Mice Infectious Agents & Diseases (Phenotypes)
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2017 Brayton MICE INFECTIOUS Jargon Mice Infectious Agents & SPF = Specific Pathogen Free – Defined by the Exclusion list Diseases (Phenotypes) Gnotobiotic = defined flora – ASF = altered Schaedler’s flora Cory Brayton, D.V.M., D.A.C.L.A.M., D.A.C.V.P. Associate Professor, Molecular and Comparative Pathobiology Director, Phenotyping Core Axenic = germ free Johns Hopkins University, School of Medicine Baltimore, MD 21205 Autochthonous flora (indigenous flora) [email protected] http://www.hopkinsmedicine.org/mcp/PHENOCORE/index.html – Microbiome/Microbiota Allochthonous flora (transient flora). 1 3 Infectious Agents & Phenotypes FELASA 2014 recommendations Discussion Plan 1. FELASA recommendations –2014, 2015 updates 3 month testing 2. Competent Mice –by agent 1. More common Annual testing : – Viral agents –Top few 2. More likely 1. Less likely – Bacteria –Top few 2. But concerning 3. Concerning – Eukaryotes –Top few 3. In a freezer near you 3. ‘Normal’ flora & the microbiome 4. In a pet store or wild 4. Immunodeficient mice ‐ by disease phenotype rodents near you… – Enteric / enterohepatic USEFUL BUT Partial list of agents… – Respiratory ‘other agents’ as ‘necessary’…. – OTHER Some will be discussed… 125. Biological Materials … http://www.uni-heidelberg.de/md/ibf/gesundzeugnis/hp-lab_anim-2014--178-92.pdf FELASA 2014 recommendations FELASA 2014 recommendations Mice Mice ‐ Viruses ‐ Bacteria 3 month testing 3 month testing Annual testing – add: 1. Helicobacter spp. x 1. MHV 1. LCMV Annual testing – Add: + H. hepaticus, H. bilis, 2. MAD1 (FL) 1. Citrobacter rodentium 2. Mouse rotavirus (EDIM) H. typhlonius 3. MAD2 (K87) 2. Clostridium piliforme 3. Murine norovirus 2. P pneumotropica 4. Mousepox 3. Corynebacterium kutscheri 4. Parvoviruses (NS1) (Ectromelia) virus 3. Strep b‐haemolytic (not 4. Mycoplasma pulmonis group D) 5. MVM 5. PVM 5. Salmonella spp 6. Reo3 4. Strep pneumoniae 6. Streptobacillus moniliformis 6. MPV 7. Sendai 7. TMEV http://www.uni-heidelberg.de/md/ibf/gesundzeugnis/hp-lab_anim-2014--178-92.pdf http://www.uni-heidelberg.de/md/ibf/gesundzeugnis/hp-lab_anim-2014--178-92.pdf [email protected] 2017 Page 1 of 42 2017 Brayton MICE INFECTIOUS FELASA 2014 recommendations FELASA 2014 recommendations Mice – Other Agents Mice – Other Agents Test as appropriate, for example due to : Viruses: Bacteria & fungi: 1. Zoonotic concern Hantaviruses CAR bacillus 2. Historical concerns (in freezers near you!) Herpesviruses Klebsiella oxytoca, 3. Pet or wild rodent exposures (MCMV, MTV) Klebsiella pneumoniae 4. Opportunists or too common to exclude Lactate‐dehydrogenase Other Pasteurellaceae practically from competent colonies & elevating virus (LDV) Pneumocystis murina usually not a problem iin competent mice Polyomaviruses (mouse 5. Experimental risk/exposure, e.g. polyomavirus, K virus) Pseudomonas aeruginosa . Biological materials Staphylococcus aureus . Experimental infections in the area . Gene therapy vectors http://www.uni-heidelberg.de/md/ibf/gesundzeugnis/hp-lab_anim-2014--178-92.pd6 f http://www.uni-heidelberg.de/md/ibf/gesundzeugnis/hp-lab_anim-2014--178-92.pdf FELASA ‐ Mice –q 3m testing Infection phenotypes ‘endo/ectoparasites’ Ectoparasites Protozoa/Protists 1. Fleas Immune modulation 1. Eimeria 2. Lice Polyplax Cancer 2. Entamoeba 3. Myobia Neurobehavioral 4. Myocoptes 3. Giardia – Hearing, vestibular 5. Radfordia 4. Spironucleus 6. Mesostigmatid mites – CNS – development/degeneration 5. Tritrichomonas muris Helminths Metabolic 1. Aspiculuris Respiratory 2. Syphacia Cardiovascular 3. Hymenolepis 4. Rodentolepis 23 Nature: (mostly) genetics Immune modulation Phenotypes in ‘Normal’? (+/+) Mice 129? Teratomas (Ter), lung tumors, acallosity, AMP, … Autochthonous flora (Indigenous) A/J Lung tumors, anomalies, amyloid, muscular dystrophy – Microbiome AKR Thymic Lymphoma… BALB/c Plasmacytoma etc tumors, heart dz, acallosity, kill each other – Opportunist C3H TUMORS - Mammary, Liver Microphthalmia, Hydrocephalus , MUD, Osteoporosis, Presbyacusis, Allochthonous flora (transient) C57BL/6 Amyloidosis, AMP, … – Most pathogens are allochthonous DBA Deaf, seizures, glaucoma, autoimmune • Commensal FVB/N? Blind, seizures, mammary/pituitary dz • Opportunist NOD Diabetes, immunoweird SJL/J Lymphoma, muscular dystrophy, kill each other • Subclinical DEAF C57BL/6, BALB, DBA, etc • Pathogen BLIND rd1 C3H, CBA, SJL, SWR, FVB + Different susceptibilities to infection and 24 26 disease ! [email protected] 2017 Page 2 of 42 2017 Brayton MICE INFECTIOUS Examples of Some Strain Associated infectious disease phenotypes Immune Variations Agent DZ Susceptible Intermediate Resistant (More) Innate (More) Adaptive/Acquired MHV - Hc c5 hemolytic complement & TH1, TH2 biases B6, BALB/c SJL/J demyelination Sclc11a1 solute carrier family 11a MHC Parvo MPV1 member 1 (formerly Nramp1) C3H/HeNDISCLAIMERBALB/c, ICR, DBA B6 seroconversion Natural Killer Cell function - TMEV This is an over simplification of strain responses to Variation in NK complex Klra (Ly49) Tlr4 Toll like receptor 4 SJL/J, SWR, DBA/2 CBA, C3H A, B6, B10, DBA/1 demyelination these agents Klrb (Nkrp) etc Sendai NAIP neuronal Apoptosis inhibitor Il2m1 Il 2; mutation 1 = Hypo-active Emphasizes someDBA, 129 responses A, withBALB, SWRrelatively recentB6, SJL Pneumonia proteins & Nlrp- NOD like receptor variant of IL-2 with decreased T cell data protein polymorphisms activation DBA, BALB/c, C3H, Ectromelia B6, AKR immune def Sirpα in NOD phagocytosis Tcrbv8 T cell receptor beta variable 8 BALB/c, C3H, A/J Mycoplasma B6, B10 Slamf signaling lymphocyte activation DBA/2, AKR Cathepsin E function molecule family (CD48) polymorphisms A/J 3H/HeJ & N H hepaticus Nu scid B6, FVB/N Mx1, Mx2 variation 28 IL10- Rag2- Some immune relevant B6 BALB/c DBA background strain genotypes Sclc11 MHC c5 Ahr ApoA2 Il3ra Rmcf OTHER (Nramp) oversimplified 129 H2 b ~~~~~~ Beware of substrain variations ~~~ Slc11a1R A H2 a Hc0 Ahrb-2 Apoa2c Il3ram1 Rmcfs Tnfrsf13c Bcmd1-A B6 BALB/c DBA A/J DBA/1 H2 q AKR H2 k Hc0 Ahrb-2 Apoa2a Il3ram1 Rmcfs H2 b H2 d DBA/2 H2 d BALB/c H2 d Ahrb-2 Apoa2b Slc11a1s BALB/cBy TH1 bias IL12 TH2 bias IL4 TH2 bias IL4 C3H More cell mediated More humoral response H2b-2 Ahrb-2 Apoa2b Slc11a1R Tlr4Lps-d C3H/HeJ InT-Hi NK more Ly49 Int-less NK NK lack THy1.1 C57BL/6J Apoa2a H2 b Ahrb-1 Slc11a1s Specif Klr NK complex Klrd1DBA/2J C57BL/6N (Dock2Hsd) DBA/1 H2 q Slc11a1s More macrophage Less macrophage Ahrd Rmcfr DBA/2 H2 d Hc0 Slc11a1R activity , TNFa, IL12, activity, TNFa, IL12, FVB/N H2 q Hc0 Ahrb-2 Apoa2b bacterial killing ; more bacterial killing ; more local/less systemic systemic & acute MRLlpr H2 k Il2m1 Foxq1sa-J Faslpr response phase response, NOD H2 g7 Hc0 Il2m1 Sirpa B6J / B6N variation in Il2m1 SJL/J H2s Ahrd Apoa2c Rmcfs Ceacam1Hv2-r Th17response FELASA 2014 recommendations Viral Agents Mice ‐ Viruses Top Few 3 month testing 1998 2003 2009 2001 2009 Annual testing – add: Jacoby & Livingston Pritchett 1. MHV FELASA Mahler 1. LCMV Lindsay * & al Corning 1 MHV > 70% MHV MHV MNV MNV 2. Mouse rotavirus (EDIM) 2. MAD1 (FL) 2 Parvos ~ 40% MRV (EDIM) Parvoviruses MHV MHV 3. Murine norovirus 3. MAD2 (K87) 3 TMEV ~ 35% Parvoviruses MRV (EDIM) Parvoviruses Parvoviruses 4. Parvoviruses (NS1) 4. Mousepox 4 MRV(EDIM) ~30% PVM SEN MRV (EDIM) MRV (EDIM) 5. MVM (Ectromelia) virus 5 Sen ~20% SEN TMEV TMEV TMEV 5. PVM 6 PVM ~20% TMEV 6. MPV 6. Reo3 *% of positive non–spf facilities by survey 7. TMEV 7. Sendai Norovirus (MNV) is fairly new to the list Sendai & PVM are less common – Isolation by ventilated caging ? http://www.uni-heidelberg.de/md/ibf/gesundzeugnis/hp-lab_anim-2014--178-92.pdf 37 [email protected] 2017 Page 3 of 42 2017 Brayton MICE INFECTIOUS Mouse Viruses Mouse viruses Similar findings & recommendations in different countries. Most common/likely (quarterly testing) Most ‘Prevalences’ seem pretty low (< 5%) ‐ or are they? 1. MNV = Mouse Norovirus (Calicivirus) Why test for an agent that’s not excluded? . NO disease expected in seropositive mice … 1. Less testing of positive areas fewer + 2. More testing to confirm negative status more – 2. MHV = Mouse hepatitis virus (Coronavirus) . 3. Outbreak testing more –(or more + ?) Disease unlikely in seropositive mice today . Usually detected by serology now, LIVIM = lethal intestinal virus of infant mice – NOT by obvious clinical disease… 3. Parvoviruses ‐ NO disease expected Surveillance (Sentinel & Quarantine testing) represent a lot of 4. MRV = Mouse Rotavirus (Type A rotavirus) time & $$£€ to test for agents that rarely kill, or even cause . EDIM = epizootic diarrhea of infant mice disease 5. TMEV (Gd7)= Theiler’s mouse encephalitis virus All infections immunomodulate, potentially impact diverse . NO disease expected –famous for ‘mouse polio ‘ research …. (paralysis in susceptible strains) 38 39 More viruses in mice MNV ‐ Murine Norovirus(es) Historical concerns that cause significant disease Calicivirus (MNV1‐4…..) Henderson & al 2008 – Sendai – Single Stranded RNA virus – Ectromelia virus – Human Noroviruses = primary cause of non bacterial human gastroenteritis Part of the genome (& Genetic engineers) Seroprevalence: 30%‐(60%?!) in research colonies – Retroviruses – 0‐ low in vendor production colonies Transmission: Fecal / oral In freezers, pet stores, or wild mice near you – Like other Norwalk viruses – Arterivirus – LCMV Competent mice – Seroconvert, no obvious disease Common – ‘emerging’ Immune deficient mice – USUALLY NO disease – Astroviruses small round enteric viruse… – Pneumonia,