The Staphylococcus aureus Map protein is an immunomodulator that interferes with T cell–mediated responses

Lee, Lawrence Y.; Miyamoto, Yuko; McIntyre, Bradley W.; Höök, Magnus; McCrea, Kirk W.; McDevitt, Damien; Brown, Eric L.

doi:10.1172/jci200216318

Cited by 19 publications

(13 citation statements)

References 53 publications

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“…Staphylococcal abscesses mature over weeks and, following rupture and release into the peritoneal cavity, lead to new infectious lesions (stage 4). Mutations in eap have no effect on staphylococcal load or early abscess formation (d 5); however, these variants are defective in persistence and are, therefore, assigned to stage 4 (35). Notably, C57/BL6 mice, as well as BALB/c mice, are unable to clear S. aureus from their tissues and eventually succumb to infection.…”

Section: Discussionmentioning

confidence: 99%

Genetic requirements forStaphylococcus aureusabscess formation and persistence in host tissues

et al. 2009

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Staphylococcus aureus infections are associated with abscess formation and bacterial persistence; however, the genes that enable this lifestyle are not known. We show here that following intravenous infection of mice, S. aureus disseminates rapidly into organ tissues and elicits abscess lesions that develop over weeks but cannot be cleared by the host. Staphylococci grow as communities at the center of abscess lesions and are enclosed by pseudocapsules, separating the pathogen from immune cells. By testing insertional variants in genes for cell wall-anchored surface proteins, we are able to infer the stage at which these molecules function. Fibrinogen-binding proteins ClfA and ClfB are required during the early phase of staphylococcal dissemination. The heme scavenging factors IsdA and IsdB, as well as SdrD and protein A, are necessary for abscess formation. Envelope-associated proteins, Emp and Eap, are either required for abscess formation or contribute to persistence. Fluorescence microscopy revealed Eap deposition within the pseudocapsule, whereas Emp was localized within staphylococcal abscess communities. Antibodies directed against envelope-associated proteins generated vaccine protection against staphylococcal abscess formation. Thus, staphylococci employ envelope proteins at discrete stages of a developmental program that enables abscess formation and bacterial persistence in host tissues.

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Section: Discussionmentioning

confidence: 99%

Genetic requirements forStaphylococcus aureusabscess formation and persistence in host tissues

et al. 2009

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“…Several studies have reported that toxic shock syndrome toxins (TSST) can alter T cell functions by targeting the T cell receptor (TCR) activation pathway (Llewelyn & Cohen, 2002). By its ability to interfere with antigen presentation mediated by MHC class II, the extracellular adherent protein (Eap) may exert an important role in subverting the adaptive immune response (Lee et al, 2002). Furthermore, staphylococcal protein A was shown to modulate B cell functions (Goodyear & Silverman, 2004).…”

Section: Introductionmentioning

confidence: 99%

The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen‐reactivity to in vivo anergy

et al. 2011

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Staphylococcus aureus is an important human pathogen that can cause long-lasting persistent infections. The mechanisms by which persistent infections are maintained involve both bacterial escape strategies and modulation of the host immune response. So far, the investigations in this area have focused on strategies used by S. aureus to persist within the host. Here, we used an experimental mouse model to investigate the host response to persistent S. aureus infection. Our results demonstrated that T cells, which are critical for controlling S. aureus infection, gradually lost their ability to respond to antigenic stimulation and entered a state of anergy with the progression of infection towards persistence. The T cell hyporesponsiveness was reverted by co-stimulation with the phorbol ester PMA, an activator of protein kinase C, suggesting that a failure in the T cell receptor (TCR)-proximal signalling events underlie the hyporesponsive phenotype. The presence of these anergic antigen-specific T cells may contribute to the failure of the host immune response to promote sterilizing immunity during persistent S. aureus infection and also offers new possibilities for novel immunotherapeutic approaches.

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“…In accordance with our previous findings on eap transcription (Joost et al, 2009), here, we observed that patients with deep infections showed significantly higher anti-Eap titers than patients with superficial infection. Eap is known for its adhesive properties and has often been assigned a role in chronic infections (Lee et al, 2002;Harraghy et al, 2003;Athanasopoulos et al, 2006). We found that patients with long-lasting infections like abscesses or spondylodiscitis exhibited high antibody titers against Eap.…”

Section: Discussionmentioning

confidence: 99%

Antibody response to the extracellular adherence protein (Eap) ofStaphylococcus aureusin healthy and infected individuals

Joost

Jacob

Utermöhlen

et al. 2011

FEMS Immunol Med Microbiol

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The extracellular adherence protein (Eap) from Staphylococcus aureus has been suggested as a vaccine candidate and for therapeutic use due to its immunomodulating and antiangiogenic properties; however, little is known about anti-Eap antibodies in humans. We determined anti-Eap antibody titers by enzyme-linked immunosorbent assay and Western blot and measured serum samples from 92 patients with proven S. aureus infections and 93 healthy controls. The functionality of antibodies was assessed by a phagocytosis assay using Eap-coated fluorescent microspheres. Antibodies were detected in all human samples, but not in mice. Patients showed significantly higher titers than controls [immunoglobulin M (IgM), P=0.007; IgG, P<0.0001]. Patients with deep or severe infections showed higher titers than those with superficial or mild disease. Eap alone was sufficient to promote phagocytosis by peripheral blood mononuclear cell and granulocytes that was moderately enhanced in the presence of human serum, but no correlation was found with the levels of anti-Eap antibodies. Anti-Eap antibodies are prevalent in all tested humans and correlate with the severity of S. aureus infection; however, they do not seem to provide protection against invasive infections. Before considering Eap for therapy or as a vaccine candidate, further studies are warranted to assess the impact of the interference between Eap and its specific antibodies.

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The Staphylococcus aureus Map protein is an immunomodulator that interferes with T cell–mediated responses

Cited by 19 publications

References 53 publications

Genetic requirements forStaphylococcus aureusabscess formation and persistence in host tissues

Genetic requirements forStaphylococcus aureusabscess formation and persistence in host tissues

The dynamics of T cells during persistent Staphylococcus aureus infection: from antigen‐reactivity to in vivo anergy

Antibody response to the extracellular adherence protein (Eap) ofStaphylococcus aureusin healthy and infected individuals

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