title: Tissue-specific patterning of host innate immune responses by Staphylococcus aureus α-toxin.
abstract: Immunomodulatory cytotoxins are prominent virulence factors produced by Staphylococcus aureus, a leading cause of bacterial sepsis, skin infection, and pneumonia. S. aureus α-toxin is a pore-forming toxin that utilizes a widely expressed receptor, ADAM10, to injure the host epithelium, endothelium, and immune cells. As each host tissue is characterized by a unique composition of resident cells and recruited immune cells, the outcome of α-toxin-mediated injury may depend on the infected tissue environment. Utilizing myeloid lineage-specific Adam10 knockout mice, we show that α-toxin exerts tissue-specific effects on innate immunity to staphylococcal infection. Loss of ADAM10 expression exacerbates skin infection, yet affords protection against lethal pneumonia. These diverse outcomes are not related to altered immune cell recruitment, but rather correlate with a defect in toxin-induced IL-1β production. Extension of these studies through analysis of ADAM10 double-knockout mice affecting both the myeloid lineage and either the skin or lung epithelium highlight the prominence of toxin-induced injury to the epithelium in governing the outcome of infection. Together, these studies provide evidence of tissue specificity of pore-forming cytotoxin action in the modulation of host immunity, and illustrate that the outcome of infection is a collective manifestation of all effects of the toxin within the tissue microenvironment.
authors.affiliation: Department of Microbiology, The University of Chicago, Chicago, Ill., USA.
authors.forename: Russell E N
authors.initials: RE
authors.lastname: Becker
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Berube
authors.forename: Georgia R
authors.initials: GR
authors.lastname: Sampedro
authors.forename: Andrea C
authors.initials: AC
authors.lastname: DeDent
authors.forename: Juliane
authors.initials: J
authors.lastname: Bubeck Wardenburg
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D020869:Gene Expression Profiling; D006460:Hemolysin Proteins / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D012867:Skin / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D013203:Staphylococcal Infections / Q000276:immunology* / Q000635:transmission; D013211:Staphylococcus aureus / Q000276:immunology* / Q000472:pathogenicity; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D053583:Interleukin-1beta; D008565:Membrane Proteins; D037521:Virulence Factors; C021091:staphylococcal alpha-toxin; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse