Recurrent infections and immune evasion strategies of Staphylococcus aureus
Highlights
► Staphylococcus aureus causes recurrent infections without eliciting immunity. ► Escape from protective immunity involves staphylococcal spa, sbi and adsA genes. ► Interference of B cell development is blocked by antibodies against protein A (SpA). ► SpA and Sbi interfere with staphylococcal opsonophagocytic killing. ► Adenosine synthase (AdsA) dampens immune responses by providing a host signal.
Introduction
The Gram-positive pathogen Staphylococcus aureus causes a wide swath of human diseases including skin and soft tissue infections (SSTI) and invasive diseases that lead to bacteremia, sepsis, endocarditis or pneumonia [1]. S. aureus colonizes the skin and nares of 20–30% of the human population [2]. Owing to the frequent use of antibiotics, S. aureus strains have evolved resistance against the most abundantly used therapeutics [3]. These drug-resistant strains are historically referred to as methicillin-resistant S. aureus (MRSA) [4]. Infections with methicillin-sensitive S. aureus (MSSA) or MRSA originate both in the community and in hospitals [5, 6]. The therapy of severe MRSA infections is complicated by the fact that these strains are susceptible to only few antimicrobials—vancomycin, daptomycin or linezolid [5]. Because of the severity of invasive disease, MRSA infections are associated with a poor outcome even when appropriate antibiotic therapies have been implemented [7, 8]. A key feature of staphylococcal SSTI is its recurrence, which occurs in approximately 30% of all cases. These clinical observations as well as experiments with animals that had been repeatedly challenged with S. aureus suggest that infections with this pathogen do not generate protective immune responses [9, 10••]. The current epidemic of community- and hospital-acquired MRSA infections in developed and developing countries is testimony for the successful spread and immune evasive attributes of this pathogen [11]. Here we review what is known about the immune evasive strategies of S. aureus.
Section snippets
Staphylococcal immune evasion strategies—an overview
Upon entry into subepidermal tissues or blood, S. aureus encounters the cellular and proteinaceous elements of host innate immune defenses. S. aureus is uniquely programmed to compromise the effectiveness of both components by secreting proteins that inhibit complement deposition or activation as well as the chemotaxis of polymorphonuclear leukocytes (neutrophils) [12, 13•, 14•, 15, 16••, 17]. Other secreted polypeptides display lytic activities towards neutrophils, the primary line of defense
Controlling inflammation—adenosine synthase A (AdsA)
Adenosine synthase A is an immune evasion factor that was initially identified in a genetic screen probing for the relative contributions of cell wall anchored surface proteins towards staphylococcal survival in blood [43••]. Both wild-type and adsA variants are phagocytosed by neutrophils when inoculated into fresh blood, however wild-type S. aureus survives within neutrophils whereas adsA mutants are killed [43••]. Similar to SpA, AdsA is synthesized as a precursor with an N-terminal signal
Protein A
Staphylococcal protein A is an abundant cell wall anchored surface protein, initially discovered as a bacterial trait to precipitate immunoglobulins [59]. Later studies demonstrated that SpA binds tightly to the complement binding (Fcγ) portion of IgG [60] and also stimulates B lymphocyte proliferation [61], provoking their clonal expansion and subsequent cell death [37, 62] (Figure 1b). SpA molecules of staphylococcal isolates carry four or five 56–61 residue Ig binding domains (IgBDs) [63].
Therapeutic and preventive strategies to tame staphylococcal immune evasion
As is outlined above, staphylococci deploy a wide spectrum of strategies to avoid innate immune attacks such as complement deposition and killing by neutrophils. The complexity and functional redundancy of factors engaged in innate immune evasion renders the development of therapeutic or preventive approaches arduous. Similarly, variability of an immune-modulatory trait among S. aureus strains is an exclusion criterion for vaccine development. In contrast to most genes in the IEC clusters, SpA,
Future prospects
Rapid spread of antibiotic resistance traits among S. aureus isolates as well as the acquisition of enhanced virulence attributes have precipitated a public health crisis that can no longer be addressed with the development of new antibiotics alone [81]. Several recent efforts have been directed towards the development of staphylococcal vaccines [82, 83, 84, 85, 86]. Although several staphylococcal antigens have shown promise in preclinical trials, those subjected to protective efficacy
Competing interests
The authors declare a conflict of interests as inventors of patent applications that are related to the development of Staphylococcus aureus vaccines and are currently under commercial license.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID), Infectious Diseases Branch (AI52474, AI92711 and AI52767). D.M.M. and O.S. acknowledge membership within and support from the Region V ‘Great Lakes’ Regional Center of Excellence in Biodefense and Emerging Infectious Diseases Consortium (NIH Award 1-U54-AI-057153). V.T. acknowledges support from the American Heart Association postdoctoral fellowship 10POST4590023.
References (88)
- et al.
What determines nasal carriage of Staphylococcus aureus?
Trends Microbiol
(2001) - et al.
Anti-opsonic properties of staphylokinase
Microbes Infect
(2005) - et al.
The innate immune modulators staphylococcal complement inhibitor and chemotaxis inhibitory protein of Staphylococcus aureus are located on beta-hemolysin-converting bacteriophages
J Bacteriol
(2006) - et al.
Egc-encoded superantigens from Staphylococcus aureus are neutralized by human sera much less efficiently than are classical staphylococcal enterotoxins or toxic shock syndrome toxin
Infect Immun
(2004) - et al.
Survival of Staphylococcus aureus inside neutrophils contributes to infection
J Immunol
(2000) - et al.
Effect of the carbocyclic nucleoside analogue MDL 201,112 on inhibition of interferon-gamma-induced priming of lewis (LEW/N) rat macrophages for enhanced respiratory burst and MHC class II Ia+ antigen expression
J Leukoc Biol
(1994) - et al.
Binding of immunoglobulins to protein a and immunoglobulin levels in mammalian sera
J Immunol Methods
(1983) - et al.
Lymphocyte stimulation by protein a of Staphylococcus aureus
Eur J Immunol
(1976) - et al.
Crystal structure of a Staphylococcus aureus protein a domain complexed with the fab fragment of a human igm antibody: structural basis for recognition of B-cell receptors and superantigen activity
Proc Natl Acad Sci USA
(2000) - et al.
The Sbi protein is a multifunctional immune evasion factor of Staphylococcus aureus
Infect Immun
(2011)