title: Shedding of tumor necrosis factor receptor 1 induced by protein A decreases tumor necrosis factor alpha availability and inflammation during systemic Staphylococcus aureus infection.
abstract: Staphylococcus aureus infections are an important public health concern due to their increasing incidence and high rates of mortality. The success of S. aureus as a pathogen is highly related to its enormous capacity to evade the host immune response. The critical role of tumor necrosis factor alpha (TNF-α) in the initial host defense against systemic staphylococcal infection has been demonstrated in experimental models and may partially explain the lack of significant benefits observed in clinical trials attempting to neutralize this cytokine in septic patients. S. aureus protein A plays a key role in regulating inflammation through its ability to bind and signal through the TNF-α receptor 1 (TNFR1). In this study, we demonstrate that S. aureus, via protein A-mediated signaling, induces early shedding of TNFR1, which precedes the secretion of TNF-α in vitro and in vivo. The results obtained using a protein A-deficient mutant and tnfr1(-/-) mice strongly suggest that the increased levels of soluble TNFR1 present during experimental S. aureus infection may neutralize circulating TNF-α and impair the host inflammatory response. Early shedding of TNFR1 induced by protein A may constitute a novel mechanism by which S. aureus subverts the host immune response.
authors.affiliation: Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM), Consejo Nacional de Investigaciones Científicas y Tecnológicas, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Constanza
authors.initials: C
authors.lastname: Giai
authors.forename: Cintia
authors.initials: C
authors.lastname: Gonzalez
authors.forename: Camila
authors.initials: C
authors.lastname: Ledo
authors.forename: Ailin
authors.initials: A
authors.lastname: Garofalo
authors.forename: María Silvia
authors.initials: MS
authors.lastname: Di Genaro
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Sordelli
authors.forename: Marisa I
authors.initials: MI
authors.lastname: Gomez
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D057131:Immune Evasion; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000276:immunology*; D013205:Staphylococcal Protein A / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000276:immunology* / Q000472:pathogenicity; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D013205:Staphylococcal Protein A; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors