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

Frank, Karen M.; Zhou, Tong; Moreno‐Vinasco, Liliana; Hollett, Brian; Garcia, Joe G.N.; Wardenburg, Juliane Bubeck

doi:10.1128/iai.00191-12

Cited by 36 publications

(33 citation statements)

References 76 publications

(94 reference statements)

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“…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).…”

Section: Adaptive Immune Responses To Pftsmentioning

confidence: 51%

“…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.…”

Section: Other Pft Functions and Effectsmentioning

confidence: 99%

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Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Los

Randis

Aroian

et al. 2013

Microbiol Mol Biol Rev

347

351

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SUMMARY Pore-forming toxins (PFTs) are the most common bacterial cytotoxic proteins and are required for virulence in a large number of important pathogens, including Streptococcus pneumoniae , group A and B streptococci, Staphylococcus aureus , Escherichia coli , and Mycobacterium tuberculosis . PFTs generally disrupt host cell membranes, but they can have additional effects independent of pore formation. Substantial effort has been devoted to understanding the molecular mechanisms underlying the functions of certain model PFTs. Likewise, specific host pathways mediating survival and immune responses in the face of toxin-mediated cellular damage have been delineated. However, less is known about the overall functions of PFTs during infection in vivo . This review focuses on common themes in the area of PFT biology, with an emphasis on studies addressing the roles of PFTs in in vivo and ex vivo models of colonization or infection. Common functions of PFTs include disruption of epithelial barrier function and evasion of host immune responses, which contribute to bacterial growth and spreading. The widespread nature of PFTs make this group of toxins an attractive target for the development of new virulence-targeted therapies that may have broad activity against human pathogens.

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“…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).…”

Section: Adaptive Immune Responses To Pftsmentioning

confidence: 51%

Section: Other Pft Functions and Effectsmentioning

confidence: 99%

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Los

Randis

Aroian

et al. 2013

Microbiol Mol Biol Rev

347

351

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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cStaphylococcus aureus is an invasive bacterial pathogen, and antibiotic resistance has impeded adequate control of infections caused by this microbe. Moreover, efforts to prevent human infections with single-component S. aureus vaccines have failed. In this study, we evaluated the protective efficacy in rats of vaccines containing both S. aureus capsular polysaccharides (CPs) and proteins. The serotypes 5 CP (CP5) and 8 CP (CP8) were conjugated to tetanus toxoid and administered to rats alone or together with domain A of clumping factor A (ClfA) or genetically detoxified alpha-toxin (dHla). The vaccines were delivered according to a preventive or a therapeutic regimen, and their protective efficacy was evaluated in a rat model of osteomyelitis. Addition of dHla (but not ClfA) to the CP5 or CP8 vaccine induced reductions in bacterial load and bone morphological changes compared with immunization with either conjugate vaccine alone. Both the prophylactic and therapeutic regimens were protective. Immunization with dHla together with a pneumococcal conjugate vaccine used as a control did not reduce staphylococcal osteomyelitis. The emergence of unencapsulated or small-colony variants during infection was negligible and similar for all of the vaccine groups. In conclusion, addition of dHla to a CP5 or CP8 conjugate vaccine enhanced its efficacy against S. aureus osteomyelitis, indicating that the inclusion of multiple antigens will likely enhance the efficacy of vaccines against both chronic and acute forms of staphylococcal disease.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia

et al. 2015

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c Th17 immunity in the gastrointestinal tract is regulated by the intestinal microbiota composition, particularly the presence of segmented filamentous bacteria (sfb), but the role of the intestinal microbiota in pulmonary host defense is not well explored. We tested whether altering the gut microbiota by acquiring sfb influences the susceptibility to staphylococcal pneumonia via induction of type 17 immunity. Groups of C57BL/6 mice which differed in their intestinal colonization with sfb were challenged with methicillin-resistant Staphylococcus aureus in an acute lung infection model. Bacterial burdens, bronchoalveolar lavage fluid (BALF) cell counts, cell types, and cytokine levels were compared between mice from different vendors, mice from both vendors after cohousing, mice given sfb orally prior to infection, and mice with and without exogenous interleukin-22 (IL-22) or anti-IL-22 antibodies. Mice lacking sfb developed more severe S. aureus pneumonia than mice colonized with sfb, as indicated by higher bacterial burdens in the lungs, lung inflammation, and mortality. This difference was reduced when sfb-negative mice acquired sfb in their gut microbiota through cohousing with sfb-positive mice or when given sfb orally. Levels of type 17 immune effectors in the lung were higher after infection in sfb-positive mice and increased in sfb-negative mice after acquisition of sfb, as demonstrated by higher levels of IL-22 and larger numbers of IL-22؉ TCR␤ ؉ cells and neutrophils in BALF. Exogenous IL-22 protected mice from S. aureus pneumonia. The murine gut microbiota, particularly the presence of sfb, promotes pulmonary type 17 immunity and resistance to S. aureus pneumonia, and IL-22 protects against severe pulmonary staphylococcal infection.

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

Abstract: ABSTRACTStaphylococcus aureuspneumonia causes significant morbidity and mortality. Alpha-hemolysin (Hla), a pore-forming cytotoxin ofS. aureus, has been identified through animal models of pneumonia as a critical vir… Show more

Cited by 36 publications

References 76 publications

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

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

Intestinal Microbiota of Mice Influences Resistance to Staphylococcus aureus Pneumonia

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