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Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice

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Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice. / Cohen, Taylor S. ; Takahashi, Virginia; Bonnell, Jessica et al.

In: Journal of Clinical Investigation, Vol. 129, No. 5, 01.05.2019, p. 2133-2144.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Harvard

Cohen, TS, Takahashi, V, Bonnell, J, Tovchigrechko, A, Chaerkady, R, Yu, W, Jones-Nelson, O, Lee, Y, Raja, R, Hess, S, Stover, CK, Worthington, JJ, Travis, MA & Sellman, BR 2019, 'Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice', Journal of Clinical Investigation, vol. 129, no. 5, pp. 2133-2144. https://doi.org/10.1172/JCI126938

APA

Cohen, T. S., Takahashi, V., Bonnell, J., Tovchigrechko, A., Chaerkady, R., Yu, W., Jones-Nelson, O., Lee, Y., Raja, R., Hess, S., Stover, C. K., Worthington, J. J., Travis, M. A., & Sellman, B. R. (2019). Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice. Journal of Clinical Investigation, 129(5), 2133-2144. https://doi.org/10.1172/JCI126938

Vancouver

Cohen TS, Takahashi V, Bonnell J, Tovchigrechko A, Chaerkady R, Yu W et al. Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice. Journal of Clinical Investigation. 2019 May 1;129(5):2133-2144. Epub 2019 Apr 15. doi: 10.1172/JCI126938

Author

Cohen, Taylor S. ; Takahashi, Virginia ; Bonnell, Jessica et al. / Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 5. pp. 2133-2144.

Bibtex

@article{b4bae28e8b984e639905fcc77b2a0c56,
title = "Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice",
abstract = "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, given their release of large amounts of NETs. Our goal was to describe what drives LDN increases during S. aureus infection in the diabetic host and mechanisms that promote increased NET production by LDNs. LDN development is dependent on TGF-β, which we found to be more activated in the diabetic host. Neutralization of TGF-β, or the TGF-β–activating integrin αvβ8, reduced LDN numbers and improved survival during S. aureus infection. Targeting S. aureus directly with MEDI4893*, an α toxin–neutralizing monoclonal antibody, blocked TGF-β activation, reduced LDNs and NETs, and significantly improved survival. A comparison of gene and protein expression in high-density neutrophils and LDNs identified increased GPCRs and elevated phosphatase and tensin homolog (PTEN) in the LDN subset. Inhibition of PTEN improved the survival of infected diabetic mice. Our data identify a population of neutrophils in infected diabetic mice that correlated with decreased survival and increased NET production and describe 3 therapeutic targets, a bacterial target and 2 host proteins, that prevented NET production and improved survival.",
author = "Cohen, {Taylor S.} and Virginia Takahashi and Jessica Bonnell and Andrey Tovchigrechko and Raghothama Chaerkady and Wen Yu and Omari Jones-Nelson and Young Lee and Rajiv Raja and Sonja Hess and Stover, {C. Kendall} and Worthington, {John Joseph} and Travis, {Mark A} and Sellman, {Bret R.}",
year = "2019",
month = may,
day = "1",
doi = "10.1172/JCI126938",
language = "English",
volume = "129",
pages = "2133--2144",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

RIS

TY - JOUR

T1 - Staphylococcus aureus drives expansion of low-density neutrophils in diabetic mice

AU - Cohen, Taylor S.

AU - Takahashi, Virginia

AU - Bonnell, Jessica

AU - Tovchigrechko, Andrey

AU - Chaerkady, Raghothama

AU - Yu, Wen

AU - Jones-Nelson, Omari

AU - Lee, Young

AU - Raja, Rajiv

AU - Hess, Sonja

AU - Stover, C. Kendall

AU - Worthington, John Joseph

AU - Travis, Mark A

AU - Sellman, Bret R.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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, given their release of large amounts of NETs. Our goal was to describe what drives LDN increases during S. aureus infection in the diabetic host and mechanisms that promote increased NET production by LDNs. LDN development is dependent on TGF-β, which we found to be more activated in the diabetic host. Neutralization of TGF-β, or the TGF-β–activating integrin αvβ8, reduced LDN numbers and improved survival during S. aureus infection. Targeting S. aureus directly with MEDI4893*, an α toxin–neutralizing monoclonal antibody, blocked TGF-β activation, reduced LDNs and NETs, and significantly improved survival. A comparison of gene and protein expression in high-density neutrophils and LDNs identified increased GPCRs and elevated phosphatase and tensin homolog (PTEN) in the LDN subset. Inhibition of PTEN improved the survival of infected diabetic mice. Our data identify a population of neutrophils in infected diabetic mice that correlated with decreased survival and increased NET production and describe 3 therapeutic targets, a bacterial target and 2 host proteins, that prevented NET production and improved survival.

AB - 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, given their release of large amounts of NETs. Our goal was to describe what drives LDN increases during S. aureus infection in the diabetic host and mechanisms that promote increased NET production by LDNs. LDN development is dependent on TGF-β, which we found to be more activated in the diabetic host. Neutralization of TGF-β, or the TGF-β–activating integrin αvβ8, reduced LDN numbers and improved survival during S. aureus infection. Targeting S. aureus directly with MEDI4893*, an α toxin–neutralizing monoclonal antibody, blocked TGF-β activation, reduced LDNs and NETs, and significantly improved survival. A comparison of gene and protein expression in high-density neutrophils and LDNs identified increased GPCRs and elevated phosphatase and tensin homolog (PTEN) in the LDN subset. Inhibition of PTEN improved the survival of infected diabetic mice. Our data identify a population of neutrophils in infected diabetic mice that correlated with decreased survival and increased NET production and describe 3 therapeutic targets, a bacterial target and 2 host proteins, that prevented NET production and improved survival.

U2 - 10.1172/JCI126938

DO - 10.1172/JCI126938

M3 - Journal article

C2 - 30985291

VL - 129

SP - 2133

EP - 2144

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -