collagen and proteoglycans ECM glycoproteins, by synthesizing m Unexpectedly - icrobial icrobial dimensional ultrastructure ultrastructure dimensional

On the pathogen side, side, pathogen On the an active role for the ECM in the immune response to infection to immuneresponse the ECM the for in active role an

s specific signals signals specific urface urface ECM and the innate immune response to response immune innate ECM the and on balance and transcriptional and post and transcriptional and balance on - pathogen interactions pathogen , activated i , activated

and may foster novel antimicrobial approaches. antimicrobial novel mayand foster and grow grow and c .

immune omponents omponents The i The

infection. trcin f p of nteractions are employed employed are mmune cells participate in the remodelling of inremodelling the participate mmune cells that the ECM conveys to immune cells at the the at immune cells to conveys ECMthat the while evading evading while defen undergo undergo a variety of surface of surface a variety to modify the ECM the to modify

such as such r at specific sites at specific ecognizing ecognizing

s This review explores and discusses discusses and This review explores e .

are remarkably specific remarkably are On the host side, the ECM the side, host On the significant

cell surface receptors and receptors surface cell t hat athogens with athogens or overcoming overcoming or a

interact with interact dhesive dhesive . Microbial pathogens pathogens Microbial

modifications , and

evade immune immune evade - transcriptional transcriptional m secreted secreted microbial microbial atrix atrix eukaryotic cells eukaryotic different different ot immune host m

and involve involve and olecules olecules , which

ECM . ,

This article isThis article by protected copyright. All rights reserved. implicat and pathogens, microbial with interactions its and ECM antimicrobial new develop to respond cells host how invade and colonise to pathogens breach to barrier provid simply than rather infection in role I circuits regulatory and infection and proliferation activation, cell differentiation. immune and tissues infected within and into migration cells to signals specific pathways immunological into tissue host ago years 40 accumulate degrade components individual research. ha mportant mportant

Accepted Article s

been cellular re ion of ion fclttn ahso ad eerto it te host the into penetration and adhesion facilitating , pair intensively L question ess

take place take

microenvironment microenvironment , notably, notably, , the ECM in ECMin the

attention has been givenattentionthe been to has Moreover ; ii) ii) ; close s

to emerge from these studies studies these from emerge to stud

hc ECM which of the ECM are substrates to which pathogens can directly bind to or or to bind directly can pathogens which to substrates are ECM the of

ly link the ECM and the immune system. ECMandthe the ly link a specific specific te C cmoiin undergo composition ECM the , nd ied the immune response to response immune the

(2, 3) (2, thereby thereby s

pat is

trategies

in microbiology, immunology, cell biology, genetics and ecology ecology and genetics biology, cell immunology, microbiology, in (4, 5) (4, also also hogen . where most of the events leading to infectio to leading events the of most where Furthermore immune

- host tissues, tissues, host . pathogen interactions interactions pathogen a reservoir of diverse and tissue and diverse of a reservoir

modul R

s ecent or improve existing ones existing improve or ; and

at ing cell ly, ing

iii) iii)

, the ECM the ,

evidence has emerged that that emerged has evidence

host host

safl fr atra adhesion bacterial for scaffold a ye apa to appear types and a w itree ih hs itrcin to interactions these with interfere we can essential immune functions, immune cell cell immune functions, immune essential infection extra /or include

bypass

cellular matrix (ECM) matrix cellular is significantly significantly

. discuss the evidence evidence the discuss

es a fundamental component of the of component fundamental a

i)

eiec fr hs tre to started this for evidence ; does the ECM play an active active an play ECM the does

significant alterations during during alterations significant . host defences host

Here

otiue o that. to contribute - specific signals that feed thatfeed specific signals , we briefly briefly we impact the n , .

ECM , and

However, h aiiy of ability the disease

r en a being or f direct a of review review influenc conveys conveys

Thus, Thus,

and and the the t he he e

This article isThis article by protected copyright. All rights reserved. by produced are enzymes these infection, and injury is activity whose (ADAMTS motifs thrombospondin with metalloproteinases and disintegrin a and (ADAMs) and disintegrin a (MMPs), metalloproteinases matrix by accomplished by orchestrated a by maintained and determined are function normal regulated strictly yet dynamic highly a is ECM The structures ECM membrane I of inflammation sites to recruitment membranes basement isoforms and reactions, immune triggering ones of new capable generate or epitopes cryptic unveil can which modifications, posttranslational glycoproteins ( space extracellular proteins different distinct and infections Most T nterstitial nterstitial the Accepted Article he

ECM “matrisome” . Additionally

ECM signature ECM

:

ih itnt functions distinct with

are s an immunological p immunological an ECM , laminar sheet laminar

found in in found (6) s

) , cytokines cytokines

controll , . in include include . specialised specialised os fib loose hs vr nraig ubr of number increasing ever This the resulting resulting the C m ECM varying concentrations and geometries within within geometries and concentrations varying s secondary lymphoidorgans secondary

which arise from complex and dynamic combination dynamic and complex from arise which contribute to immune cell subtype selectivity during leukocyte leukocyte during selectivity subtype cell immune to contribute ed s approximately approximately

uh as such by that anchor cell layers to underlying tissues underlying to layers cell anchor that ril olecular multiplicity multiplicity olecular -

reticular fibre network fibre reticular ie matri like ise niios f metalloproteinase of inhibitors tissue erspective

7 8) (7, mue epne ae tissue are responses immune (9, 10) (9, rnfrig rwh factor growth transforming . e ta fill that ces 43 collagen subunits, subunits, collagen 43 . For instance, instance, For

lentv slcn, which splicing, alternative

(11, 12) (11, s tissue component tissue

and complexity are amplified by by amplified are complexity and

fine balance balance fine

p combining features of features combining roteins h tissue the

laminins laminins ciae immune activated .

hc cnrbt t matrices to contribute which 6 proteo 36 - - 

specific. Each tissue has has tissue Each specific. between between

 stroma ( 4 and and 4 s TGF h three the

. (TIMP Its composi Its , are basic forms of of forms basic are , metalloproteinases metalloproteinases - generat  , and and , glycans and 200 200 and glycans ) , and turnover, turnover, and , ECM ECM 

s these two these s 5

el sc as such cells ) of

- (13) dimensional dimensional isoforms isoforms up to up es synthesis basement basement

tion and and tion . several During During

~300 ~300 ECM ECM s in in ) , ,

This article isThis article by protected copyright. All rights reserved. of release the through regeneration and repair ECM promote cells Acceptedintertwined clearance pathogen cells epithelial cells (PRRs) receptors recognition pattern activating damage endogenous of class a form expression (FN specif oligosaccharides sulfate heparan and hyaluronan response of differentiation instance an chemokines cytokines, including activity, immunomodulatory involve discoidin and Article integrins including receptors, and molecules adhesion surface cell through signalling is mechanism such One mechanisms Several m for guidance and adhesion for support to addition in activation, and differentiation contact cells immune ECM. the tissue. a of structure unique the to contributes and cells provides ECM the how describes biology matrix of dogma central The tissue monocytes - EDA

(e.g. (e.g. ically induced upon tissue injury tissue upon induced ically damage

TGF , idn, trg, ciain n rlae f ertd oeue wt potent with molecules secreted of release and activation storage, binding, )

, versican and biglycan) and versican , H (19) / : signals from signals : arpae ad edii cells dendritic and macrophages macrophages or exhibiting chemoattractant properties properties chemoattractant exhibiting or ost i ost . -

)

 and

Moreover mmune responses are carried out in the context of the ECM ECM the of context the in out carried are responses mmune

lr the alert a be shown been has ot mue el types cell immune most affect their ability to mount inflammatory respon inflammatory tomount ability their affect , but also but , the ECM the r rsosbe o the for responsible are

the ECM help coordinat help ECM the ,

and immune immune bioactive bioactive

tissue repair tissue

, they receive vital instructions for their survival, proliferation, proliferation, survival, their for instructions vital receive they , promote immune cell migration into sites of infection and and infection of sites into migration cell immune promote - oan eetr (DDRs) receptors domain

promote inflammation by inflammation promote n vitro in ytm o ise aae and damage tissue to system - ECM fragments generated by tissue destruction destruction tissue by generated fragments ECM associated molecular patterns (DAMPs) patterns molecular associated (e.g. (e.g.

(23) and , modulating nearly all stages of the immune immune the of stages all nearly modulating , fibronectin isoforms co isoforms fibronectin )

omncto bten the between communication .

n non and

such as such n vivo in Thus, the ECM and the immune system are are system immune the and ECM the Thus, e )

and ECM molecules whose expression is expression whose molecules ECM and immune responses and, in turn, immune immune turn, in and, responses immune ( reviewed in in reviewed

to affect affect to

- However, this is only one function of function one only is this However,

toll immune cells cells immune -

like receptors (TLRs) receptors like induc (reviewed in in (reviewed d activation, proliferation and and proliferation activation, growth factors factors growth (20, 21) (20, ing

cytokines such cytokines ses ntaining extra domain A A domain extra ntaining

pro infection

(14) structural support for support structural (e.g. - ). These molecules molecules These ). inflammatory gene inflammatory 1, 16) (15, .

ECM

irbat and fibroblasts therefore (22)

ht initiate that (17, 18) (17,

, which, by by which, , in as and cells. cells. and )

. Others Others . igration. immune immune tumour

wh . (e.g. For For en en s

This article isThis article by protected copyright. All rights reserved. aureus of interaction the characterised fibrone on sites binding aureus Staphylococcus by 1978 in published was interaction pathogen elsewhere of binding The membrane m called are components a tropism tissue to or molecule a between interactions establish and microbes system host the a Tissue A ECM molecu ECM interferon (TNF), factor necrosis dhesins are components of capsules, cell walls, cell capsules, of components are dhesins

lcls MCAM. H (MSCRAMM). olecules Accepted Article adhesion of tale - pathogen interactions pathogen

s and .

dherence represents the first essential essential first the represents dherence

at sites of entry of sites at

Failure to do so result so do to Failure employ (1, 3, 25, 26) 25, 3, (1, and “ tetccu pyogenes Streptococcus les. les. receptor

microb ECM

,

a number of physico of number a

and and colonization pce specificity species

components components ” ial

on the host tissue. host the on ctin, in the N the in ctin,

. The s The .

pathogens to specific ECM specific to pathogens o fibronectin to and will be will and m ost receptors are usually glycoproteins glycoproteins usually are receptors ost icrobial icrobial

urface of host cells and the ECM are negatively charged and and charged negatively are ECM the and cells host of urface s - this ubiquitous this 

in the organism being removed by by removed being organism the in (IFN (24)

of thehost -

briefly briefly wih a a eakby ag nme o fibronectin of number large remarkably a has which , and C and s .

- - microb urface urface 

(2) and genetic specificity within a species. species. a within specificity genetic and chemical forces forces chemical ) and TGF and ) These interactions are highly specific, specific, highly are interactions These

and, - discussed here discussed terminus terminus a lgn or ligand ial

c and promiscuous promiscuous and

omponents omponents mechanism

a Kuusela Kuusela pili or fimbriae or pili -  few years later, revealed two separate separate two revealed later, years few , which , proteins respectively respectively

to overcome these repulsive forces forces repulsive these overcome to t al et . “

adhesi regulate the expression of many many of expression the regulate

The first report of a host ECM host a of report first The that has been extensively reviewed reviewed extensively been has r ecognizing ecognizing . , who and those and

bacteria ECM glycoprotein ECM (27) n”

physiological physiological and a complementary complementary a and studied .

Other groups groups Other found

adopt a that dhesive dhesive

t

e idn of binding he

bind to ECM to bind n h cell the on

contributing contributing to colo to cleansing cleansing Bacterial Bacterial

with with further further m atrix atrix ni z S. S. e -

This article isThis article by protected copyright. All rights reserved. in cells host by components ECM of turnover and synthesis the altering by ECM the modify survival. and toxin migration adhesion, bacterial cell necrosis, host and tissue diffusion favour also can but pathogens, of spread the facilitates in reported collagenases and using components ECM the modify to ways distinct developed in This disease. most host, the colonized Having B (35) catch a by endothelia with interactions bacterial stabilizes and strengthens it Specifically, surfaces vascular with interact to fibronectin exploits example, For methods Cutting interactions. these demonstrate to experiments inhibition and molecules, ECM and adhesins recombinant studies Early 34) tenascin chondroitin and binding reaking down barriers to invade the host invade to down barriers reaking Acceptedvolvi Article ; . Table 1) Table

g h cosn o bsmn mmrns n itrtta matrices interstitial and membranes basement of crossing the ng adhesin - , C,

have now started now have have since since have Table 2 and reviewed elsewhere elsewhere reviewed and 2 Table .

were mostly limited by the use of binding assays, involving bacterial cells or cells bacterial involving assays, binding of use the by limited mostly were Niddam Niddam

requir eris n idcs oyeiain f oul pam fboetn that fibronectin plasma soluble of polymerization induces and recruits s , caus , upae vitronectin sulphate, (28

“invasins” or bacterial tissue degrading enzymes degrading tissue bacterial or “invasins” s h bekon f rmr ado seconda and/or primary of breakdown the es - edge technologies, technologies, edge - 33 et al et been ing ) .

Several other ECM proteins proteins ECM other Several local tissue damage tissue local . showed that the Lyme disease spirochete disease Lyme the that showed .

to rev to implicated in s in implicated eal the implications of these interactions in in interactions these of implications the eal

pathogens trmopni, lsi, oe sialoprotein bone elastin, thrombospondin, ,

nldn lv cl iaig and imaging cell live including pecific

1 36) (1, 2, 36) (26, . need to invade tissues in order to cause cause to order in tissues invade to need Specific e Specific interactions with pathogenic pathogenic with interactions .

Dgaain of Degradation .

uh s aii, olgn hepar collagen, laminin, as such under physiological shear stress. stress. shear physiological under

of xamples They can directly degrade ECM ECM degrade directly can They

Pathogens can also indirectly indirectly also can Pathogens ry defences of the host, host, the of defences ry

such as hyaluronidases hyaluronidases as such these interactions these Borrelia burgdorferi burgdorferi Borrelia the Pathogens . -

bond mechanism mechanism bond particle

ECM pathogenesis bacteria bacteria

- not tracking tracking

have ( only only

(26, (26, and and are are a n . This article isThis article by protected copyright. All rights reserved. immune detection including ligands, pathogenic and fragments disacch into tissue pro process hyaluronidases besides their Specifically, invasion. evasion immune allows activity whose hyaluronidases, secrete bacteria responses immune and property tissues through invasion an spread own their facilitate to system plasminogen host the of advantage take bacteria uses and plasmin, i and to evasion complement for plasmin converted is which plasminogen, to binds (PE) E protein surface The (36). decorin with interaction specific its by explained partly be may this instance, For responses. immune not molecules ECM exploit undoubtedly pathogens numerous Although S defence. host and behaviour cytokines) and receptors surface cell (e.g. molecules active biologically many MMP activating manipulate (38) host misuse or review). this in later (discussed presence their to response

Accepted Article the tohost evade trategies

always always and to adhere to adhere to suooa aeruginosa Pseudomonas the plasminogen the clear whether pathogens pathogens whether clear rds wih lc TLR2/4 block which arides, th

zymogen proteolytic proteolytic e (43) plasminogen binding ability of vitronectin to protect itself from innate innate from itself protect to vitronectin of ability binding plasminogen (42) .

. and degrade degrade and Furthermore, Group B Group Furthermore, s 4, 41) (40,

that systems - immune immune

plasmin system thereby degrading laminin and fibronectin and fibronectin and laminin degrading thereby system plasmin

not only degrade all types of ECM pr ECM of types all degrade only not B . . .

Notably, Notably, burgdorferi o ins For response tissues tissues

nnate immune escape (37). escape immune nnate neat with interact (39) signalling

tance, tance, for efficient host efficient for among other common pathogenic bacteria, bacteria, pathogenic common other among H ? .

Streptococci iooyacaie ( lipopolysaccharide c pylori an avoid antibody avoid an S

. these these rgee b host by triggered

aureus benefits the complement regulatory regulatory complement the benefits -

inflammatory hyaluronan fragments fragments hyaluronan inflammatory components

ECM Moreover, pathogens can pathogens Moreover,

(GBS) (GBS)

coloniz (37)

molecules , Several other pathogenic pathogenic other Several - ampiu influenzae Haemophilus and other Gram other and mediated clearance and and clearance mediated oteins, but also process process also but oteins, LPS ation

and ECM and - derived hyaluronan hyaluronan derived ) ,

and invasion and thereby thereby

also to evade evade to also that direct that H . -

associated associated influenzae - evading evading positive positive

hijack hijack , it is is it ,

cell

This article isThis article by protected copyright. All rights reserved. TGF together in be to shown been colonization bacterial integrin through expression fibronectin and osteopontin enhanc laminin of upregulation in results ERK1/2 via cell the in receptors gp83 of activation that shown have cruzi Trypanosoma (45) III collagen and fibronectin enhances infection the to cells ASM of migration IV, collagen and perlecan fibronectin, TLR7/8 thrombospondins, are which proteoglycans deposition. and repair tissue and inflammation of mediators upo activated pathways transduction Signal deposition and ECM synthesis discuss in establish The Altered

Accepted Article synthesis, ECM . -

 C undergo ECM

1 ing ion of ion Systems biology approaches elucidating the ECM interactome network regulated by by regulated network interactome ECM the elucidating approaches biology Systems signalling

ECM dynamics in infection in dynamics ECM  ment of ment and, and, ih hs o MMP of those with -

ad hobsodn xrsin o aiiae rpmsioe recruitment trypomastigotes facilitate to expression thrombospondin and 1 normally normally ellr infection cellular

their implications in pathogenesis. in implications their ) as well as as well as ) n turn in

infection and the host the and infection

hs involves This in airway smooth muscle (ASM) cells that leads to increased deposition of deposition increased to leads that cells (ASM) muscle smooth airway in galectins, galectins,

and its gp83 ligand, which mediates trypanosome attachment and entry and attachment trypanosome mediates which ligand, gp83 its and es erdto and degradation duc absent or scarcely scarcely or absent of the intestine intestine the of ,

signific ed in in ed procollagen non eacn, etc.) tenascins, -

murine acute a acute murine

3, TIMP1, TIMP1, 3, ant alterations upon infection that that infection upon alterations ant - (46) structural structural structural structural . -

apa RA xrsin n fibrosis and expression mRNA 1alpha a

and its implications its and post (47)

In mice, mice, In contributing to airway remodelling and and remodelling airway to contributing expression and deposition, accelerating wound repair repair wound accelerating deposition, and expression

respon

urokinase . site site - ECM expressed

translational translational High expression levels of o of levels expression High ECM during . nd chronic coxsackievirus (CV) coxsackievirus chronic nd s o isac, hnvrs a rhinovirus instance, For n pathogen entry and recognition and by by and recognition and entry pathogen n (44)

e opnns emd mtiellr proteins’, ‘matricellular termed components

irbce rodentium Citrobacter to .

proteins

infection infection -

ye lsioe activator plasminogen type it IL

. in

- Below 33 modification modification -

linked kinase activation, facilitating facilitating activation, kinase linked healthy

signalling

eg collagens (e.g. all

is an overview of the changes changes the of overview an is

contribute to ECM synthesis synthesis ECM to contribute

tissue

rmt o inhibit or promote during nue by induced steopontin ha steopontin s (e.g. osteopontin, osteopontin, (e.g. s

ctivates TLR3 and and TLR3 ctivates infection induces induces infection

,

neto and infection

B3 . Accordingly, Accordingly, . facilitating the facilitating laminins -

myocarditis (uPA) and and (uPA) . aureus S. ve

also also and the

a , ,

This article isThis article by protected copyright. All rights reserved. (e.g. (e.g. E molecules components they as such enzymes degrading functio biological and barrier supportive, the upon altered affecting also infection, is ECM the remodels and down breaks that machinery catabolic The ECM degradation repair. and tissue response immunecell invasion, t compounds bioactive of presentation and structure to are dis spatial the alter influenza from emerges it also as components can infection levels, expression besides hyalu T which to hyaluronan, I:C Poly mimetic response domains binding factor growth and molecule proteoglycan sulfate chondroitin a versican, Furthermore with patients formed is tissue scar until and in also myocarditis fibrosis cardiac decreases D vitamin by transcription osteopontin

Accepted biophysical its influencing inevitably ECM, the of changes compositional distinct generate Article

enriched with either fibronectin or collagen collagen or fibronectin either with enriched MCP ronidase ronidase lae h bsmn mmrn E membrane basement the cleave - (55) 1 and IL and 1 -

, the lungs of mice infected with gram with infected mice of lungs the , myocarditis viral from protected are mice null sepsis, sepsis, (e.g. (e.g. . ramn or treatment Similarly, Similarly, results in in results -

te deposit they , cadherin) -  8) can f aii 5) laminin of chain 2 pa

and rapneumonic infection rapneumonic - el ail adhere avidly cells

when when cytokines upregulation of tenascin of upregulation ;

activate, deactivate or regulate the bioavailability of bioavailability the regulate or deactivate activate, MMPs escn nioy uig arx formation matrix during antibody versican (49) primary human lung fibroblasts fibroblasts lung human primary

higher a

. Elevated tenascin Elevated . play a crucial role in regulating immune cell recruitment cell immune regulating in role crucial a play

(e.g. IL (e.g. CM - netd ug, hc so dsic rgos that regions distinct show which lungs, infected ; - -

order structured ECM, rich in versican and and versican in rich ECM, structured order 1

; agt non target  and and ,

with (57)

xoe rpi pro cryptic expose , tuberculosis and TNF and

ht is that

cease cease . - multiple cytokine, chemokine, adhesion adhesion chemokine, cytokine, multiple - negative bacteria show bacteria negative C before immune cell infiltration occurs occurs infiltration cell immune before C T hus, hat impact bacterial colonization and and colonization bacterial impact hat - C

- - ECM  implicated

levels migrat specific infectious diseases diseases infectious specific ) ;

and and id ye animals type wild and proteins ion have also been reported in reported been also have S.aureus shed cell surface receptors receptors surface cell shed

are are - ns of the ECM. ECM. the of ns inhibition of osteopontin osteopontin of inhibition , an effect reversed by by reversed effect an , migratory sites of ECM ECM of sites migratory

in the innate immune immune innate the in treated with the viral viral the with treated

uh as such

tribution of ECM ECM of tribution

(56) infection infection

accumulation of accumulation .

chemokines chemokines Importantly, Importantly, (48)

adhesion adhesion (50 Tissue Tissue . seem seem - Viral 54) . :

This article isThis article by protected copyright. All rights reserved. IFN Accepted in 12 grade scarring enzymes modifying ECM these of pattern expression the study collagen and production decorin regulates that protein matricellular MMP downregulates it while MMP upregulates blindness, and trachoma heparin been has infection injury neuronal meningitis of secretion to lead all can meningitis pneumococcal and persistence and damage tissue However, recruit ArticleT and MMP of production MMP pyogenes including pathogens, Several proteins) TNF (e.g. novo exception the With migration cell with associated - 

- viral myocarditis caused by caused myocarditis viral synthesis

1, - et n gauoa formation granuloma and ment cell erto ad ot rtcin etaellr MMP extracellular protection, host and secretion - binding epidermal growth factor (EGF) factor growth epidermal binding

(61) MMP -

, - d 

and derived cytokines and causes ECM causes and cytokines derived ysregulation of MMP production at late stages of the infection could could infection the of stages late at production MMP of ysregulation MMP

and IL and .

-

and inflammation. and

, MMP 2, H and, that (65 - of infection of . 9

-

pylori - 2 and MMP and 2 has been has of neutrophils, tissue degrading enzymes are not stored, but require require but stored, not are enzymes degrading tissue neutrophils, of

implicated in the development of gastric cancer cancer gastric of development the in implicated - 1) and also by bacterial products (e.g. products bacterial by also and 1) 67) is strictly regulated strictly is by by . compromising , -

, MMP 7, iial, gastrin Similarly, nue xrsin n activity and expression induce

- (62) 10 and and 10

suggested to contribute to blood to contribute to suggested eg CD44) (e.g. - 9 during during 9 .

coxsa yoatru bovis Mycobacterium -

9

Interestingly, a dual function has bee has function dual a Interestingly, SPARC (secreted protein, acidic, cysteine acidic, protein, (secreted SPARC Systemic Systemic and ,

tissue integrity tissue ckievirus type B3 type ckievirus both

and can be induced by induced be can and m

ycobacteria infection is regulated by macrophage by regulated is infection ycobacteria - MMP inflammation modulating , eedn idcin f MMP of induction dependent

protective immune responses to mycobacteria. mycobacteria. to responses immune protective - , MMP 7, E. coli E. breakdown - (64) 13

.

(62 , infection, acute Lyme neuroborreliosis neuroborreliosis Lyme acute infection, Chlamydia trachomatis Chlamydia - , MMP 9, may may , . While While .

- 64)

- 12 12 f nme of number a of tuberculosis Mycobacterium . This . LPS facilitate facilitate . cleaves high - In particular, the extensive extensive the particular, In - brain barrier brain 2 n TIMP and 12 intracellular MMP intracellular

and and pro correlated correlated may be may

mut o MMP of amounts - inflammatory cytokines cytokines inflammatory bacterial disse bacterial

hog te ees of release the through chlamydial assembly (reviewed in in (reviewed h IFN the

n shown for MMP for shown n - necessary for cell cell for necessary 7 upon upon 7 MMPs ih h c the with destruction destruction , which causes causes which , - 1 expression, expression, 1 - -  rich)

contribute to contribute

(68)

heat shock shock heat - eetr 2 receptor , including including , 12 . pylori H. - (58 mination . like 1 like

causes In - linical linical - 9 , 60)

. and this this

, a a , de S In ) - - . .

This article isThis article by protected copyright. All rights reserved. tenascin and fibronectin residues arginine the infection. in altered are ECM the in PTMs whether ask to tempting is it molecules, (7) proli of hydroxylation citrullination by others while cleavage, proteolytic P ECM to response and detected are molecules, bioactive of presentation its and biophysics t clear is it However, disease. infectious every in understood well not is combination, in or individually enzymes, degrading using of case the in as enzymes activating own their I I) collagen generate mortality and murine However, null MMP myocarditis, viral of IFN of site binding n addition to addition n ost

Accepted). Article

- Given the ability of pathogens to hijack host enzymes or secrete enzymes targeting host enzymes targeting secrete host or to enzymes hijack ofpathogens ability Given the opyooa gingivalis Porphyromonas mice mice translational modifications (PTMs) modifications translational post aB a thermolysin a LasB, s -

, enhancing neutrophil infiltration to lungs lungs to infiltration neutrophil , enhancing translational translational ipa hge vrl od iflrto o CD3 of infiltration load, viral higher display pro

. and processed by immune cells into cells immune by processed and inducing MMP expression, pathogens alsoactivate can pro -

nlmaoy ECM inflammatory This is the case of case the is This

infection. MMP to citrulline in mammalian ECM proteins, including fibrinogen including proteins, ECM mammalian in citrulline to -  , preventing an uncontrolled an preventing , nes, nitrosylation of tyrosines tyrosines of nitrosylation nes, - modification 9 can also also can 9 - -

C 9 exerts a protective role by inactivating IFN inactivating by role protective a exerts 9 - (72 like hat the MMP/TIMP system changes the ECM composition and and composition ECM the changes system MMP/TIMP the hat

-

76) enzyme metalloprotease metalloprotease - enhance susceptibility to susceptibility enhance eie ppie (.. Pro (i.e. peptides derived Francisella tularensis Francisella

. While arginine is positively charged at neutral pH, pH, neutral at charged positively is arginine While add complexity add

peptidylarginine deiminase (PAD) can convert convert can (PAD) deiminase peptidylarginine

P. aeruginosa P. immune response immune signalling

and (39) (71) f arginine of

. aspartate isomerization isomerization aspartate to .

generating

pulmonary infection pulmonary +

The role of dysregulated tissue tissue dysregulated of role The the ECM. Some are generated by generated are Some ECM. the

events that direct their behaviour behaviour their direct that events

cells and tissue damage damage tissue and cells infection - Gly gyoyain cross glycosylation, , , which which - r (G) etd from peptide (PGP) Pro

environmental environmental (69)

and increase and - activates pro activates  . - / MMPs In the same model model same the In  . Indeed, MMP Indeed, .

where

, collagen II, II, collagen , (reviewed in in (reviewed by secreting secreting by

cues cues morbidity morbidity

- - Indeed MMP MMP linking, (7 that - 0) - 9 - 2 9 - . ,

This article isThis article by protected copyright. All rights reserved. permeability. Accepted sepsis wit patients in syndrome distress respiratory acute and oedema pulmonary to contribute oedema. pulmonary and permeability vascular Ma cross infection during components as such disease and proteins ECM of PTMs specific between link a supporting evidence While cell influencing that speculated have study replication, viral with correlate negatively mRNA CRTAP of levels the 3 proline for required is complex 3 prolyl ( junctions Article(CRTAP) protein associated cartilage of expression disease. Chagas o dysfunction cause to proposed been has metastasis to cancer linked cross out carries (LOX) oxidase lysyl of expression the increase to reported been has heart, the of fibrosis and inflammation extensive features which disease, Chagas of agent anticitrullinated and proteins citrullinated disease autoimmune an arthritis, rheumatoid and a structure thus, and, hydrophobicity protein increasing uncharged, is citrulline mmoto mmoto arthritis and cancer is accumulating, the implications of altered PTMs of ECM ECM of PTMs altered of implications the accumulating, is cancer and arthritis - linking mediated by LOX can significantly alter tissue structure and ECM mechanics. mechanics. ECM and structure tissue alter significantly can LOX by mediated linking (81) - hydroxylase activity, and cyclophilin B in the endoplasmic reticulum. This trimeric trimeric This reticulum. endoplasmic the in B cyclophilin and activity, hydroxylase PATJ et al et , beco , Increased Increased - function . recently showed that showed recently . cell adhesion adhesion cell ) - CRTAP . linking of collagen fibers fibers collagen of linking me much much me Similarly . LOX Notably, Notably,

associat , (79) stiffer than non than stiffer (80) e ege iu ifcin a be son o upes the suppress to shown been has infection virus dengue r ol bgnig o emerge to beginning only are CRTAP, together with PATJ, restrict dengue infection infection dengue restrict PATJ, with together CRTAP, xpression xpression . By irreversibly altering collagen structure and function, LOX LOX function, and structure collagen altering irreversibly By . - . hydroxylation of collagen of hydroxylation

. gingivalis P. es

with the proteoglycan leprecan, which has collagen collagen has which leprecan, proteoglycan the with LOX

and LOX and LOX1 protein protein LOX1 and LOX and ECM thereby thereby - - dependent dependent treated lungs and exhibited enhanced vascular vascular enhanced exhibited and lungs treated f cardiomyocytes and, in turn, of the heart in in heart the of turn, in and, cardiomyocytes f

protein antibodies protein of the joints characterised by high levels of of levels high by characterised joints the of In vivo In

periodont , alongside alongside , altering matrix stiffness, which has been been has which stiffness, matrix altering , mouse lungs lungs mouse changes in ECM mechanics control control mechanics ECM in changes

l infection al and .

, the

For example, example, For thus

(77) protein associated to tight tight to associated protein , treated with LPS, which which LPS, with treated

collagen assembly collagen isoform .

T a been has .

(78) the authors of the the of authors the lter cruzi n protein ing

. This enzyme enzyme This . activity activity collagen fiber fiber collagen , the etiologic etiologic the , ikd to linked control control . As As . 3D 3D by h

This article isThis article by protected copyright. All rights reserved. hyaluronan major the of inhibition simultaneous and 1, synthase hyaluronan and versican marrow bee also has proteoglycans of expression Macrophage transcription NF bridging by promoter osteopontin the (48) macrophages myocarditis, viral galectin 5 including 3, THP in production macrophages derived marrow tenascin induce components IFN and macrophages human by produced be to reported glycoprotein ECM first the is Fibronectin itsimplications and this However M(IL (i.e. macrophages MMP including enzymes, degrading destruction and destabilization ECM in implicated been In M (82) permeability vascular and architecture alveolar acrophages Accepted Article atra ad viral and bacterial . .

Notably, i Notably, - eie ad lelr arpae with macrophages alveolar and derived , -

 macrophages  stimulated mouse peritoneal macrophages macrophages peritoneal mouse stimulated (89) : n murine macrophages, macrophages, murine n not justdestroyers , which is negatively regulated by GSK3b regulated negatively is , which - 1 cells cells 1

- neto, ciae m activated infection, 3 truncated forms truncated 3 are discussed below. discussed are

- can also can 4)) (87) which , - epeso i hmn monocyte human in expression C , while , 5, 86) (53, infiltrating the heart heart the infiltrating

produce a number of ECM proteins ECM of number a produce

ees poess uh s MMP as such proteases release

of theECM LPS from from LPS - 9 . LPS causes the formation of chromosomal loops in loops chromosomal of formation the causes LPS

, in primary human macrophages macrophages human primary in , .

P from LPS Similarly, parasitic infections infections parasitic Similarly, - B n AP and kB acrophages acrophages

, which which , E. coli coli E.

. coli E. . gingivalis P. are the main producers of osteopontin osteopontin of producers main the are a and IFN and - re n demonstrated. demonstrated. n

1 together, leading to osteopontin osteopontin to leading together, 1

eg M(IFN (e.g.

P rsls in results LPS (90)

restored by LOX activity LOX by restored through the the through 8, 85) (84, . - 

- upregulate nue thrombospondin induces

eie ad os bone mouse and derived .  . I - , M(LPS)) ), ncreasing evidence evidence ncreasing 1 and and 1 oevr b Moreover, secretion of tissue tissue of secretion Treatment of bone bone of Treatment rapid involve (88)

galectin MMP . In mice with with mice In .

nuto of induction

have

activated activated - inhibition 12 - acterial acterial 1 and and 1

(83) long long - of 1 - - .

This article isThis article by protected copyright. All rights reserved. collagen (FACITs; helices triple interrupted with collagens AcceptedXXVI. and XX XVI, fibroblasts) dermal in those than source matrix abundant an activated collagen 28 all of expression decrease was tissue within cells and structures interstitial anchor to receptors and ECMs with interact that structure multidomain a with filaments beaded forms signalling col decrease in demonstrated synthesis I collagen showed by synthesis niche collagen cell stem germline the in events signalling key controls Article molecules. Intriguingly the microenvironment. affects TLRactivation inturn, and, function inflammation of tenascin transcription molecule ECM to leads TLR4 of demonstrat have NF and immunoprecipitation chromatin by secreted 1 (hyaluronidases enzymes degrading lagen - C, biglycan and decorin, which can activate TLR4, this can promote autocrine loops loops autocrine promote can this TLR4, activate can which decorin, and C, biglycan d that

primary human macrophages and compared to that of human dermal fibroblasts, fibroblasts, dermal human of that to compared and macrophages human primary properties. properties.

, by In LPS

there is mounting evidence that macrophages macrophages that evidence mounting is there forms unique hexagonal lattice structures lattice hexagonal unique forms d IFN Drosophila collagen VIII synthesis synthesis VIII collagen

y IFN by 8, 3 94) 93, (86, ed that pathogenic activation of the NF the of activation pathogenic that ed - activated activated - 

However and LPS and Later, human macrophages were shown to secrete collagen VI, collagen secrete to shown were macrophages human Later,

- mammalian mammalian 

, phagocytes phagocytes , n LS bt nrae uo IL upon increased but LPS, and

mouse peritoneal macrophages macrophages peritoneal mouse (95) Tu, h ifce clua microen cellular infected the Thus, . ,

- LPS LPS treatment noig RA ws uniid n steady in quantified was mRNAs encoding

. of Steady collagen mRNAs with the exception of collagen III, X III, collagen of exception the with mRNAs collagen specifically specifically arpae w macrophages mouse mouse /2 (hemocytes)

- and secretion secretion and - kB reporter gene assays, some of these studies studies these of some assays, gene reporter kB (97, 98) (97, state m state ) (91) peritoneal macrophages macrophages peritoneal increased the expression of expression the increased . 8, 9 93 89, (86,

. acrophages expressed expressed acrophages Serglycin

C ollagen ollagen

ere published in in published ere produce functional collagen IV, which which IV, collagen functional produce

in - and possesses and kB decorin , -

- human human 95) VIII 4 treatment treatment 4 VII, signalling (92 . s

- is a short a is XII, . motnl, n the in Importantly, 94) vironment vironment

can can Expression of collagen VI VI collagen of Expression (96) macrophages

.

XV, n bgya ae also are biglycan and

. pathway downstream downstream pathway h 1990s the synthesize collagen collagen synthesize

h frt eot of reports first The

By using inhibition, inhibition, using By both (99) basal levels basal XIX and XXI), the the XXI), and XIX and - chain, nonfibrillar chain, - tt ad LPS and state fibril influence . structural and and structural Recently, the the Recently, the - cell surface surface cell associated associated

.

that was was that h f The

ae of case second

TLR s (lower (lower which , XI, , irst -

This article isThis article by protected copyright. All rights reserved. broad found been has which proteins ECM Certain albicans Candida against activities antimicrobial vitronectin isoforms, laminin from derived peptides fragments. ECM bioactive generate properties. which employs system immune innate The of activity Antimicrobial T be to remain macrophages collagen with they as molecules collagen secreted their to vitro stabilization tissue therefore macrophages activation, of mode their upon depending studies previous confirming XXIV collagen and XXVIII collagenase AcceptedECM he Article , monocytes adhere strongly to collagen VI collagen to strongly adhere monocytes ,

- expression expression spectrum HIV spectrum id o eai ad emtn sulphate dermatan and heparin to bind : an integral part of the innate immune response to response immune innate ofthe part integral : an

- During the inflammatory response to infection, tissue degrading enzymes enzymes degrading tissue infection, to response inflammatory the During eitn clae V te collagen the V, collagen resistant clarified.

and its potential role in macrophage adhesion and immune response response immune and adhesion macrophage in role potential its and eg itgis n proteoglycans) and integrins (e.g.

was not increased not was (100 - 1 , V XVIII, IV, I,

- - neutralizing protein protein neutralizing 102) r as fud n ilgcl lis Oe uh rti is protein such One fluids. biological in found also are theECM in human human .

(99)

n repair and

g

, and collagen XIII and XVII XVII and XIII collagen and , ram XXV and and XXV breast milk milk breast . - LPS

positive and and positive endogenous nme of number A

n to and

also downregulate also (103) XXVII

express express (2.2

glycosaminoglycans - . cell (99) containing von Willebrand factor collagen collagen factor Willebrand von containing . Tenascin C g - etds ie a like peptides - thrombospondin , 671 el n cell and cell ram ) lae II ollagen . Furthermore, macrophages macrophages Furthermore, . studie .

several

- oee, c However,  eaie bacteria negative g/ml) g/ml) - may C directly directly C s d the expression of collagen VI, collagen of expression the d (95)

, VIII, IX, XIII, XIV, XXIII and and XXIII XIV, XIII, IX, VIII, , showed that that showed

receptors known to interact interact to known receptors contribute to the ECM and and ECM the to contribute hr it where infection - . arx in matrix

lpha

By secreting secreting By and lae scein by secretion ollagen captures

- and fibronectin exert exert fibronectin and eesn n LL and defensin

have ? act teractions (e.g. (e.g. teractions , and and ,

heparin s

as an innate innate an as HIV antimicrobial antimicrobial

tenascin the fungus fungus the collagens may bind bind may - 1 vir 1 - binding binding in vivo in ions ions - 37 - C in , , ,

This article isThis article by protected copyright. All rights reserved. of moieties Accepted protein ECM this that showed authors the mindin, recombinant TNF impaired display mindin or streptococcus B group positive mindin Moreover, LPS to response immune innate the of part integral an as function to proposed been has and pathogens microbial for has proteins, ECM secreted (PAMPs). patterns molecular associated pathogen called pathogens, microbial in motifs conserved recognize to (PRRs), receptors receptors, conserved highly employs system immune innate The ECM could antimicrobial Articleactivity antimicrobial that protein the of loop beta exposed an on sequence domain terminal walls cell bacterial bacteria. of ingestion the after phagolysosomes which has activity antimicrobial Direct milk of activity neutralizing binding coreceptor chemokine binding by -

mediated recognition of microbial pathogens microbial of recognition mediated serve as templates for serve templates as is abundantly expressed in mature tissue macrophages and and macrophages tissue mature in expressed abundantly is - induced shock and systemic and shock induced

to g ram the HIV the molecules molecules

- - positive and and positive f MMP of null mice mice null (105) and

(104) - 1 Envelope Envelope 1 .

di from complex biological mixtures. mixtures. biological complex from He

. - srupt (103) 12, T feature et al et de novo de ogether, t ogether, emerged as a unique pattern unique a as emerged - 

g

site ram s also

but not not but .

n IL and

.,

gp120 ellr membranes cellular H. influenza H. that showed .

- impaired bacterial clearance in lungs infected with infected lungs in clearance bacterial impaired negative bacteria negative Accordingly been reported for the ECM the for reported been

synthesis of novel antimicrobial molecules. antimicrobial of novel synthesis S. typhimurium S. hese data hese - production 6

protein at protein its Mindin, a member of the mind the of member a Mindin,

catalytic domain, domain, catalytic .

In genetic ablation ablation genetic I , t , nside phagolysosomes, MMP phagolysosomes, nside may help may , macrophage activation and and activation , macrophage vitro enascin a CD4 a

l components and, and, components l and n dfcie phagocytosis defective and , , m ,

iln the killing

- acrophages inducible epitope that overlaps the overlaps that epitope inducible - S. pneumoniae S. -

C depletion abolishes the HIV the abolishes depletion C s nqe n aue n confers and nature in unique is recognition molecule in the ECM ECM the in molecule recognition the search for search the Furthermore contains a four amino acid acid amino four a contains - associated protein MMP protein associated of mindin confers resistance resistance confers mindin of namely

bacteria. bacteria. mobilized to macrophage macrophage to mobilized recognizes carbohydrate carbohydrate recognizes

and mast cells lacking lacking cells mast and in -

by binding to the to binding by F pattern ,

safe, endogenous safe, - infections infections idn epitopes binding spondin family of of family spondin oal, t Notably, - 12 adheres to adheres 12 phagocytosis

- recognition recognition . By using using By in vivo in he g ram - 12, 12, - m, m, C 1 - - - - .

This article isThis article by protected copyright. All rights reserved. question. function immune essential same the exert phagocytosis mediated u investigated, fully been yeast and parasites N (e.g. glycolipids and galectin is pathogens microbial of productio infiltr with cornea Tyr aeruginosa clear to fail ba animals as increased is mice deficient lumican of mortality infection, lung of LPS to responsive hypo are mice null CD14 promoting neutrophils, and le of (106) influenza this Following pattern specific cells mast and macrophages recognition authors the LPS, by activation macrophage inhibited glucose As bacteria. agglutinates it

Accepted tissues. from cteria Article - 20 as a a as 20 ucine rich motifs similarly to PRRs, to similarly motifs rich ucine ation and lumican and ation .

Furthermore

n of pro of n virus clearance clearance virus of micro of atra ymcohgs s mard n h asne f lumican of absence the in impaired is macrophages by bacteria vital . aeruginosa P. , the innate immune function of mindin has been extended to to been extended mindin has of immunefunction innate , the - eonto mlcl a it as molecule recognition

- residue residue inflammatory cytokines cytokines inflammatory , bial pathogens is a secondary stimulation necessary for the activation of activation the for necessary stimulation secondary a is pathogens bial (110) the proteoglycan lumican, whose core protein contains tandem repeats repeats tandem contains protein core whose lumican, proteoglycan the This study showed that CD14 that showed study This - , at least least at , null mice display poor resolution of bacterial keratitis and sustained sustained and keratitis bacterial of resolution poor display mice null - acetyl . for CD14 binding and phagocytosis phagocytosis and binding CD14 for from Although the the Although o mcoraim recognition microorganism pon

edl increases readily (105)

- the nasal cavity cavity nasal the D - - - n vitro in TLR4 3, which binds to carbohydrate structures on glycoproteins glycoproteins on structures carbohydrate to binds which 3, lactosamine and LPS) from (myco)bacteria, protozoan protozoan (myco)bacteria, from LPS) and lactosamine

(Fig. - induced septic shock septic induced - in vivo in mediated responses to LPS to responses mediated interacts with CD14 on the surface of macrophages macrophages of surface the on CD14 with interacts

1 (109) s (111) )

only only . in humans represents an outstanding, important important outstanding, an represents humans in

Notably, Notably, ocue ta mindin that concluded

not only only not

lumican expression before inflammatory cell cell inflammatory before expression lumican . function of galectin of function

Another ECM protein that senses a number number a senses that protein ECM Another recognizes and opsonizes opsonizes and recognizes by allowing by (Fig. (Fig. - mediated p mediated mindin is not not is mindin 1 ) mind binding to pathogens but also also but pathogens to binding mind .

Whether these ECM components components ECM these Whether ,

(107) efficient macrophage activation activation macrophage efficient it

(108) otiue t macrophage to contributes hagocytosis of hagocytosis . - In a In 3 during infection has not not has infection during 3 . a - (Fig. (Fig. mediated carbohydrate carbohydrate mediated

Finally, infection of the the of infection Finally, universal, but a rather rather a but universal, P. aeruginosa aeruginosa P. 1 include ) certain certain .

Thus

and identified identified and E. coli E.

promot , lumican , bacteria.

and model model ing P. - -

This article isThis article by protected copyright. All rights reserved. with infection helminthic Acceptedgalectin tenascin from DCs cells Th17 of generation DCs of function polarizing cell T the check. in response inflammatory fungi and bacteria intracellular obligate and facultative infection parasitic in cells Th2 viruses, repertoire elici microbes of classes Distinct lymphoid to migrate and mature pathogens, antigen main the are (DCs) cells Dendritic infection. of stages later at or reversed infection post hours 24 littermates. deficient osteopontin Articleand survivin. inhibitor apoptosis the of expression g and myeloid common neutrophils of supply with infection systemic during populations cell lymphoid and myeloid of balance the skewed osteopontin Kan population. leukocyte required the generating including IL which response, myelopoiesis leukocyt emergency of numbers large demands infection Severe population Leukocyte significantly higher mortality of wild type mice with systemic fungal infection compared to to compared infection fungal systemic with mice type wild of mortality higher significantly - 3 .

n C cnrl te antd o T el priming cell T of magnitude the controls DCs in - Helper T1 (Th1) cells are involved in infection by intracellular bacteria and and bacteria intracellular by infection in involved are cells (Th1) T1 Helper 6, GM C .

albicans - - CSF and G and CSF C -

null balance in infection: emerging roles roles infection:emerging in balance and

ranulocyte (112)

Schistosoma

by (112) mice is significantly impaired significantly is mice Ly6C E. coli E. . - However, it is unclear is it However, . CSF

Specifically, the authors showed that osteopontin osteopontin that showed authors the Specifically, +

The detrimental effect of osteopontin was observed early observed was osteopontin of effect detrimental The - pcfcEM rtis ae en hw t cnrbt to contribute to shown been have proteins ECM Specific monocytes macrophage progenitors macrophage

. This . lineage t LPS

, and ,

mansoni

or ihu afcig C development DC affecting without

protects the host from systemic infection infection from host systemic the protects

M. tuberculosis M. - Th17 is initiated by activated PRRs and cytokines, cytokines, and PRRs activated by initiated is rsnig cells presenting - - pcfc epne fo t from responses specific macrophages This resulted in in resulted This . tissues tissues Galectin in infection by infection in

ayama if this effect is maintained, exacerbat maintained, is effect this if

(113) .

where they activate naïve T cells. cells. T naïve activate they where

R - es that is compensated by the the by compensated is that es 3 deficient mice have significantly significantly have mice deficient 3 for egulatory T cells (Tregs) cells T egulatory

stimulated bone marrow bone stimulated through a downregulation of the of downregulation a through t al et .

by ECM components Furthermore, and, greater fungal load in kidneys kidneys in load fungal greater

n vitro in enhanc extracellular pathogens extracellular hv rcnl fud that found recently have .

u o cpuig microbial capturing pon

ing and e fetr cell T effector he the h aotss of apoptosis the F . n vivo in expression of expression

or instance, instance, or limit by quickly by quickly

hold the hold -

derived derived ed during during

and the ed ed ,

This article isThis article by protected copyright. All rights reserved. MMP Additionally, protection. host NFKBIA MMP lower and infections, virus syncytial respiratory elastase) Marchant by study elegant An at thetranscriptional and post i regulated inflammatory initiates PRRs via recognition Pathogen pathways post and Transcriptional inflammation, to leads populations cell T effector unbalanced and immunity adaptive to innate Rac1 GTPases integrins via mindin with interact i from W mechanism response. the explain not does it cells, T by release galectin that shows study this responses Th1 humoral and cellular higher and spleen their in cells T less 60 s mplicates a role for ECM for role a mplicates

Accepted Article mindin from DCs hen - Salmonella typhosa Salmonella - 70% lower than that of wild type mice. mice. type wild of that than lower 70% 12 is taken up by virus by up taken is 12

promoter, driving driving promoter,

to allow microbial clearance with minimal damage to the host. host. the to damage minimal with clearance microbial allow to Efficient T cell priming by DCs has also been shown to depend on mindin on depend to shown been also has DCs by priming cell T Efficient n immunity in leve understanding s of ls /2, which are known to regulate DC priming of T cells cells T of priming DC regulate to known are which /2, IFN

- - - against against

 n transcriptional roles for ECM for roles transcriptional or and ECM and its its ull mice mice ull ,

which is essential for viral immunity. Mechanistically, secreted secreted Mechanistically, immunity. viral for essential is which

E. coli E. how the ECM can how the - transcription - - infected cells cells infected transcriptional level during the immune response to to immune the response level during transcriptional 3 expression by DCs modulates the proliferation and cytokine cytokine and proliferation the modulates DCs by expression 3 el al el  viral infection infection viral 4

 and lipoteichoic acid from acid lipoteichoic and a - 1 . associated proteins proteins associated MMP e ciae wt bceil opnns icuig LPS including components, bacterial with activated re

and - on tasrpinl oe for role transcriptional a found 2 regulate 12 , which is essential for optimal IFN optimal for essential is which ,  - 12 5 and  - 1 null ,

regulate Investigation of this this of Investigation leading to upregulat to leading

traffics (69)

mice display increased viral load, mortality mortality load, viral increased display mice s

. pcfc substr specific

signalling During molecules

to the nucleus, where it binds to the the to binds it where nucleus, the to T

in regulating inflammatory networks networks inflammatory regulating in

cell

responsible for the biased Th1 Th1 biased the for responsible S. aureus S.

response coxackievirus type B3 and and B3 type coxackievirus

pathways which are are which pathways

in ed demonstrated host defense defense host ates by two distinct distinct two by ates MMP

expression of the Rho the of expression s ,

CD4 is crucial is (115) - Recent research research Recent 12

-  (114) +

. secretion and and secretion T cell priming priming cell T

(macrophage (macrophage

As pathological pathological . infection. . Although .

signalling that DCs DCs that DCs link link DCs (115) tightly tightly

.

This article isThis article by protected copyright. All rights reserved. Accepted tune post and transcriptional unknown previously LPS to response miR miRNA tenascin Specifically, LPS. to response t after, Soon miR of levels IL represses translationally pro the of expression activat anti the of levels the reduces amount Articledecorin in miRNAs regulating post the At INF systemic elevates wildmice type infected in MMP extracellularly, 1 protein like and protein, cap immunoproteasome mechanisms:

the innate imm innate the - 12 clears systemic INF systemic clears 12 es

i decorin in s levels

ERK and p38 MAP kinases kinases MAP p38 and ERK - - enascin 155 rncitoa lvl a oe o dcrn n tenascin and decorin for role a level, transcriptional , which decreases their mRNA and protein levels in MMP in levels protein and mRNA their decreases which , -

21

1) through DNA binding of gene exons (e.g. (e.g. exons gene of binding DNA through 1) through substrate protein cleavage (e.g. INF (e.g. cleavage protein substrate through n etc ains n mc wt LPS with mice and patients septic in , which represses represses which , , allowing , n vivo in une response to infection. toinfection. response une - - C was shown to shown C was They mice. null - LPS in flammat

(53) optimal TNF optimal - - induced 10. Secondly, decorin i decorin Secondly, 10. -  . -

nlmaoy yoie IL cytokine inflammatory Th and, ory modulator modulator ory us PDCD4 sepsis sepsis , accordingly orchestrate

secreted protein acidic and rich in cystei in rich and acidic protein secreted eosrtd that demonstrated pcfc C ad ECM and ECM specific downstream of TLR2 and TLR4 and TLR2 of downstream - -  C regulate C

production in macrophages in production

expression 5, 3 116) 93, (53, - transcriptional regulatory regulatory transcriptional

- , selective i selective , PDCD4 

the secretion of specific cytokine subsets in subsets cytokine specific of secretion the

levels and reduces viral replication replication viral reduces and levels nhibits TGF nhibits s

the biosynthesis of the the of biosynthesis the

- and nue sepsis induced

- i te rsne f LPS, of presence the in , (programmed cell death 4), which which 4), death cell (programmed . 0 i to ehnss Frty it Firstly, mechanisms. two via 10

Merline Merline thus thus nhibition - 

receptor 2 binding site). Thus, Thus, site). binding 2 receptor - exons encoding PSME3, the the PSME3, encoding exons -  associated proteins possess possess proteins associated decreas 1 signaling, leading to leading signaling, 1 et al et

of extracellular MMP extracellular of - C has been found in in found been has C

and -

, activities

. detected increased increased detected . 12 thereby inducing the the inducing thereby es n eeae IL elevated and -

null mice); and 2) 2) and mice); null effective immune immune effective IL LPS - 10 levels 10 ne , which which , - responsive responsive

( SPARC decorin (69) lower (93) fine - - . 10 10 12

) - - .

This article isThis article by protected copyright. All rights reserved. but granuloma, the surrounding mostly were they that showed arrangement their of Analysis formation granuloma during proteoglycans and fibers elastic III, collagen I, collagen brasiliensis granulomas within granulomas around III and I collagens of tenascin of expression revealed tuberculosis and mycobacteriosis granulomas tenascin osteopontin, detected weakly and rings core necrotic central markedly the in not but cells, giant multinucleated and cells epithelioid macrophages, is osteopontin granulomas, tuberculosis multinucleate by caused those been has osteopontin humans, In disease granulomatous cells. epithelial by surrounded G are which granulomas, in found also are fibroblasts and cells foam into differentiate or cells m of numbers large contain pathogens. specific to response in generated are that clusters cell immune host considered Traditionally granulomas. of formation the by few characterized diseases infectious of a examples are measles and mononucleosis infectious toxoplasmosis, syphilis, Tuberculosis, granulomas infectious ECMin The

Accepted Article ranulomas (54) These . in , Gonzalez , Gonzalez d giant cells at the center of lesions in the early phase of infection infection of phase early the in lesions of center the at cells giant d the lo contain also (54)

- rtcie tutrs ifciu gauoa ae opc, orga compact, are granulomas infectious structures, protective granuloma and in epithelioid and multinucleated giant cells. Notably, Notably, cells. giant multinucleated and epithelioid in and granuloma . Analysis of human lung biopsies from patients with with patients from biopsies lung human of Analysis . granuloma inside

aaocdods brasiliensis Paracoccidioides that - et al et ad galectin and C

pathogenesis

,

colocalized with myofibroblasts myofibroblasts with colocalized n h EM A ifs ECM diffuse A ECM. the in

. detected increased expression of laminin, fibronectin, fibrinogen, fibrinogen, fibronectin, laminin, of expression increased detected . ECM proteins, whose expression and function function and expression whose proteins, ECM as san togy o tenascin for strongly stain also s ature macrophages, which can fuse into multinucleated giant giant multinucleated into fuse can which macrophages, ature

detected .

Neutrophils, dendritic cells, B, T and T B, cells, dendritic Neutrophils,

has only recently been inves recentlybeen only has - 9 . P . are recursor proteins of collagen I collagen of proteins recursor in granulomas of diverse etiology etiology diverse of granulomas in

bet n non in absent , it localizes in ECM, macrophages and and macrophages ECM, in localizes it , - soitd tiig f galectin of staining associated

expressed within lymphocytes, lymphocytes, within expressed (119) - C in the the in C I mc ifce wit infected mice In . - infectious Crohn disease disease Crohn infectious tigated. tigated. - C and precursor proteins proteins precursor and C surrounding surrounding

natural killer cells, cells, killer natural

were (117) in Granulomas Granulomas also also infectious infectious (118)

atypical atypical and, in and, fibrotic fibrotic (120) found found nised nised h - 9 . In In . P. is .

