Department of Microbial Sciences.
Department of Translational Medicine and Pharmacogenetics.
J Clin Invest. 2019 Apr 15;129(5):2133-2144. doi: 10.1172/JCI126938.
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.
糖尿病患者感染金黄色葡萄球菌（S. aureus）的风险很大，然而，导致这种易感性增加的机制尚不清楚。与非糖尿病对照相比，我们观察到糖尿病小鼠在静脉内感染金黄色葡萄球菌后死亡率增加，这与低密度中性粒细胞（LDN）和中性粒细胞胞外陷阱（NETs）数量增加有关。鉴于 LDN 释放大量 NETs，它们已被牵涉到狼疮等疾病的炎症病理中。我们的目标是描述在糖尿病宿主中金黄色葡萄球菌感染期间导致 LDN 增加的原因，以及促进 LDN 产生更多 NET 的机制。LDN 的发展依赖于 TGF-β，我们发现糖尿病宿主中的 TGF-β更为活跃。中和 TGF-β或 TGF-β 激活整合素 αvβ8 可减少 LDN 数量并改善金黄色葡萄球菌感染期间的生存率。用 MEDI4893*（一种中和α毒素的单克隆抗体）直接靶向金黄色葡萄球菌，可阻断 TGF-β 激活，减少 LDN 和 NETs，并显著提高生存率。对高密度中性粒细胞和 LDN 中的基因和蛋白质表达进行比较，发现 LDN 亚群中 GPCRs 增加，磷酸酶和张力蛋白同源物（PTEN）升高。抑制 PTEN 可提高感染性糖尿病小鼠的生存率。我们的数据确定了感染性糖尿病小鼠中与生存率降低和 NET 产生增加相关的中性粒细胞群体，并描述了 3 种治疗靶点，即细菌靶点和 2 种宿主蛋白，这些靶点可防止 NET 产生并提高生存率。
