Tissue-specific patterning of host innate immune responses by staphylococcus aureus α-Toxin

Russell E.N. Becker, Bryan J. Berube, Georgia R. Sampedro, Andrea C. Dedent, Juliane Bubeck Wardenburg

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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.

Original languageEnglish
Pages (from-to)619-631
Number of pages13
JournalJournal of Innate Immunity
Volume6
Issue number5
DOIs
StatePublished - Aug 2014

Keywords

  • ADAM10
  • Innate immunity
  • Myeloid lineage-specific knockout
  • Pathogenesis
  • Staphylococcus aureus
  • α-Toxin

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