Sex-dependent phagocyte clearance of Staphylococcus aureus

项目摘要：许多传染病表现出不同性别的严重程度。 然而，推动这种先天偏见的机制尚不完全清楚。葡萄球菌 金黄色葡萄球菌(SA)，包括耐甲氧西林金黄色葡萄球菌(MRSA)，是导致皮肤和皮肤柔软的最常见原因 美国的组织感染(SSTI)，男性的发病率是男性的两倍多 感染与女性。中性粒细胞对于清除SA皮肤感染是必不可少的，我们 研究发现，与小鼠感染结果一致，雌性小鼠的中性粒细胞效果更好 与雄性小鼠的中性粒细胞相比，能够在体外清除SA。的主要贡献者 中性粒细胞对SA的杀伤包括氧化猝发、中性粒细胞颗粒中的抗微生物因子以及 中性粒细胞胞外陷阱(净)。因此，在这项探索性建议中，我们的目标是将 反应性测定对金黄色葡萄球菌中性粒细胞吞噬和体外杀伤作用的影响 氧物种(ROS)和一氧化氮(NO)的产生、网络形成和基因变化 和蛋白质的表达和激活，以确定性别特异性吞噬细胞的机制(S) 对金黄色葡萄球菌的疗效。此外，我们已经确定了性别特异性调节因子，它们可以增强 并将决定这些调节剂增强吞噬细胞功能的机制 天生的防御。在成功实现这些目标后，我们将获得重大收获 洞察性别特异性吞噬细胞对抗SA的作用机制，以及 增强宿主固有防御的机制和/或目标。

PROJECT SUMMARY: Many infectious diseases exhibit differential severity between the sexes yet the mechanisms driving such innate biases are incompletely understood. Staphylococcus aureus (SA), including methicillin-resistant (MRSA), is the most common cause of skin and soft tissue infection (SSTI) in the US, and males have a greater than 2-fold higher incidence of infection versus females. Neutrophils are essential for clearance of SA skin infections, and we found that, consistent with murine infection outcomes, neutrophils from female mice are better able to clear SA ex vivo compared to neutrophils from male mice. Major contributors to neutrophil killing of SA include oxidative burst, antimicrobial factors in neutrophil granules, and neutrophil extracellular traps (NET). Therefore, in this exploratory proposal, we aim to align the efficacy of neutrophil phagocytosis and killing of SA ex vivo with measurements of reactive oxygen species (ROS) and nitric oxide (NO) production, NET formation, and changes in gene and protein expression and activation, to define the mechanism(s) of sex-specific phagocyte efficacy against SA. Furthermore, we have identified sex-specific modulators which enhance phagocyte efficacy and will determine the mechanisms by which these modulators augment innate defense. Upon the successful completion of these aims, we will have gained significant insight into the mechanisms of sex-specific phagocyte efficacy against SA, as well as mechanisms and/or targets for augmenting host innate defense.