A Serologic Correlate of Protective Immunity Against Community-Onset Staphylococcus aureus Infection

Staphylococcus aureus is a versatile organism that commonly exists as a benign commensal of human skin, seamlessly transitioning to an invasive pathogen that causes primary and recurrent skin and soft tissue infections (SSTI), pneumonia, bone and joint infections, bacteremia, and sepsis. As a leading infectious cause of human morbidity and mortality, S. aureus is a premier target for vaccine and immunotherapy development. Success has been elusive owing to the complexity of the organism and a lack of knowledge of the desired immunoprotection signature in the human population. Pressing the need for disease prevention, methicillin-resistant S. aureus (MRSA) strains have recently evolved to cause a worldwide epidemic of cutaneous and invasive infections in otherwise healthy individuals, leading to the designation of community-associated MRSA (CA-MRSA) [1–4]. The predominant MRSA clone in the United States is designated USA300 [5–7]. Illustrating the versatility of this pathogen, USA300 isolates are now found worldwide [8], and we and others have reported community-acquired infections caused by methicillin-susceptible S. aureus variants of this lineage [9, 10]. The molecular attributes underlying virulence of S. aureus isolates causing historic and contemporary human disease are incompletely defined. Considerable interest has focused on the staphylococcal pore-forming cytotoxins α-hemolysin (Hla; α-toxin) and Panton–Valentine leukocidin (PVL). Hla is genome encoded by almost all S. aureus strains and, through molecular epidemiologic studies, was recently demonstrated to contribute to the success of S. aureus phage 80/81 epidemic strains of the 1950s and subsequent infections through the present day in healthy individuals [11]. Hla plays important roles in staphylococcal pneumonia, dermonecrotic infection, and sepsis by co-opting the enzymatic function of its eukaryotic receptor ADAM10 to promote epithelial injury [12–15]. Many contemporary CA-MRSA isolates also carry phage DNA that harbors the lukF-PV and lukS-PV genes that encode the heterodimeric leukotoxin PVL. These strains are epidemiologically associated with severe SSTI and lethal invasive disease, especially necrotizing pneumonia [1, 16–24]. Studies in experimental animals have demonstrated mixed observations on the role of PVL as a cytolytic and immunomodulatory leukotoxin in disease (eg, SSTI and pneumonia), likely reflecting dissimilarities among model systems and across species [25–27]. Dysregulated exotoxin secretion has been proposed as a mechanism that governs strain-specific virulence properties; this is supported by our prior finding of augmented exotoxin gene expression within human cutaneous MRSA abscesses [28]. Based on these studies and preclinical successes of immunization strategies in animal models of disease [29, 30], Hla and PVL have been considered primary targets for vaccine and monoclonal antibody–based approaches. However, evidence has not convincingly equated toxin-neutralizing human immunologic responses with protection against disease. Further, the field must infer from animal studies the disease states or individuals best targeted by these approaches—a jeopardy in the wake of unsuccessful clinical trials of anti-staphylococcal vaccines. Ongoing vaccine and therapeutics efforts will benefit from an enhanced understanding of exotoxin secretion and cognate host responses in human infection, including identification of immunodominant epitopes and assessment of the protection afforded by antitoxin antibodies. Here, we report serologic responses to Hla and PVL in children with asymptomatic S. aureus colonization as well as cutaneous and invasive S. aureus infections, revealing novel features of these responses. Most importantly, we demonstrate that convalescent anti-Hla titers correlate with protection from subsequent infection during 12 months of follow-up, thereby specifying a marker of protective immunity in a defined population.