This article isThis article by protected copyright. All rights reserved. gain and stages disease Accepted various ECM and ECM of analyses global unbiased include conditio hypoxic the account into take should work Future load bacterial and formation granuloma reduced viamarimastat inhibition non with patients from biopsies in and model tissue Parasa this, with line cells infected of survival increase fibrils collagen intact Conversely, pathogen. response immune the diverting thus cavitation, and necrosis caseous into of survival the reduces that event pathological initial (122) with infection upon granulomas within necrosis. caseous initiate Elkington to proposed been now has destruction collagen Conversely, pathogenesis. tuberculosis of cornerstone the be to thought was dissemination bacterial Spec Article infection. of dissemination mycobacteria, infecting host a considered Traditionally immunopathology. tuberculosis in turnover ECM on studies Recent granuloma fibrosis progressive limit to shown been has system fibrinolytic the infection, mycobacterial chronic during Notably, may cytokines and that factors growth of distribution enhance point and integrity tissue to contribute anchorage an from originated which arrangement, concentric compact, inside sporadically . They then demonstrated that proteolytic collagen destruction of the lung ECM is the the is ECM lung the of destruction collagen proteolytic that demonstrated then They . et al et (121) . have fir have . .

it . Initially arranged in a disorganised manner, EC manner, disorganised a in . Initiallyarranged t al et st shown that MMP that shown st

tuberculosis with plasminogen regulating the turn the regulating plasminogen with . reported upregulation of MMP1, 3, 9 and 12 in a human lung lung human a in 12 and 9 3, MMP1, of upregulation reported . ifically, caseous necrosis leading to ECM destruction and and destruction ECM to leading necrosis caseous ifically, -

n loss and

granuloma has been implicated in the expansion and and expansion the in implicated been has granuloma M. tuberculosis M. - 1 - of - expressing mice develop collagen destruction destruction collagen develop mice expressing - function experiments in 3D systems and/or and/or systems 3D in experiments function

granuloma has helped rewrite tuberculosis tuberculosis rewrite helped has granuloma - protective structure that ‘quarantines’ the ‘quarantines’ that structure protective - associated molecules in granulomas at granulomas in molecules associated M. tuberculosis M.

- in the absence of caseous necrosis caseous of absence the in

aiay ueclss Goa MMP Global tuberculosis. cavitary ns in infectious granulomas and and granulomas infectious in ns over of ECM proteins within the the within proteins ECM of over M fibres later acquired a acquired later M fibres - infected cells, resulting resulting cells, infected

(125)

in favour of the the of favour in . (123, 124) (123,

(120) . In In . . This article isThis article by protected copyright. All rights reserved. compromised engineering strategies therapeutic challeng A microbiota. ofthe context pathways, approaches editing diseases genome and biology systems infectious individual of outcome the for responsible directly and systems model appropriate of changes significant undergoes ECM The infection. development disease here, discussed the of outcome establishment ignored the and ECM The f and remarks Concluding function. role the understand to animals modified genetically a s

Acceptedmicroenvironment cellular the Article tmcoil resistance ntimicrobial or ing

(126)

overlooked, the diverse yet specific functions of the ECM in in ECM the of functions specific yet diverse the overlooked, designin , in their effort to prolong prolong to effort their in

investigat

, virus transmission transmission virus , (129) by n dseiain of dissemination and

ECM infection mue response immune , mcaitc tde, n, n h longer the in and, studies, mechanistic g innate innate shows the breadth and complexity of ECM activity and regulation in in regulation and activity ECM of complexity and breadth the shows - ing the the ing or muooia research immunological

. improve existing ones. ones. existing improve

uture perspectives uture

immune response to infection are inextricably linked. Largely Largely linked. inextricably are infection to response immune s f lbl concern global of is now evident evident now

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This article isThis article by protected copyright. All rights reserved. 13. 20 Immunol. Semin compartments. cell immune of organizer potential a as spleen the of 11. 2009;15(5):519 inhi selectively alpha5 laminin membrane 10. 2010;88(3):523 Biol. Leukoc infla to 9. extracellular for coding genes within diversity 1993;13(6):457 Matrix. matrix proteins. coding increasing for progression: mechanism used cancer commonly in events key 8. are matrix extracellular 2011;16(3):193 Biomarkers. development. marker biochemical for opportunities the of modifications translational 7. Biol. 2012;4(1):a004903. Harb Perspect ColdSpring and functions. constituents 6. Cytokine. 5. 2010;10(10):712 4. 96. co matrix extracellular of recognition for determinants 3. 2. 27. 1. References declare. to None Disclosures with Nottingham; of BBSRC a and AMP) (University to awarded Fellowship McLaren Anne an by supported are authors The Acknowledgements

Accepted Article the mmatory loci is impaired in mice deficient in basement membrane protein laminin alpha4. J J alpha4. laminin protein membrane basement in deficient mice in impaired is loci mmatory Lokmic Z, Lammermann T, Sixt M, Cardell S, Hallmann R, Sorokin L. The extracellular matrix matrix extracellular The L. Sorokin R, Hallmann S, Cardell M, Sixt T, Lammermann Z, Lokmic basement Endothelial al. et P, Nilsson D, Vestweber R, Hallmann P, Anderson F, Ivars C, Wu recruitment cell Immune L. Lindbom EE, Eriksson P, Rotzius G, Genove O, Soehnlein E, Kenne Alternate LJ. Sandell K, Doege JE, Schwarzbauer RA, Pierce CD, Boyd Bay DJ, matrisome Leeming the of Overview A. Naba RO, Hynes Immunol. Rev Nat pathways. immunological and inflammation. matrix extracellular integrating Towards PG. Thomas DF, Boyd on matrix extracellular the of impact The L. Sorokin protein tissues: animal to adhesion Bacterial M. Desvaux T, Astruc A, Listrat C, Chagnot Nature. 1978;276(5689):718 aureus. toStaphylococcus binds Fibronectin Kuusela P. Pizarro literature search and N and search literature 2017;98:79

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Accepted Article

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Accepted Article

- aaaa , u J Dnai , isn R Ioe , rgr S, t l Seig f the of Skewing al. et SG, Gregory M, Inoue JR, Gibson K, Danzaki SJ, Xu M, Kanayama galectin of role Critical al. et I, Kuwabara BB, Sharma L, Yu JR, Apgar DK, Hsu H, Sano al. et FT, Liu WE, Schiphorst A, Remoortere van N, Franke H, Honing TK, Berg den van Extrace S. Chakravarti AR, Hamad C, Nakata SG, Scott H, Shao Gae S, Lee H, Shao F Wu of clearance intranasal promotes mindin molecule recognition Pattern YW. He H, Li W, Jia pr matrix extracellular The etal. N, Zhang LinE, CL, J,Hsu Zhang Li He YW, H, Gomis CS, Robbins WO, Hartzell AM, Houghton Tenascin al. et K, Anasti EL, Kunz C, Ho JD, Amos FH, Jaeger GG, Fouda a receptors laminin on sites Binding T. Yoshida N, Kobayashi heparin by killing Bacterial A. Schmidtchen M, Davoudi M, Malmsten Antimicrobial A. Schmidtchen L, Bjorck M, Morgelin A, Sonesson V, Rydengard E, Andersson typ of Production al. et D, Troyer H, Robenek K, Stolle J, Lorkowski P, Cullen M, Schnoor Cul B, Weitkamp J macrophages. peritoneal mouse by I type collagen of Production WJ. Lindblad J, Vaage Com al. et T, Juan M, Malbouyres D, Cerezo L, Papone G, Zimniak V, Bor De Van Piccinini Zeng Zeng MV, Nastase J, Beckmann K, Moreth R, Merline recognition molecule for microbial pathogens. Nat Immunol. 2004;5(1):88 NatImmunol. pathogens. microbial molecule for recognition - lcn con glycans - 21 - , Vij N, Roberts L, Lopez L, Roberts N, Vij , . Sci Signal. 2011;4(199):ra75. . SciSignal. Brouwers J, Beckmann J, Nastase MV, Iozzo RV, Schaefer L. De novo expression of of expression novo De L. Schaefer RV, Iozzo MV, Nastase J, Beckmann J, Brouwers - 1 - neutralizing protein in breast milk. Proc Natl Acad SciUSA.2013;110(45):1 Acad Natl breast milk. Proc in protein neutralizing M Zuliani AM, - - binding peptides binding 17. ttt a aaie atr fr galectin for pattern parasite a stitute

- - len P, Plenz G, Robenek H, Rauterberg J. Human macrophages synthesize synthesize macrophages Human J. Rauterberg H, Robenek G, Plenz P, len 42. mediated signaling pathways in macrophages. Sci Signal. 2016;9(443):ra86. Signal. Sci in macrophages. pathways mediated signaling - - Scott S, Nakata C, Chen S, Ham S, Chen C, Nakata S, Scott - -

80. 7. 19. - - +. Alvarez L, Lim JM, Midwood KS. Distinct microenvironmental cues cues microenvironmental Distinct KS. Midwood JM, Lim L, Alvarez

- 6.

. Eur J Biochem. 2004;271(6):1219 JBiochem. . Eur - Briones S, Joyce S, Chakravarti S. A novel role of the lumican lumican the of role novel A S. Chakravarti S, Joyce S, Briones

- / -

- ie hw nrae Pedmns euioa lung aeruginosa Pseudomonas increased show mice - 61. induced innate immune response. J Biol Chem. Chem. Biol J response. immune innate induced

- 72.

- - 389 300. Ruth FX, Shapiro SD. Macrophage elastase elastase Macrophage SD. Shapiro FX, Ruth ad AR, et al. Extracellular matrix lumican lumican matrix Extracellular al. et AR, ad - 97. -

Brouwers J, Tralhao JG, et al. Signaling Signaling al. et JG, Tralhao J, Brouwers - 3

- mediated immune recognition. J J recognition. immune mediated - s components for antibiotics. antibiotics. for components s - 41. llular matrix protein lumican lumican protein matrix llular 26.

- binding peptides from from peptides binding - C is an innate broad innate an is C - 97. otein mindin is a is mindin otein

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8220 - 3 in in 3 e VI VI e - 5.

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This article isThis article by protected copyright. All rights reserved. Accepted 2001;276(38):35606 J Chem. Biol ad F1 between interactions 131. Immun. Infect proteins. matrix 2011;79(9):3744 of extracellular to antigens bind O157:H7 coli rSRS9 Escherichia enterohemorrhagic and rSRS4 rBAG1, 130. for responses immune 2014;14:429. Infect Dis. BMC mice. BALB/c gondii in Toxoplasma stronger elicits adjuvant novel 129. Galectin and Fibronectin via Infection 128. 2010;16(1):83 Med. HTLV mediate assemblies viral extracellular 127. gene regulatory 126. 2017;8:2370. Microbiol. Model. Front Tissue Lung a Human in Load Bacterial Reduces w Interferes Metalloproteinases 125. 2017;6. Elife. model. dimensional host the of Dissection 124. 2015;212(3):463 JInfect Dis. inTuberculosis. Necrosis Granuloma Matrix Regulates Extracellular 123. 2011;121(5):1827 JInvest. mice. Clin transgenic and tuberculosis inhuman immunopathology 122. mycobact a during deposition 2003;163(2):517 protein matrix and dissemination 121. m Article of lungs the 2008;89(2):106 Exp Pathol. IntJ conidia. in proteins matrix extracellular of 120. 2007;38(1):147 Pathol. lung. Hum gra in myofibroblasts and 119. infection. brasiliensis Paracoccidioides 2009;47(5):495 Mycol. Med of severity the in and formation granuloma in involvement 118. Invest. 1997;77(1):103 Lab etiology. ofdiverse ingranulomas by histiocytes 117. 2014;95(3):158 Pathol. JExp Int microRNAs. 116. J.2006;25(17):4097 EMBO mindin. matrix protein extracellular 115. galectin of 2007;75(11):5148 impact Immun. cells. Infect dendritic of the functions on deficiency infection: helminthic during responses inflammatory and immune modulates 114. 2012;64(7):2179 Rheum. tenascin immunity: 113.

afn J Cneo , ia R Bti D, ors G Lon AG. Torres DJ, Tomasini MG, Ensenberger Botkin R, Vidal L, Cantero MJ, Farfan T al. et X, Wei B, Jia F, Han X, Zhang M, Mei X, Sun HIV from Derived Exosomes A. Prasad R, Kulkarni Pais a of Identification al. et J, Alden P, Banerjee A, Louzolo BT, West A, Harvey MM, Marbiah Matrix Tissue of Inhibition M. Lerm S, Brighenti C, Braian JF, Rose JR, Muvva VR, Parasa P, Brace BA, Shammari MT, Reichmann A, Chancellor MK, Bielecka LB, Tezera Shammari Al Ugarte RK, Nuttall R, Breen T, Shiomi P, Elkington in system fibrinolytic The FJ. Castellino L, Krahule E, Haalboom VA, Ploplis J, Schorey J, Sato arrangement and Expression LE. Cano A, Restrepo L, Caputo EM, Motta HL, Lenzi A, Gonzalez Osteopon E. Burger S, Kaarteenaho Cda Cunha BP, Albe RF, Molina R, Scavone AS, Nishikaku expressed strongly is Osteopontin LF. Brown HF, Dvorak EJ, Manseau K, Tognazzi I, Carlson and matrix extracellular the between interplay the Illustrating KS. Midwood AM, Piccinini dendritic Efficient YW. He W, Jia T, Oliver H, Li Tillie CM, Stijn van J, Fontaine F, Vanhoutte L, Breuilh AM, Piccinini M, Ruhmann - Correia AM, Sachse M, Guadagnini S, Robbiati V, Lasserre R, Gessain A, et al. Biofilm al. et A, Gessain R, Lasserre V, Robbiati S, Guadagnini M, Sachse AM, Correia

network associated with prion replication. EMBO J.2014;33(14):1527 EMBO replication. with prion associated network - - 31. 50. - -

9. die interleukin drives C -

Wiik R, Sademies O, Paakko P, Risteli J, Soini Y. Extracellular matrix proteins proteins matrix Extracellular Y. Soini J, Risteli P, Paakko O, Sademies R, Wiik B, Shiomi T, Tezera L, Bielecka MK, Workman V, Sathyamoorthy T, et al. The The al. et T, Sathyamoorthy V, Workman MK, Bielecka L, Tezera T, Shiomi B,

- - ahgn neato i hmn ueclss sn a iegnee 3 bioengineered a using tuberculosis human in interaction pathogen 90. nulomas of sarcoidosis, atypical mycobacteriosis, and tuberculosis of the of tuberculosis and mycobacteriosis, atypical sarcoidosis, of nulomas hesin of Streptococcus pyogenes and N and pyogenes Streptococcus of hesin - 507.

ith Mycobacterium tuberculosis Mycobacterium ith

-

13. - 53. - Johansson BR, Sottile J, Ozeri V, Hanski E, Mosher DF. Specific Specific DF. Mosher E, Hanski V, Ozeri J, Sottile BR, Johansson

-

Kong PL, Midwood KS. Endogenous activation of adaptive adaptive of activation Endogenous KS. Midwood PL, Kong 3. Scientific Reports. 2017;7. Reports. Scientific 3. - 16. - 17 synthesis in murine arthritic joint disease. Arthritis Arthritis disease. joint arthritic murine in synthesis 17 -

80. - cell 1

- to ice infected with Paracoccidioides brasiliensis brasiliensis Paracoccidioides with infected ice -

el rnmsin t virolog at transmission cell cell priming of T lymphocytes depends on the the on depends lymphocytes T of priming cell he extracellular matrix protein mindin as a a as mindin protein matrix extracellular he - i A akrN,e l MMP al. et NF, Walker CA, Gil

- - Ifce Ds eit Vrl trans Viral Mediate DCs Infected 1 - Leblond I, Cap I, Leblond 107.

- Induced Granuloma Formation and and Formation Granuloma Induced

-

terminal modules of fibronectin. fibronectin. of modules terminal erium infection. Am J Pathol. Pathol. J Am infection. erium - 8. ron M, et al. Galectin al. et M, ron -

g polar fimbriae of of fimbriae polar g 57.

cl yass Nat synapses. ical

- 47.

- 1 drives drives 1 - 33. et al. al. et - 73. -

like tin tin - -

3 3 - - This article isThis article by protected copyright. All rights reserved. Bacteriol. 2007;189(20):7174 J proteins. matrix extracellular on activity degrading with protease cysteine a is difficile, Clostridium 148. 1986;54(1):149 Immun. Infect protease. tissue 14 and 1997;247(1):416 Biochem. (ClfA) EurJ fibrinogen. factor clumping aureus Staphylococcus the between interaction the of Characterization 146. 1998;30(2):245 surface new 145. 2013;93(8):900 Invest. Lab infection. burgdorferi Borrelia chronic 144. 2017;9(1):33 Immun. J Innate Interaction. Host Yersinia enterocolitica a to Binds 143. 2007;9(2):450 Cell Microbiol. matrix. andextracellular cells epithelial enables Mip protein 142. hospital of 2009;77(11):5097 Infect Immun. adhesins novel two are MSCRAMM, binding collagen nidogen a SgrA, al. et 141. Extracellular M Host to Adherence Formation, Biofilm in faecium Enterococcus of Subunits Pilus Emp 140. Er surface protein 139. Microbiol. 2010;10:78. BMC cells. endothelial human and isolates gallolyticus subsp. gallolyticus Streptococcus 138. 2004;52(2):345 Microbiol. Mol binding. heparin of mimicry molecular for evidence module: repeat 13FnIII fibronectin the of cradle 137. 2005;57(1):196 Microbiol. Mol fibronectin. binds that factor colonization intestinal an is MisL Typhimurium serotype matrix extracellular an 136. is (MntC) C protein plasminogen transport manganese aureus Staphylococcus 135. Mi Mol Astreptococci. group in surface protein 134. blockin by pyogenes Streptococcus 2000;97(6):2858 of 1 5beta ingestion alpha integrin cell of formation epithelial inhibit can antagonist integrin 133. J. 1996;15(5):989 through adherence streptococcal A group for mechanism 132. atrix Components, and Experimental Infection. Infect Immun. 2016;84(5):1491 Immun. Infect Infection. Experimental and Components, atrix Accepted7. Article

- associated basement membrane laminin by Pseudomonas aeruginosa elastase and alkaline alkaline and elastase aeruginosa Pseudomonas by laminin membrane basement associated aor , ehn S Grosdidi S, Pechine C, Janoir of depletion and laminin soluble of Degradation DR. Abrahamson K, Morihara LW, Heck House T, Nanavaty D, McDevitt a (ClfB), B factor Clumping TJ. Foster M, Hook P, Vaudaux P, Francois S, Perkins DN, Eidhin connective of Dynamics SW. Barthold E, Hodzic S, Feng DM, Imai Vitronectin al. et J, Rinker D, Linke E, Bohn IB, Autenrieth T, Hallstrom MC, Muhlenkamp binding Collagen al. et U, Lorenz C, Unal B, Schmausser T, Kamphausen AS, Khan C, Wagner Luit van AP, Hendrickx the of Role al. et R, Spencer C, Chang P, Yadav SR, Somarajan KV, Singh MC, Montealegre outer burgdorferi Borrelia The B. Stevenson AE, Cooley A, Bowman A, Verma CA, Brissette Interacti J. Dreier K, Kleesiek D, Hinse T, Vollmer AM Keestra RA, Kingsley enterica Salmonella AJ. Baumler EH, Weening AD, Humphries MC, Laarakker CW, Dorsey fibronectin novel Castiblanco N, Salazar a of Characterization GS. Chhatwal SR, Talay B, Kreikemeyer nonpeptide A al. et JM, Smallheer W, Lorelli J, Prabhakar PJ, Southern SO, Southern D, Cue Natanson I, Burstein A, Tovi V, Ozeri

Specific Stretch within the Head Region of Yersinia Adhesin A and Thereby Modulates Modulates Thereby and A Adhesin Yersinia of Region Head the within Stretch Specific

- - located fibrinogen located binding protein. PLoS One. 20 One. PLoS binding protein. - - 211. 57. - - 63. pX binds mammalian laminin. Microbiology. 2009;155(Pt 3):863 2009;155(Pt Microbiology. laminin. mammalian pX binds 98.

einla nuohl t tasirt truh brir f NCI of barrier a through transmigrate to pneumophila Legionella - binding LPXTG surface adhesin implicated in biofilm formatio biofilm in implicated adhesin surface LPXTG binding - 80. - - - Valencia MM, da Silva LB, de Castro I, Monaris D, Masuda HP, et al. al. et HP, Masuda D, Monaris I, Castro de LB, Silva da MM, Valencia Asbroek M, Schapendonk CM, van Wamel WJ, Braat JC, Wijnands LM, LM, Wijnands JC, Braat WJ, Wamel van CM, Schapendonk M, Asbroek 55. - binding adhesin of Staphylococcus aureus. Molecular Micro Molecular aureus. Staphylococcus of adhesin binding - , de Zoete MR, Baumler AJ. The ShdA adhesin binds to the cationic cationic the to binds adhesin ShdA The AJ. Baumler MR, Zoete de ,

106.

-

fibronectin r , olgo A Cp4 a surface a Cwp84, A. Collignon C, er - 53. - 14;9(11):e112730.

24. - - Pompeo K, Bell E, Turner N, McIntire L, et al. al. et L, McIntire N, Turner E, Bell K, Pompeo Yaron S, Caparon MG, Yamada KM, et al. A two A al. et KM, Yamada MG, Caparon S, Yaron

crobiol. 1995;17(1):137 crobiol. - M1 protein complexes. Proc Natl Acad Sci U S A. A. S U Sci Acad Natl Proc complexes. protein M1 protein F to the extracellular matrix. EMBO EMBO matrix. extracellular the to F protein

n bten endocarditis between ons - 10. - acquired Enterococcus faecium. faecium. Enterococcus acquired -

62. - 51. - 45.

- tissue localization during during localization tissue - associated protein of of protein associated - 500. - 72.

n, and EcbA, a a EcbA, and n, - H292 lung lung H292 - - - biology. biology. domain domain derived derived binding binding -

and and g - This article isThis article by protected copyright. All rights reserved. vitr as such components ECM to binding by responses immune innate evade and infection, the establish pathogens can alsohijack hostproteolytic systems as such the To invasion. host facilitates pathogens by activated MMPs host enzymes degrading tissue microbial via ECM the of Degradation colonization. host helps fibronectin as such molecules ECM to binding Pathogen shown. is components ECM by R 2. Figure TLR4 cell proinflam of synthesis the induces also Mindin macrophages. bacteria, bacteria galectin and Figure legends Figure and fibronectin of activities adhesion cell tenas affect differentially gingipains periodontitis: in matrix 154. and IV collagen 153. 2004;63(5):520 152. cel on products 2010;7(2):87 degradation of effects the and collagenase Clostridium 151. 2002;283(1 Gene. 04. parahaemolyticus Vibrio 150. 2014;5:783. Microbiol. model. Front disease a arthritis as rheumatoid with autoimmunity in link missing the for evidence pathogens: microbial and molecules 149.

Acceptedpathogen of ecognition Article s.

cin

- Lumican mediated responses to LPS to responses mediated Ruggiero S, Cosgarea R, Potempa J, Potempa B, Eick S, Chiquet M. Cleavage of extracellular extracellular of Cleavage M. Chiquet S, Eick Biotechnol. B, Potempa J, Potempa R, Cosgarea S, Ruggiero Microbiol Appl bacteria. type hydrolyzes gordonii Streptococcus of protease extracellular from An MW. Stinson ZE, Juarez proteases Collagenolytic K. Watanabe by isoforms collagen human of Degradation D. Aust D, Telgenhoff A, Garcia R, Ermis L, Shi of analysis sequence and Cloning J. Cha JY, Yang SK, Kim In EH. Baker DL, Baines SD, Robertson R, Wait N, Sofat 1 - Al f hm rmt paoyoi o bcei b macrophages by bacteria of phagocytosis promote them of All . C. Biochim Biophys Acta. 2013;1832(4):517 Acta. Biochim Biophys C.

. Mindin, lumican and galectin and lumican Mindin, . causes causes - M - 95. 3 ultiple

-

collagen analogues. Infect Immun. 1999;67(1):271 Immun. Infect analogues. collagen 6. instead and recognize

their their

ucin o te C i te mue epne o infection. to response immune the in ECM the of functions

interacts with CD14 on the surface of macrophages, promoting CD14 promoting ofmacrophages, surface the withCD14on interacts opsonisation - associated molecular patterns by macrophages through PRRs and and PRRs through macrophages by patterns molecular associated bind to sugar moieties found in the the in found moieties sugar to bind

and CD14 and

and

agglutination - 3 - 2):277 : three extracellular sentinels extracellular three : - mediated phagocytosis. mediated - 26. - 86.

,

n fcltts hi paoyoi by phagocytosis their facilitates and

teraction between extracellular matrix matrix extracellular between teraction

a novel metalloprotease gene from from gene metalloprotease novel a - 8.

plasminogen aoy yoie by cytokines matory cell wall of wall cell mgain It on J. Wound Int migration. l

. .

- M several types of types several Mindin, lumican lumican Mindin, plasmin system plasmin indin binds to to binds onectin. these these or or -

This article isThis article by protected copyright. All rights reserved. Accepted Article inflammation. propagate that loops miR of biosynthesis the regulate which tenascin and decorin as such components ECM also synthesize macrophages Activated NF Pathogen stiffness. ECM pathways signalling inflammatory triggers increasing macrophages of activation fibers, mediated collagen crosslinks which LOX, of higher levels and MMPs proteins, ECM secrete and produce ECM interstitial the in Fibroblasts - kB pathway, which culminates in the synthesis of cytokines, MMPs and miRNAs. miRNAs. and MMPs cytokines, of synthesis the in culminates which pathway, kB

- 1 n miR and 21 - 5 ad eeae oiie fee positive generate and 155

such as the the as such dback dback - C, C, - fibronectin Plasma Fibronectin ECM This article isThis article by protected copyright. All rights reserved. Accepted Article study) the in tissues to adhesion 1. Table Tabl molecule es

Examples of of Examples

b Borrelia typhimurium Salmonella aureus Staphylococcus GAS) A streptococci, pyogenes Streptococcus O157:H7 Escherichia coli c Enterohemorrhagi Pathogen

u rgdorferi

and pathogenesis pathogenesis and

specific specific (group

host BBK32 ShdA d region) conserve non terminal MisL MntC Fba domain) terminal SfbII (C domain terminal F2 Pr domain) upstream l (functiona F1 Protein subunit major (LpfA1 fimbriae Lpf Adhesin otein

(C -

(

ECM

(N *

-

indicates that animal models of infection were used used were infection of models animal that indicates ) s - -

)

- pathogen interactions interactions pathogen Host uptake bacterial helping receptors integrin links Fibronectin of Colonization interaction Effect of n and polymerizatio Fibronectin colonization intestinal module repeat 13FnIII fibronectin Binding to colonization Intestinal colonization Mucosal internalization adhesion and Host cell internalization adhesion and Host internalization adhesion and GI

F1 to cell cell cell cell tract

and ,

shock syndrome streptococcal toxic myositis necrotizing fasciitis Tonsillopharyngitis; syndrome hemolytic uremic bloody diarrhea; Acute diarrhea; Disease Lyme disease Gastroenteritis endocarditis, etc. a, infections Nosocomial osteomyelitis, ;

that ,septicaemi

facilitate

;

(33) (131 (130) e Referenc (35) (137) (136) (135) (31) (134) microbial microbial

- *

133)

*

Collagen II Collagen I Laminin 45 and70 kDa) fragments proteolytic terminal Fibronectin and 70 kDa) fragments (30 proteolytic terminal Fibronectin This article isThis article by protected copyright. All rights reserved. Accepted Article

(30,

N N

- -

S ( gallolyticus Streptococcus faecium Enterococcus typhimurium Salmonella isolates endocarditis ( gallolyticus Streptococcus bu Borrelia isolates endocarditis ( gallolyticus Streptococcus aureus Staphylococcus O157:H7 Escherichia coli c Enterohemorrhagi O157:H7 Escherichia coli c Enterohemorrhagi pyogenes gallolyticus gallolyticus gallolyticus

treptococcus rgdorferi

) )

Protein and pilB FimB, gtf EmpB and EmpA subunits Pilus ShdA and pilB FimB, gtf ErpX and pilB FimB, gtf MntC subunit major (LpfA1 fimbriae Lpf subunit major (LpfA1 fimbriae Lpf domains) terminal (C F2 -

) )

colonization Mucosal of Colonization of Colonization internalization and cell adhesion Eukaryotic surfaces of c cells en invasion of Adhesion and formation and biofilm host tissue Adherence to persistence and colonization Intestinal cells en invasion of Adhesion and colonization host tissue Long cells en invasion of Adhesion and olonization GI GI vascular d d d othelial othelial othelial

- tract tract term

syndrome hemolytic uremic bloody diarrhea; Acute diarrhea; syndrome hemolytic uremic bloody diarrhea; Acute diarrhea; shock syndrome streptococcal toxic myositis necrotizing fasciitis Tonsillopharyngitis; endocarditis and infective U Gastroenteritis Infective endocarditis Lyme disease Infective endocarditis endocarditis, etc. osteomyelitis, septicaemia, infections Nosocomial TIs , bacteremia, ;

,

;

(135) (130) (130) (33) (138) (140) (137) (138) (139) (138)

*

Decorin n Thrombospondi Vitronectin Tenascin Collagen VI Collagen V Collagen IV

This article isThis article by protected copyright. All rights reserved. Accepted Article

- C

Escherichia coli c Enterohemorrhagi isolates endocarditis cruzi Trypanosoma enterocolitica Yersinia isolates endocarditis ( gallolyticus Streptococcus isolates endocarditis ( gallolyticus Streptococcus pneumophila Legionella faecium Enterococcus typhimurium Salmonella isolates endocarditis ( gallolyticus Streptococcus aureus Staphylococcus O157:H7 gallolyticus gallolyticus gallolyticus

) ) ) )

(LpfA1 fimbriae Lpf DbpA DbpA TcCRT YadA and pilB FimB, gtf and pilB FimB, gtf Mip EcbA d region) conserve non terminal MisL (N and pilB FimB, gtf MntC subunit major

-

) -

Host tissue colonization Intestinal cells en invasion of Adhesion and colonization Mucosal of Colonization l Specific infection of cellular Enhancement survival bacterial improved tissue host Adhesion to cells en invasion of Adhesion and cells en invasion of Adhesion and dissemination and bacterial lung tissue Adhesion to formation biofilm adhesion and ocalization GI d d d othelial othelial othelial

cells and tract ;

to

Gastroenteritis Infective endocarditis endocarditis, etc. a, osteomyelitis, infections Nosocomial syndrome hemolytic uremic bloody diarrhea; Acute diarrhea; Infective endocarditis diseases Enteric and systemic Infective endocarditis Infective endocarditis Legionellosis endocarditis and infective U TIs,

bacteremia,

,septicaemi

(141) (136) (138) (135) (130) (144) (46) (143) (138) (138) (142)

* * * *

beta (alpha f immobilized Soluble and 2 Nidogen 1 and ibrinogen

This article isThis article by protected copyright. All rights reserved. serine calreticulin; cruzi Trypanosoma TcCRT: A protein binding collagen FimB; protein autotransport MisL: C; protein transport su fibronectin gastrointestinal; GI:

Accepted Article- chains) -

and - glutamate repeat containing protein A protein containing glutamate repeat t: gl gtf:

u fc bnig rti I; b: irnci bnig protein; binding fibronectin Fba: II; protein binding rface cosyltransferase; cosyltransferase; burgdorferi Borrelia aureus Staphylococcus faecium Enterococcus

T: rnr tat infection; tract urinary UTI:

; I: arpae netvt potentiator; infectivity macrophage MIP:

iB tp 4 ibil seby protein assembly fimbrial 4 type pilB: DbpB and Clf SgrA A, Clf

DdpA/ DdpB: DdpA/ B

;

ClfA/ClfB: clumping fac clumping ClfA/ClfB: spread bacterial implants; of Colonization formation biofilm adhesion and Host tissue of infection persistence tissue; connective myocardial an adventitia tunica niches decorin

MisL biomaterial d

pA: l LpfAI:

; in the -

rich FimB: d

ecorin binding protein A and B; and A protein binding ecorin

ong polar fimbrae subunit 1; SfbII: SfbII: 1; subunit fimbrae polar ong

type I fimbriae regulatory protein protein regulatory fimbriae I type a, osteomyelitis, infections,septicaemi Nosocomial endocarditis and infective U Lyme disease Chagas disease endocarditis, etc. TIs , bacteremia, tor A and B. A and tor

aA adhes YadA:

;

MntC: manganese manganese MntC: EcbA:

E. (145, (145, 146) (141) n YadA in faecium faecium

SgrA: SgrA:

;

(large Tenascin Vitronectin Fibronectin Collagen IV and V II, I Collagen Collagen I Laminin molecule ECM This article isThis article by protected copyright. All rights reserved. study) infection through 2. Table

Accepted IV III, Article I

V , -

C

iet erdto o EM components ECM of degradation direct

, and

Examples of specific specific of Examples Pathogen gingivalis Porphyromonas difficile Clostridium gordonii Streptococcus histolyticum Clostridium parahaemolyticus Vibrio gingivalis Porphyromonas difficile Clostridium aeruginosa Psedomonas gingivalis Porphyromonas difficile Clostridium

ex vivo ex

mammalian tissue degradation models, respectively, respectively, models, degradation tissue mammalian

n Kgp gingipains RgpB and HRgpA, C RgpB HRgpA supernatant gingivalis in Gingipains Cwp84 Serine protease (Col II and collagenase I Class VppC Metalloprotease supernatant gingivalis in Gingipains Cwp84 protease alkaline Elastase; enzyme Microbial wp84 G E

CM , gingipain

ColH)

-

pathogen interactions that facilitate host invasion invasion host facilitate that interactions pathogen

; s

and s P. P.

degradation; tissue Necrotic Tissue damage degradation toxin Tissue diffusion of facilitation loss; integrity Tissue and necrosis invasion Tissue cleavage Effect ofECM activity of of activity adhesive Enhanced toxin diffusion of facilitation loss; integrity Tissue death destruction; tissue and detachment fibroblast of gingival fibronectin; region cell of inactivation and toxin Cleavage diffusion of facilitation loss; integrity Tissue breakdown membrane Basement migration keratinocyte promote

( * - binding

and

#

anti

indicate - ;

a gangrene, infective endocarditis Gas Acute gastroenteritis Periodontal disease diarrhea nosocomial and colitis Pseudomembranous soft tissue infections septic UTI shock, pneumonia, Necrotizing Disease Periodontal disease diarrhea nosocomial and colitis Pseudomembranous Periodontal disease diarrhea nosocomial and colitis Pseudomembranous Infective endocarditis

that animal models of of models animal that

were used in the in used were si and skin ,

(151, (150) (149) (148) (147) Reference (154) (148) # 154) (149, (148) (153)

152) # #

isoforms) This article isThis article by protected copyright. All rights reserved. Accepted Article gingipains; p Cwp84:

ttv cl surface cell utative Kgp

: lysine - gingipains.

- associated cysteine cysteine associated

destruction tissue and apoptosis de fibroblasts g tenascin ingival tachment, protease -

C;

; HRgpA

and

RgpB arginine : - This article isThis article by protected copyright. All rights reserved. Accepted Article