Watson Rebekah G, Hole Camaron R
Department of Clinical Pharmacy and Translational Science, The University of Tennessee Health Science Center, Memphis, TN, USA.
bioRxiv. 2025 Jun 27:2025.06.24.661434. doi: 10.1101/2025.06.24.661434.
is a globally distributed fungal pathogen that causes severe opportunistic infections, particularly in individuals with impaired cell-mediated immunity, such as AIDS patients and organ transplant recipients. Chitosan, a deacetylated derivative of chitin, plays a key role in modulating immune responses during infection. We previously showed that mice inoculated with a heat-killed (HK) chitosan-deficient strain lacking chitin synthase 3 () undergo rapid, neutrophil-dependent mortality within 36 hours, despite the absence of viable organisms. Here, we investigated the immune mechanisms underlying this lethal inflammatory response. We assessed the role of inflammatory cytokines, adaptive immunity, and neutrophil-derived effector functions in this lethal response. IL-6-deficient and Rag1-deficient mice exhibited only modest survival benefits, suggesting that IL-6 signaling and adaptive immune cells play limited roles. In contrast, mice lacking NADPH oxidase 2 (NOX2), the catalytic subunit of the phagocyte oxidase complex required for reactive oxygen species (ROS) production, were completely protected. Despite equivalent pulmonary neutrophil recruitment in wild-type and NOX2-deficient mice, only the former displayed elevated proinflammatory cytokine and chemokine levels and succumbed to disease. These findings indicate that neutrophils are not intrinsically pathogenic but mediate lethal immunopathology through ROS-dependent inflammatory amplification.
是一种全球分布的真菌病原体，可引起严重的机会性感染，尤其是在细胞介导免疫受损的个体中，如艾滋病患者和器官移植受者。壳聚糖是几丁质的脱乙酰化衍生物，在感染期间调节免疫反应中起关键作用。我们之前表明，接种缺乏几丁质合酶3（）的热灭活（HK）壳聚糖缺陷菌株的小鼠，尽管没有活的生物体，但在36小时内会经历快速的、中性粒细胞依赖性死亡。在此，我们研究了这种致命炎症反应背后的免疫机制。我们评估了炎症细胞因子、适应性免疫和中性粒细胞衍生的效应功能在这种致命反应中的作用。白细胞介素-6缺陷和Rag1缺陷小鼠仅表现出适度的生存益处，这表明白细胞介素-6信号传导和适应性免疫细胞起的作用有限。相比之下，缺乏NADPH氧化酶2（NOX2）的小鼠得到了完全保护，NADPH氧化酶2是产生活性氧（ROS）所需的吞噬细胞氧化酶复合物的催化亚基。尽管野生型和NOX2缺陷小鼠的肺部中性粒细胞募集相当，但只有前者显示出促炎细胞因子和趋化因子水平升高并死于疾病。这些发现表明，中性粒细胞本身并非致病性的，而是通过ROS依赖性炎症放大介导致命的免疫病理学。
