Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Jun 1.
Published in final edited form as: Curr Opin Infect Dis. 2015 Jun;28(3):253–258. doi: 10.1097/QCO.0000000000000156

Host Factors that Contribute to Recurrent Staphylococcal Skin Infection

Christopher P Montgomery 1, Michael Z David 2,3, Robert S Daum 2
PMCID: PMC4414914  NIHMSID: NIHMS678845  PMID: 25887613

Abstract

Purpose of review

Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTI) in the United States and elsewhere. Recurrent infections occur frequently in patients with S. aureus SSTI, underscoring the need to better understand the nature of protective immunity against these infections. Here, we review recent findings concerning the host factors that predispose to S. aureus SSTI.

Recent findings

Recurrent infections occur in nearly half of all patients with S. aureus SSTI. Epidemiologic and environmental factors, such as exposure to health care, age, household contacts with S. aureus SSTI, and contaminated household fomites are associated with recurrence. The majority of the population has evidence of antistaphylococcal antibodies, but whether these are protective remains enigmatic. In contrast, recent clinical and experimental findings clearly highlight the critical roles of innate and T cell-mediated immunity in defense against these infections. S. aureus interferes with innate and adaptive immunity by a number of recently elucidated mechanisms.

Summary

Recurrent S. aureus SSTIs are common, suggesting incomplete or absent protective immunity among these patients. Our understanding of protective immunity against recurrent infections is incomplete, and further basic and translational investigation is urgently needed to design strategies to prevent and treat these infections.

Keywords: MRSA, skin infection, recurrence, antibody-mediated immunity, innate immunity, T cell-mediated immunity

INTRODUCTION

S. aureus is a commensal bacterium and a pathogen that causes a range of infections in health care settings and in the community, including sepsis, pneumonia, osteomyelitis, septic arthritis, bloodstream infection, and skin and soft tissue infection (SSTI) [1]. S. aureus is by far the most common cause of SSTI in the United States, and these infections represent an enormous burden, both in terms of financial and health-care related resources [2]. Recurrent SSTIs are common and the emergence of multi-drug resistant S. aureus isolates limits available antimicrobial therapies. A recent report documented that, among adults and children with a S. aureus SSTI in Chicago and Los Angeles, a recurrent SSTI was reported in 39% of patients within 3 months, and more than 50% within 6 months [3]. The extremely high rate of recurrence in this study is concordant with other reports [4] and underscores the need to better understand the host factors that predispose to recurrent infection.

TEXT OF REVIEW

Epidemiology of recurrent S. aureus SSTI – populations at risk

Although many risk factors for recurrent S. aureus SSTI have been identified, it is important to recognize that the vast majority of recurrent infections occur in individuals without identified risk factors. Individuals with persistent exposure to health care settings have a high rate of recurrent infections, which is likely due to a combination of health care exposure and the presence of comorbid conditions that predispose to S. aureus infections, such as diabetes mellitus, chronic renal failure requiring hemodialysis, and any condition necessitating surgical correction or palliation [5].

An important risk factor for recurrent infection is age: children may be particularly susceptible to recurrence. Of 95 children who were treated for a purulent SSTI at the Johns Hopkins ED in 2006–7, 22% had another SSTI within 3 months. It is possible that the genetic background of the infecting isolate or the antibiogram may have had an impact on the risk of recurrence because those with an initial MRSA infection were more likely than those with an MSSA infection to have a recurrence (28% vs. 5%) [6]. In one retrospective study, at least 5% of children with community-associated S. aureus infections had at least one recurrence; remarkably, more than 70% of these children had no known risk factors for recurrent infection, and fewer than 5% of the infections were not an SSTI [7]. In another study, recurrent infection (primarily SSTI) occurred in 50% of children with S. aureus SSTI within 12 months, compared with 22% of children with invasive S. aureus infection [4].

Although recurrent S. aureus SSTIs occur frequently in children, they are also common among adults. For example, recurrence rates among adults with a community-onset SSTI have been reported to be 21 – 50% [3,8]. Populations with increased frequency of recurrent S. aureus infection include incarcerated individuals [9], military personnel [10], men who have sex with men [11], and travellers to certain regions [12]. Environmental factors may also be important in recurrence; for example, recurrent infections in patients with a S. aureus SSTI were associated with contaminated household fomites and SSTI in household contacts [3].

Innate and adaptive immunity against S. aureus SSTI – Overview

Many interactions of S. aureus with host immunity have been well characterized. As is the case with many pathogens, innate immunity is the first line of defense against S. aureus. Innate defenses against cutaneous S. aureus infection include the barrier function of skin, antimicrobial peptides, complement, neutrophils, macrophages, and other innate immune cells, such as γδ T cells [13]. It is less well understood how (and if) the adaptive immune system reacts to S. aureus infection or colonization in order to shape memory responses that protect against recurrent infections. Adaptive immunity is traditionally classified into cell-mediated (T lymphocyte) and humoral (B lymphocyte/antibody) immunity. Vaccines against S. aureus infections have targeted humoral immunity, but the failure of several candidates despite high levels of vaccine-specific antibody among vaccinated individuals [14] demonstrates a need to better understand both the mechanisms of protective immunity and those employed by S. aureus to evade immune surveillance and defense.

Neutrophils as the first line of innate defense against primary S. aureus SSTI

Neutrophils have long been established as critical for defense against S. aureus SSTI. For example, chronic granulomatous disease or congenital neutropenia result in a high risk of recurrent infection [15]. Congruent with human disease, neutrophils are required for defense in a mouse model of S. aureus SSTI [16]. However, demonstrating a role for neutrophils is highly dependent on assay conditions, particularly in the presence of opsonizing antibody [17]. Moreover, the timing of the neutrophil response may be critical. For example, abrogation of integrin-mediated neutrophil crawling prior to infection worsened lesion severity in a mouse model of S. aureus SSTI, but abrogation shortly after infection improved outcomes [18]. This suggests that, although neutrophils are clearly critical to control S. aureus SSTI, a sustained neutrophil response may prevent resolution of infection.

Innate defenses against S. aureus SSTI – other considerations

Other recent mechanistic insights into important immune pathways include the identification of the proinflammatory interleukin (IL) -1β, acting via the IL-1R and the NALP3 inflammasome, as critical for defense against S. aureus SSTI [13]. The innate γδ T cells are a key source of IL-17 after S. aureus infection, and have been identified as critical in a mouse model of SSTI [13,19]. This role may be distinct from the role of IL-17 in adaptive immunity against S. aureus SSTI (discussed below). IL-33 increases the antibacterial capacity of dermal macrophages, and thereby promotes defense against S. aureus SSTI, by activation of inducible nitric oxide synthase [20]. At the same time, the IL-20 cytokine family, implicated in inflammatory skin diseases such as atopic dermatitis, suppresses IL-17 and IL-1β responses to promote S. aureus SSTI in mice [19].

The importance of innate immunity is highlighted by several recent reports documenting novel mechanisms by which S. aureus subverts innate defenses. For example, α-hemolysin (Hla) binds the cellular receptor ADAM10, thereby disrupting epithelial integrity in the skin, lung, and vascular endothelium [21]. Interestingly, the Hla-ADAM10 interaction in myeloid-lineage cells protects against S. aureus SSTI, but exacerbates S. aureus pneumonia [22], suggesting that the role of specific immune effector mechanisms may be highly dependent on the site and type of infection. Therefore, what is relevant in one model or infectious syndrome may not be in another. Hla also lyses perivascular macrophages, leading to decreased neutrophil transmigration and more severe skin lesions [23]. Other recently elucidated innate evasion mechanisms include S. aureus promoting neutrophil killing by binding to the chemokine receptors CXCR1 and CXCR2 via the leukotoxins LukED and HlgAB [24,25]. S. aureus toxins also bind the chemokine receptors CCR2 (HlgAB) and CCR5 (Panton Valentine leukocidin – PVL) [25,26]. PVL and HlgBC also interfere with complement-mediated innate immunity by binding to the complement receptors C5aR and C5L2 [25,27].

Adaptive immunity against S. aureus SSTIs – limitations of animal models

A key unanswered question is whether or not S. aureus SSTIs (or any S. aureus infections) elicit immunity that protects against recurrent infection. Because of the uncertainty resulting from clinical studies, there is an urgent need to better understand protective immunity in experimental models of S. aureus SSTI. Several mouse models of primary S. aureus SSTI in naïve animals have been reported. For example, subcutaneous or epicutaneous inoculation results in dermonecrotic lesions with underlying abscess formation that resemble infections in humans [28,29]. These models have proven invaluable for understanding the microbial determinants of virulence and innate immune responses. However, these models employ infection in mice that are immunologically naïve to S. aureus, a major limitation given the nearly ubiquitous presence of antistaphylococcal antibodies in the human population.

There are other important limitations to the mouse models. First, mice are probably not a natural reservoir of S. aureus, and are believed to be resistant to the effects of superantigens, limiting our ability to understand the contributions of these important virulence factors to the pathogenesis of these infections [30]. Second, the structure of mouse skin is different from human skin [31]. Third, there are important differences between human and mouse innate and adaptive immune responses, particularly when considering the role of innate immune cells such as γδ T cells [32]. However, the relatively low cost, availability, and the ability to interrogate host immune mechanisms through the use of genetically modified mice are significant advantages that must be considered.

Cell-mediated immunity

T lymphocytes are clearly important in adaptive immunity against S. aureus SSTI. For example, patients with the Hyper-IgE syndrome, characterized by defects in Th17/IL-17 immunity, are at high risk for recurrent skin and pulmonary infections [33]. These observations have led many to believe that targeting the Th17/IL-17 pathway will be essential to vaccine design. Along these lines, at least one candidate vaccine in preclinical evaluation, NDV-3, protects against S. aureus SSTI via IL-17A and the related T cell cytokine, IL-22 [34]. However, the mechanisms underlying recurrent staphylococcal disease in Hyper-IgE syndrome remain incompletely understood and are likely more complex than simply IL-17 deficiency; the immunodeficiency is actually comprised of a heterogenous collection of phenotypes caused by multiple genetic mutations [35].

In further support of a role for T cells in defense against S. aureus SSTI, patients with poorly controlled HIV (as assessed by low CD4+ T cell counts and high viral loads) frequently have recurrent SSTI [36], although there are conflicting data on the importance of CD4+ counts as a predictor of SSTI risk [37]. Patients with atopic dermatitis are also susceptible to S. aureus SSTI, which may be partly due to increased levels of Th2 cytokines and subsequent STAT6 expression, that may increase susceptibility to Hla-induced keratinocyte death [38].

A recently reported mouse model has provided experimental support for a role for T cells in protection against recurrent S. aureus SSTI. In this model, primary and secondary SSTI were separated by 8 weeks [39]. Interestingly, primary SSTI protected BALB/c, but not C57BL/6 mice against recurrent experimental SSTI, resulting in smaller skin lesions, a decrease in the number of bacteria recovered from the skin lesions, and attenuated local inflammation. Effector T cell mechanisms were critical, because protection occurred even in the absence of B cells and antibody, and adoptive transfer of T cells from S. aureus-infected BALB/c mice protected naïve mice. Primary SSTI elicited differential T cell polarization, with a Th17/IL-17A-biased response in BALB/c mice, compared with a Th1/IFNγ-biased response in C57BL/6 mice, suggesting opposing roles for Th17 and Th1 responses in protection. Indeed, neutralization of IL-17A abrogated protection, and neutralization of IFNγ enhanced protection.

In further support of a role for T cell-mediated immunity, Murphy et al reported that intraperitoneal infection of mice with S. aureus elicits γδ T cell-mediated protection against secondary infection [40]. Although γδ T cell-mediated protection against primary infection required IL-1 signaling, consistent with other reports documenting the importance of this cytokine in innate immune defense against S. aureus SSTI [13], IL-1 was dispensable for expansion of the memory γδ T cell population. These findings highlight the potential distinction between innate and adaptive mechanisms, and underscore the importance of investigating immune defenses in the setting of animals that have previously been exposed to S. aureus.

Antibody-mediated immunity

Whereas T cell-mediated immunity is clearly important in adaptive immunity against S. aureus, a role for antibody-mediated immunity has not been definitively established. Patients with defects in antibody-mediated immunity, such as X-linked hypogammaglobulinemia, may have increased risk of recurrent S. aureus SSTI, but this association is not entirely clear [41]. Natural antibodies against S. aureus in humans are detectable shortly after birth, but have not been demonstrated to be protective [42]. Furthermore, a substantial body of evidence suggests that infection elicits antibody responses in patients, but whether these are protective is not clear. Children with S. aureus SSTIs developed transient humoral responses that were not associated with protection against recurrent SSTI; however, invasive S. aureus infection elicited higher antibody levels against Hla, and these children had a lower risk of recurrent infection, suggesting a protective role for these antibodies [4]. Compared with healthy controls, children with invasive S. aureus infection, but not S. aureus SSTI, had higher levels of antibody against bicomponent leukotoxins, but it is not known if these are associated with protection against subsequent infection [43]. Therefore, it is clear that anti-staphylococcal antibodies are common in the population, regardless of known infection history, and that these antibody repertoires are not entirely protective.

In the mouse model of recurrent SSTI discussed above, adoptive transfer of serum and purified antibody from previously infected BALB/c mice protected naïve BALB/c and C57BL/6 mice against S. aureus SSTI, demonstrating a clear role for antibody-mediated immunity in this model [39]. Importantly, serum from infected C57BL/6 mice did not protect mice of either genetic background, suggesting that comparison of protective BALB/c and nonprotective C57BL/6 serum might identify antigen-specific protective antibody repertoires, an important direction for future research.

Another model of reinfection has recently been reported, in which primary SSTI with 1 × 107 CFU in C57BL/6 mice was followed 21 days later by secondary SSTI with 3–4 × 107 CFU [44]. Mice that were primarily infected with S. aureus had larger lesions after a second SSTI, compared with mice that were primarily infected with an isogenic S. aureus isolate in which Hla was deleted. There were no significant differences in the number of bacteria recovered from skin lesions 1 or 3 days after the second SSTI. Therapeutic delivery of a recombinant inactive Hla mutant or an ADAM10 inhibitor decreased the severity of secondary SSTI. These results support the hypothesis that Hla suppresses local inflammatory responses and the subsequent development of Th1 and Th17 responses [45].

Interfering with protective antibody?

The findings that some antibody responses may protect against S. aureus SSTI are difficult to reconcile with the notion that the nearly ubiquitous anti-staphylococcal antibody repertoire have not been demonstrated to be protective. One possible explanation is that only a limited antigen-specific repertoire is protective, and the majority of anti-staphylococcal antibodies are not protective. It appears that S. aureus is capable of patterning the host antibody response in order to favor nonprotective responses. For example, in a small study of patients with S. aureus infection (primarily SSTI), Pauli et al demonstrated that activation of B cells was limited, with a predominant bias toward those having specificity toward staphylococcal protein A (SpA), suggesting that this response limits development of antibody against other S. aureus antigens [46]. Therefore, it is plausible that this immunodominant response prevents the development of an otherwise protective antibody repertoire.

CONCLUSION

Recurrent S. aureus SSTI are extremely common, occurring in up to half of infected patients. Environmental and epidemiologic factors are clearly associated with recurrence, as are comorbid conditions. Clinical investigations have identified innate and T cell-mediated immunity as important mechanisms of protection against recurrent infection, but the role of antistaphylococcal antibodies, which are present in nearly all sampled individuals, is less clear. It is likely that S. aureus inhibits protective antibody responses, at least partly via protein A, with a resulting antibody response that is skewed toward a nonprotective repertoire. Several recently described animal models of recurrent infection show promise, and point to multiple mechanisms of defense against recurrent SSTI requiring both antibody- and T cell-mediated immunity. Additional investigation is necessary to define the nature of protective immunity elicited by S. aureus infections.

KEY POINTS.

  • Recurrent S. aureus SSTI is very common.

  • Most recurrent S. aureus SSTIs occur in patients without identified risk factors.

  • Innate immunity is the first line of defense against S. aureus SSTI.

  • T cell-mediated immunity is clearly important in adaptive defense against recurrent S. aureus SSTI.

  • The role of antibody-mediated immunity against recurrent S. aureus SSTI remains incompletely defined.

ACKNOWLEDGEMENTS

None.

Financial support and sponsorship.

This work was funded by the Department of Pediatrics at the University of Chicago (C.P.M.) and the National Institute for Allergy and Infectious Diseases (AI076596 to C.P.M., AI095361 to M.Z.D., AI067584 and AI103342 to R.S.D.).

R.S.D. reports serving as a paid consultant for Pfizer and receiving a research grant from Pfizer.

Footnotes

Conflicts of interest.

C.P.M. and M.Z.D. report no conflicts to declare.

REFERENCES

  • 1.David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev. 2010;23:616–687. doi: 10.1128/CMR.00081-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Ray GT, Suaya JA, Baxter R. Microbiology of skin and soft tissue infections in the age of community-acquired methicillin-resistant Staphylococcus aureus. Diagn Microbiol Infect Dis. 2013;76:24–30. doi: 10.1016/j.diagmicrobio.2013.02.020. [DOI] [PubMed] [Google Scholar]
  • 3. Miller LG, Eells SJ, David MZ, Ortiz N, Taylor AR, Kumar N, Cruz D, Boyle-Vavra S, Daum RS. Staphylococcus aureus Skin Infection Recurrences Among Household Members: An Examination of Host, Behavioral, and Pathogen-Level Predictors. Clin Infect Dis. 2014 doi: 10.1093/cid/ciu943. This is a comprehensive study of microbial, host, and environmental factors that influence recurrent S. aureus SSTI.
  • 4.Fritz SA, Tiemann KM, Hogan PG, Epplin EK, Rodriguez M, Al-Zubeidi DN, Bubeck Wardenburg J, Hunstad DA. A serologic correlate of protective immunity against community-onset Staphylococcus aureus infection. Clin Infect Dis. 2013;56:1554–1561. doi: 10.1093/cid/cit123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Lowy FD. Staphylococcus aureus infections. N Engl J Med. 1998;339:520–532. doi: 10.1056/NEJM199808203390806. [DOI] [PubMed] [Google Scholar]
  • 6.Chen AE, Cantey JB, Carroll KC, Ross T, Speser S, Siberry GK. Discordance between Staphylococcus aureus nasal colonization and skin infections in children. Pediatr Infect Dis J. 2009;28:244–246. doi: 10.1097/INF.0b013e31818cb0c4. [DOI] [PubMed] [Google Scholar]
  • 7.Bocchini CE, Mason EO, Hulten KG, Hammerman WA, Kaplan SL. Recurrent community-associated Staphylococcus aureus infections in children presenting to Texas Children's Hospital in Houston, Texas. Pediatr Infect Dis J. 2013;32:1189–1193. doi: 10.1097/INF.0b013e3182a5c30d. [DOI] [PubMed] [Google Scholar]
  • 8.Sreeramoju P, Porbandarwalla NS, Arango J, Latham K, Dent DL, Stewart RM, Patterson JE. Recurrent skin and soft tissue infections due to methicillin-resistant Staphylococcus aureus requiring operative debridement. Am J Surg. 2011;201:216–220. doi: 10.1016/j.amjsurg.2009.12.024. [DOI] [PubMed] [Google Scholar]
  • 9.David MZ, Mennella C, Mansour M, Boyle-Vavra S, Daum RS. Predominance of methicillin-resistant Staphylococcus aureus among pathogens causing skin and soft tissue infections in a large urban jail: risk factors and recurrence rates. J Clin Microbiol. 2008;46:3222–3227. doi: 10.1128/JCM.01423-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Leamer NK, Clemmons NS, Jordan NN, Pacha LA. Update: Community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infection surveillance among active duty military personnel at Fort Benning GA, 2008–2010. Mil Med. 2013;178:914–920. doi: 10.7205/MILMED-D-13-00082. [DOI] [PubMed] [Google Scholar]
  • 11.Szumowski JD, Wener KM, Gold HS, Wong M, Venkataraman L, Runde CA, Cohen DE, Mayer KH, Wright SB. Methicillin-resistant Staphylococcus aureus colonization, behavioral risk factors, and skin and soft-tissue infection at an ambulatory clinic serving a large population of HIV-infected men who have sex with men. Clin Infect Dis. 2009;49:118–121. doi: 10.1086/599608. [DOI] [PubMed] [Google Scholar]
  • 12.Artzi O, Sinai M, Solomon M, Schwartz E. Recurrent Furunculosis in Returning Travelers: Newly Defined Entity. J Trav Med. 2014 doi: 10.1111/jtm.12151. [DOI] [PubMed] [Google Scholar]
  • 13.Miller LS, Cho JS. Immunity against Staphylococcus aureus cutaneous infections. Nat Rev Immunol. 2011;11:505–518. doi: 10.1038/nri3010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Daum RS, Spellberg B. Progress toward a Staphylococcus aureus vaccine. Clin Infect Dis. 2012;54:560–567. doi: 10.1093/cid/cir828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Holland SM. Chronic granulomatous disease. Clin Rev Allergy Immunol. 2010;38:3–10. doi: 10.1007/s12016-009-8136-z. [DOI] [PubMed] [Google Scholar]
  • 16.Molne L, Verdrengh M, Tarkowski A. Role of neutrophil leukocytes in cutaneous infection caused by Staphylococcus aureus. Infect Immun. 2000;68:6162–6167. doi: 10.1128/iai.68.11.6162-6167.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Lu T, Porter AR, Kennedy AD, Kobayashi SD, DeLeo FR. Phagocytosis and killing of Staphylococcus aureus by human neutrophils. J Innate Immun. 2014;6:639–649. doi: 10.1159/000360478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Harding MG, Zhang K, Conly J, Kubes P. Neutrophil Crawling in Capillaries; A Novel Immune Response to Staphylococcus aureus. PLoS Pathog. 2014;10:e1004379. doi: 10.1371/journal.ppat.1004379. This study identifies a novel mechanism by which neutrophils migrate toward S. aureus infections and suggests that the importance of neutrophils in defense against S. aureus is highly dependent on the timing of the neutrophil response.
  • 19. Myles IA, Fontecilla NM, Valdez PA, Vithayathil PJ, Naik S, Belkaid Y, Ouyang W, Datta SK. Signaling via the IL-20 receptor inhibits cutaneous production of IL-1beta and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus. Nat Immunol. 2013;14:804–811. doi: 10.1038/ni.2637. This study establishes the importance of the IL-20 family of cytokines in inhibiting protective proinflammatory IL-1β and IL-17A responses in a mouse model of S. aureus SSTI.
  • 20. Li C, Li H, Jiang Z, Zhang T, Wang Y, Li Z, Wu Y, Ji S, Xiao S, Ryffel B, et al. Interleukin-33 increases antibacterial defense by activation of inducible nitric oxide synthase in skin. PLoS Pathog. 2014;10:e1003918. doi: 10.1371/journal.ppat.1003918. This study establishes a role for IL-33 and inducible nitric oxide synthase in defense against S. aureus SSTI.
  • 21.Berube BJ, Bubeck Wardenburg J. Staphylococcus aureus alpha-toxin: nearly a century of intrigue. Toxins. 2013;5:1140–1166. doi: 10.3390/toxins5061140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Becker RE, Berube BJ, Sampedro GR, Dedent AC, Bubeck Wardenburg J. Tissue-Specific Patterning of Host Innate Immune Responses by Staphylococcus aureus alpha-Toxin. J Innate Immun. 2014 doi: 10.1159/000360006. This work demonstrates that α-toxin-ADAM10 interactions in myeloid-lineage cells have different effects depending on the site of S. aureus infection.
  • 23. Abtin A, Jain R, Mitchell AJ, Roediger B, Brzoska AJ, Tikoo S, Cheng Q, Ng LG, Cavanagh LL, von Andrian UH, et al. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat Immunol. 2014;15:45–53. doi: 10.1038/ni.2769. Using multiphoton intravital microscopy, this work demonstrates that perivascular macrophages are a key source of neutrophil chemoattractants and are important in neutrophil migration toward S. aureus infection, a process that is interfered with by α-toxin.
  • 24. Reyes-Robles T, Alonzo F, 3rd, Kozhaya L, Lacy DB, Unutmaz D, Torres VJ. Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection. Cell Host Microbe. 2013;14:453–459. doi: 10.1016/j.chom.2013.09.005. This study establishes that leukotoxin ED binds CXCR1 and CXCR2 and promotes neutrophil killing, thereby enhancing the pathogenesis of S. aureus infection.
  • 25. Spaan AN, Vrieling M, Wallet P, Badiou C, Reyes-Robles T, Ohneck EA, Benito Y, de Haas CJ, Day CJ, Jennings MP, et al. The staphylococcal toxins gamma-haemolysin AB and CB differentially target phagocytes by employing specific chemokine receptors. Nat Commun. 2014;5:5438. doi: 10.1038/ncomms6438. This work identifies the cellular receptors of the γ-toxins AB and CB, providing a likely explanation for differential toxin targeting of specific cell types.
  • 26.Alonzo F, 3rd, Kozhaya L, Rawlings SA, Reyes-Robles T, DuMont AL, Myszka DG, Landau NR, Unutmaz D, Torres VJ. CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature. 2013;493:51–55. doi: 10.1038/nature11724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Spaan AN, Henry T, van Rooijen WJ, Perret M, Badiou C, Aerts PC, Kemmink J, de Haas CJ, van Kessel KP, Vandenesch F, et al. The staphylococcal toxin Panton-Valentine Leukocidin targets human C5a receptors. Cell Host Microbe. 2013;13:584–594. doi: 10.1016/j.chom.2013.04.006. [DOI] [PubMed] [Google Scholar]
  • 28.Malachowa N, Kobayashi SD, Braughton KR, DeLeo FR. Mouse model of Staphylococcus aureus skin infection. Meth Mol Biol. 2013;1031:109–116. doi: 10.1007/978-1-62703-481-4_14. [DOI] [PubMed] [Google Scholar]
  • 29.Prabhakara R, Foreman O, De Pascalis R, Lee GM, Plaut RD, Kim SY, Stibitz S, Elkins KL, Merkel TJ. Epicutaneous model of community-acquired Staphylococcus aureus skin infections. Infect Immun. 2013;81:1306–1315. doi: 10.1128/IAI.01304-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Salgado-Pabon W, Schlievert PM. Models matter: the search for an effective Staphylococcus aureus vaccine. Nature reviews. Microbiology. 2014;12:585–591. doi: 10.1038/nrmicro3308. [DOI] [PubMed] [Google Scholar]
  • 31.Abdullahi A, Amini-Nik S, Jeschke MG. Animal models in burn research. Cell Mol Life Sci. 2014;71:3241–3255. doi: 10.1007/s00018-014-1612-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Chien YH, Meyer C, Bonneville M. Gamma delta T cells: first line of defense and beyond. Annu Rev Immunol. 2014;32:121–155. doi: 10.1146/annurev-immunol-032713-120216. [DOI] [PubMed] [Google Scholar]
  • 33.Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452:773–776. doi: 10.1038/nature06764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Yeaman MR, Filler SG, Chaili S, Barr K, Wang H, Kupferwasser D, Hennessey JP, Jr, Fu Y, Schmidt CS, Edwards JE, Jr, et al. Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection. Proc Natl Acad Sci U S A. 2014;111:E5555–5563. doi: 10.1073/pnas.1415610111. This study demonstrates that the NDV-3 vaccine mediates protection against S. aureus SSTI via T cell-mediated mechanisms.
  • 35.Marodi L, Cypowyj S, Toth B, Chernyshova L, Puel A, Casanova JL. Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species. J Allergy Clin Immunol. 2012;130:1019–1027. doi: 10.1016/j.jaci.2012.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Vyas KJ, Shadyab AH, Lin CD, Crum-Cianflone NF. Trends and factors associated with initial and recurrent methicillin-resistant Staphylococcus aureus (MRSA) skin and soft-tissue infections among HIV-infected persons: an 18-year study. J Int Assoc Prov AIDS Care. 2014;13:206–213. doi: 10.1177/2325957412473780. [DOI] [PubMed] [Google Scholar]
  • 37.Hemmige V, McNulty M, Silverman E, David MZ. Predictors of skin and soft tissue infections in HIV-infected outpatients in the community-associated methicillin-resistant Staphylococcus aureus era. Eur J Clin Microbiol Infect Dis. 2014 doi: 10.1007/s10096-014-2237-1. [DOI] [PubMed] [Google Scholar]
  • 38.Brauweiler AM, Goleva E, Leung DY. Th2 cytokines increase Staphylococcus aureus alpha toxin-induced keratinocyte death through the signal transducer and activator of transcription 6 (STAT6) J Invest Dermatol. 2014;134:2114–2121. doi: 10.1038/jid.2014.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Montgomery CP, Daniels M, Zhao F, Alegre ML, Chong AS, Daum RS. Protective immunity against recurrent Staphylococcus aureus skin infection requires antibody and interleukin-17A. Infect Immun. 2014;82:2125–2134. doi: 10.1128/IAI.01491-14. This study establishes a mouse model of recurrent S. aureus SSTI and demonstrates that antibody and IL-17A are important in adaptive immunity against recurrent SSTI and that protective immunity is dependent on the genetic background of the mouse.
  • 40. Murphy AG, O'Keeffe KM, Lalor SJ, Maher BM, Mills KH, McLoughlin RM. Staphylococcus aureus infection of mice expands a population of memory gamma delta T cells that are protective against subsequent infection. J Immunol. 2014;192:3697–3708. doi: 10.4049/jimmunol.1303420. This study demonstrates that γδ T cells have an important role in recall responses in a mouse model of recurrent S. aureus peritoneal infection.
  • 41.Chan HY, Yang YH, Yu HH, Chien YH, Chiang LL, Chiang BL. Clinical characteristics and outcomes of primary antibody deficiency: a 20-year follow-up study. J Formos Med Assoc. 2014;113:340–348. doi: 10.1016/j.jfma.2012.07.005. [DOI] [PubMed] [Google Scholar]
  • 42.Verkaik NJ, Lebon A, de Vogel CP, Hooijkaas H, Verbrugh HA, Jaddoe VW, Hofman A, Moll HA, van Belkum A, van Wamel WJ. Induction of antibodies by Staphylococcus aureus nasal colonization in young children. Clin Microbiol Infect. 2010;16:1312–1317. doi: 10.1111/j.1469-0691.2009.03073.x. [DOI] [PubMed] [Google Scholar]
  • 43.Thomsen IP, Dumont AL, James DB, Yoong P, Saville BR, Soper N, Torres VJ, Creech CB. Children with invasive Staphylococcus aureus disease exhibit a potently neutralizing antibody response to the cytotoxin LukAB. Infect Immun. 2014;82:1234–1242. doi: 10.1128/IAI.01558-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Sampedro GR, Dedent AC, Becker RE, Berube BJ, Gebhardt M, Cao H, Bubeck Wardenburg J. Targeting Staphylococcus aureus alpha-toxin as a novel approach to reduce severity of recurrent skin and soft tissue infections. J Infect Dis. 2014 doi: 10.1093/infdis/jiu223. This study establishes a mouse model of recurrent S. aureus SSTI and demonstrates the importance of α-toxin in interfering with adaptive immunity.
  • 45.Tkaczyk C, Hamilton MM, Datta V, Yang XP, Hilliard JJ, Stephens GL, Sadowska A, Hua L, O'Day T, Suzich J, et al. Staphylococcus aureus alpha toxin suppresses effective innate and adaptive immune responses in a murine dermonecrosis model. PLoS One. 2013;8:e75103. doi: 10.1371/journal.pone.0075103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Pauli NT, Kim HK, Falugi F, Huang M, Dulac J, Dunand CH, Zheng NY, Kaur K, Andrews SF, Huang Y, et al. Staphylococcus aureus infection induces protein A-mediated immune evasion in humans. J Exp Med. 2014 doi: 10.1084/jem.20141404. This work demonstrates that the B cell repertoire of patients acutely infected with S. aureus are skewed toward anti-protein A responses, suggsting that protein A activity leads to immunodominance and interference with antibody responses against other S. aureus antigens.

RESOURCES