Tissue-Specific Patterning of Host Innate Immune Responses by <b><i>Staphylococcus aureus</i></b> 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.

The psm α Locus Regulates Production of Staphylococcus aureus Alpha-Toxin during Infection

“…Similarly, Hla elicits chemokine and cytokine release from host immune cells, epithelial cells, and endothelial cells (59)(60)(61)(62)(63)(64)(65), including the proinflammatory cytokine interleukin-1␤ (IL-1␤), an indicator of inflammasome activation and a major cytokine involved in the recruitment of neutrophils to the site of infection (66). Primary neutrophils display resistance to the lytic effects of Hla unless this toxin is present at high concentrations that would not likely be achieved early in the course of infection (65,67). Once recruited to the site of infection, host neutrophils would therefore either be subject to the lytic action of extracellular PSM peptides or sustain lysis from the intracellular compartment as engulfed bacteria produce PSMs (29).…”

Nonredundant Roles of Interleukin-17A (IL-17A) and IL-22 in Murine Host Defense against Cutaneous and Hematogenous Infection Due to Methicillin-Resistant Staphylococcus aureus

“…This study utilized MRSA strain Xen 30 (Xenogen/Caliper Life Sciences, Inc.), which was derived from S. aureus strain 16 and contains a luxABCDE operon in the chromosome, allowing for detection via bioluminescence in vivo (30). Although MRSA strains can vary in alphatoxin production (31)(32)(33), the virulence of the study strain was confirmed as equivalent to that of USA300 in the model as used in our prior studies (25). The virulence of strain Xen 30 was assessed in a previous study and demonstrated to be equivalent to that of other clinically relevant MRSA strains in the SSSI murine model (25).…”

Vaccine Protection of Leukopenic Mice against Staphylococcus aureus Bloodstream Infection

“…Staphylococcal alpha-toxin (␣-hemolysin) is encoded by the hla gene, and the primary translation product functions as a precursor that is cleaved by signal peptidase and secreted into the extracellular medium (43). Association of the soluble, monomeric form of Hla with its ADAM10 host cell receptor triggers oligomerization and membrane pore formation (44), causing injury to vascular endothelial cells, epithelial cells, as well as platelets and cells of the myeloid lineage (45,46). During bloodstream infection of immunocompetent mice, the hla mutant of S. aureus Newman displayed reduced mortality and increased time to death (47).…”