Host Response Signature to Staphylococcus aureus Alpha-Hemolysin Implicates Pulmonary Th17 Response

Abstract

<jats:title>ABSTRACT</jats:title><jats:p><jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Staphylococcus aureus</jats:named-content>pneumonia causes significant morbidity and mortality. Alpha-hemolysin (Hla), a pore-forming cytotoxin of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">S. aureus</jats:named-content>, has been identified through animal models of pneumonia as a critical virulence factor that induces lung injury. In spite of considerable molecular knowledge of how this cytotoxin injures the host, the precise host response to Hla in the context of infection remains poorly understood. We employed whole-genome expression profiling of infected lungs to define the host response to wild-type<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">S. aureus</jats:named-content>compared with the response to an Hla-deficient isogenic mutant in experimental pneumonia. These data provide a complete expression profile at 4 and at 24 h postinfection, revealing a unique response to the toxin-expressing strain. Gene ontogeny analysis revealed significant differences in the extracellular matrix and cardiomyopathy pathways, both of which govern cellular interactions in the tissue microenvironment. Evaluation of individual transcript responses to Hla-secreting staphylococci was notable for upregulation of host cytokine and chemokine genes, including the p19 subunit of interleukin-23. Consistent with this observation, the cellular immune response to infection was characterized by a prominent Th17 response to the wild-type pathogen. These findings define specific host mRNA responses to Hla-producing<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">S. aureus</jats:named-content>, coupling the pulmonary Th17 response to the secretion of this cytotoxin. Expression profiling to define the host response to a single virulence factor proved to be a valuable tool in identifying pathways for further investigation in<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">S. aureus</jats:named-content>pneumonia. This approach may be broadly applicable to the study of bacterial toxins, defining host pathways that can be targeted to mitigate toxin-induced disease.</jats:p>

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

“…Consistently, host IL-23 levels were found to be upregulated specifically in response to alpha-toxin in mice in vivo (also see "Other PFT Functions and Effects") (378).…”

“…Using a mouse model of lung infection, host microarray analysis was performed on lung tissue after 4 and 24 h of infection with wild-type S. aureus or an alphatoxin knockout (378). Interestingly, at the 4-h time point, no differences were found between genes up-or downregulated in response to the wild-type and alpha-toxin knockout strains.…”

Protein Antigens Increase the Protective Efficacy of a Capsule-Based Vaccine against Staphylococcus aureus in a Rat Model of Osteomyelitis

“…In addition, S. aureus Hla activates the immune system via a toll-like receptor 2 (TLR2)-independent mechanism whereby NOD2 signaling results in protection against a murine staphylococcal infection (46). The fact that a Th17 response is relevant to host defense against S. aureus (47,48) and that Hla is able to induce interleukin 17A (IL-17A) in blood (49) has renewed the interest in Hla as vaccine component. Our results in the osteomyelitis model support the use of dHla in a multicomponent S. aureus vaccine.…”

“…Similarly, a recent study aimed at evaluating how well research from murine clinical models mimics human disease indicates that the transcriptional response to inflammatory stresses in mice is a poor reflection of the human response to similar stresses (51). Thus, data from animal models, although informative, are not necessarily predictive of efficacy in humans (47,48). Further clinical trials of vaccines that include CP5/8, ClfA, and/or dHla are required to ascertain whether the findings of the present investigation translate into success in humans.…”

Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia

“…Type 17 immunity has been described to be important in defense against S. aureus pneumonia in several other studies, although some with conflicting results (9-11). The S. aureus virulence factor ␣-hemolysin leads to increased transcription of host cytokine and chemokine genes, including that encoding the p19 subunit of IL-23, producing a prominent cellular Th17 response (37). Mice lacking the IL-17 receptor or IL-22 or which are coinfected with influenza A virus and thereby have an inhibited Th17 immunity display impaired clearance of S. aureus compared to wild-type or influenza virus-free mice (10).…”