pathogens Review Bacteria and Host Interplay in Staphylococcus aureus Septic Arthritis and Sepsis Tao Jin 1,2,* , Majd Mohammad 1 , Rille Pullerits 1,2,3 and Abukar Ali 1 1 Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 46 Gothenburg, Sweden; [email protected] (M.M.); [email protected] (R.P.); [email protected] (A.A.) 2 Department of Rheumatology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden 3 Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden * Correspondence: [email protected] Abstract: Staphylococcus aureus (S. aureus) infections are a major healthcare challenge and new treatment alternatives are needed. S. aureus septic arthritis, a debilitating joint disease, causes permanent joint dysfunction in almost 50% of the patients. S. aureus bacteremia is associated with higher mortalities than bacteremia caused by most other microbes and can develop to severe sepsis and death. The key to new therapies is understanding the interplay between bacterial virulence factors and host immune response, which decides the disease outcome. S. aureus produces numerous virulence factors that facilitate bacterial dissemination, invasion into joint cavity, and cause septic arthritis. Monocytes, activated by several components of S. aureus such as lipoproteins, are responsible for bone destructions. In S. aureus sepsis, cytokine storm induced by S. aureus components leads to the hyperinflammatory status, DIC, multiple organ failure, and later death. The immune suppressive therapies at the very early time point might be protective. However, the timing of treatment is crucial, Citation: Jin, T.; Mohammad, M.; Pullerits, R.; Ali, A. Bacteria and Host as late treatment may aggravate the immune paralysis and lead to uncontrolled infection and death. Interplay in Staphylococcus aureus Septic Arthritis and Sepsis. Pathogens Keywords: Staphylococcus aureus; septic arthritis; sepsis; virulence factors; immunity 2021, 10, 158. https://doi.org/ 10.3390/pathogens10020158 Academic Editors: Seav-ly Tran, 1. S. aureus and Its Virulence Factors Priscilla Branchu, Grégory Jubelin Nearly half of the human population is at some point colonized by Staphylococcus and Nicolas Personnic aureus (S. aureus). Of these, 20% are persistently colonized while around 30% are intermit- Received: 30 December 2020 tently colonized, mostly in the anterior nares and the skin [1]. However, one should not Accepted: 30 January 2021 make the mistake of assuming that S. aureus is a harmless microbe that is only part of the Published: 3 February 2021 normal flora. Rather, S. aureus is indeed a very virulent bacteria that causes a wide range of diseases, from simple wound infections and food poisoning to life-threatening conditions Publisher’s Note: MDPI stays neutral such as sepsis, meningitis, and endocarditis [2]. In this review, we focus on septic arthritis with regard to jurisdictional claims in and sepsis, which are two of the many severe infections caused by S. aureus. published maps and institutional affil- S. aureus is a very resilient pathogen due to the various virulence factors it contains iations. and produces, some of which are described below and illustrated in Figure1. The biological function of S. aureus virulence factors and their roles in infections are summarized in Table1 , reviewed in [3]. Copyright: © 2021 by the authors. 1.1. Cell Wall Components Licensee MDPI, Basel, Switzerland. S. aureus expresses a capsular polysaccharide (CP) that functions as a virulent factor, This article is an open access article enabling the bacteria to evade phagocytosis [4]. Several serotypes of the CP have been distributed under the terms and identified and of those, CP5 and CP8 are the major ones. Most of the clinical isolates of conditions of the Creative Commons S. aureus S. aureus Attribution (CC BY) license (https:// have the capability to produce either CP5 or CP8 [4]. strains expressing creativecommons.org/licenses/by/ the CP5 capsule significantly increase mortality and arthritis frequency and severity in 4.0/). S. aureus induced sepsis and septic arthritis, respectively, compared to the strains lacking Pathogens 2021, 10, 158. https://doi.org/10.3390/pathogens10020158 https://www.mdpi.com/journal/pathogens Pathogens 2021, 10, 158 2 of 25 the CP5 capsule [5]. This can be due to the downregulatory effects of CP5 on the uptake and intracellular killing ability of the phagocytes [5]. The CP8 serotype seems to be less virulent Pathogens 2021, 10, x FOR PEER REVIEW than the CP5 serotype as demonstrated by the ability of CP5 to cause higher bacteremia2 of 25 than the CP8 serotype in a mouse model of bacteremia. The CP5 producing strain also exhibited greater resistance to in vitro opsonophagocytic killing by neutrophils compared to the CP8 serotype [6]. Figure 1. Schematic diagram illustrating the basic structure of Staphylococcus aureus and its ability to express various virulence factors. TSST-1 = Toxic shock syndrome toxin-1, Clfs = clumping factors, FnBPs = fibronectin binding proteins, Cna = Collagen adhesin, Lpp = lipoproteins, vWbp = von Willebrand factor-binding protein. The cell wall of S. aureus is made up of a 20–30 nm thick layer of peptidoglycan (PGN). Figure 1. Schematic diagram illustratingApart from the beingbasic structure a protective of Staphylococcus barrier of the aureus bacteria, and PGNits ability has otherto express functions various such vir- as Pathogens 2021, 10, x FOR PEER REVIEW 3 of 25 ulence factors. TSST-1 = Toxic shockbeing syndrome a scaffold, toxin-1, whereby Clfs surface = clumping proteins factors, that areFnBPs fundamental = fibronectin for binding bacterial proteins, virulence Cna can = Collagen adhesin, Lpp = lipoproteins,attach [ 7vWbp]. The = major von Willebrand structural featuresfactor-binding of PGN protein. consist of linear glycan strands made up of alternating N-acetylglucosamine and N-acetylmuramic acid residues that are linked 1.1. Cellbybyβ Wall-1-4 β-1 - bondsComponents4 bonds [8 ].[8] The. The glycan glycan strands strands are are cross-linked cross-linked byby shortshort peptidespeptides made up of D- D-alanine,alanine, L-lysine,L-lysine, D-glutamicD-glutamic acid,acid, andand L-alanineL-alanine [[99].]. The ɛ--aminoamino groups L-lysineL-lysine of ofS. nearbyaureus peptidesexpressespeptides areare a cross-linked capsularcross-linked polysaccharide to to D-alanine D-alanine of (CP)of other other that peptides peptides functions through through as a pentaglycine virulent pentaglycine factor, enablingbridges,bridges, the thus bacteria thus giving giving to rise evade rise to theto thephagocytosis 3-dimensional 3-dimensional structure[4]. structure Several of theof serotypes the PGN PGN [10 ].[10of Due ].the Due to CP theto thehave critical critical been identifiedrolerole it playsand it plays of in those, maintainingin maintaining CP5 and bacterial bacterialCP8 are structure, structure,the ma growth,jor growth ones. and ,Most and viability, viability, of the PGN clinical PGN is ais targetisolates a target for offor S. aureusantibiotics antibioticshave the and capability and for for the the immune toimmune prod system.uce system. either Nod-likeNod CP5-like or receptors CP8 [4]. (NLRs), (NLRs),S. aureus mannose mannose-binding strains-binding expressing lec- the CP5lectin,tin capsule, andand lysozymelysozyme significantly areare some some increase of of the the components mortalitycomponents and of of the arthritisthe immune immune frequency system system that thatand can can severity recognize recognize in S. aureusand andinduced target target PGN sepsis PGN [11 [ ].11and PGN]. PGN septic is ais strong aarthritis, strong inducer inducer resp ofectively, inflammationof inflammation compared and and stimulates to stimulates the strains the the release releaselacking of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin the CP5of capsule proinflammatory [5]. This cancytokines be due such to theas t umordownregulatory necrosis factor effects alpha of ( TNFCP5- αon), ithenterleukin uptake and intracellular(IL)-1β, and killing IL-6. Furthermore, ability of the studies phagocytes have shown [5]. thatThe PGN CP8 alone serotype can induce seems arthritis to be less in mice [12] and repetitive inhalation of PGN components can lead to bone loss [13]. How- virulent than the CP5 serotype as demonstrated by the ability of CP5 to cause higher bac- ever, compared to an extremely potent effect of S. aureus lipoproteins (Lpps) the proin- teremiaflammatory than the CP8 capacity serotype of PGN in ais mouse mild and model transient of bacteremia. [14]. The CP5 producing strain also exhibitedBesides, greater secondary resistance modifications to in vitro of opsonophagocytic the PGN cell wall are killing of vital by importance neutrophils in order com- pared toto theresist CP8 host serotype immune [6].response enforcements [15]. Antibacterial enzymes produced by the Thehost, cell such wall as oflysozyme, S. aureus also is known made asup muramidase, of a 20–30 cannm cleave thick PGNlayer in of the peptidoglycan β-1,4 linkage (PGN).site Apart locali fromzed beingbetween a protective the sugar residuesbarrier of of the N-acetylglucosamine bacteria, PGN has and other N- acetylmuramicfunctions such as beingacid, a scaffold, thereby inhibitingwhereby surfacebacterial proteins overgrowth that [ 15are]. However,fundamental S. aureus