Proteomics

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S. aureus drives expansion of low density neutrophils in the diabetic host


ABSTRACT: Abstract S. aureus is a major opportunistic pathogen infecting patients with diabetes. Increased mortality was observed following IV S. aureus infection in diabetic mice compared to non-diabetic controls, correlating with increased numbers of low density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDN development is dependent on TGFβ, which was more activated in the diabetic host. Neutralization of TGFβ, or the integrin responsible for its activation α5β8, reduced numbers of LDNs and improved survival. Comparison of high and low density neutrophils identified PTEN signaling as a central regulator of LDN NET release. Inhibition of PTEN improved survival and decreased NET production in infected diabetic mice. MEDI4893*, a monoclonal antibody that neutralizes alpha toxin (AT) in development for prevention of S. aureus infection, was able to block TGFβ activation, reduce LDNs and NETs, and significantly improve survival. Our data identify a population of neutrophils in infected diabetic mice which correlated with decreased survival and increased NET production. Targeting a single virulence factor of S. aureus prevented emergence of the LDN population and improved survival, supporting potential use of pathogen specific antibodies for treating diabetic infections.

OTHER RELATED OMICS DATASETS IN: GSE122195

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Neutrophil

SUBMITTER: Raghothama Chaerkady  

LAB HEAD: Sonja Hess

PROVIDER: PXD012176 | Pride | 2019-04-26

REPOSITORIES: Pride

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Diabetic individuals are at considerable risk for invasive infection by Staphylococcus aureus, however, the mechanisms underlying this enhanced susceptibility to infection are unclear. We observed increased mortality following i.v. S. aureus infection in diabetic mice compared with nondiabetic controls, correlating with increased numbers of low-density neutrophils (LDNs) and neutrophil extracellular traps (NETs). LDNs have been implicated in the inflammatory pathology of diseases such as lupus,  ...[more]

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