Role of eosinophils in SIV infection

项目摘要 慢性HIV感染与包括糖尿病在内的合并症风险增加有关， 心血管疾病、神经功能障碍和癌症，由于持续的炎症状态 以及由病毒引起的免疫功能紊乱此外，HIV引起肠道渗漏和肠道感染。 感染病人胃肠道的炎症。嗜酸性粒细胞是一种重要的先天性细胞 在具有肠道稳态功能的小肠和大肠中高度富集的亚群，但它们的 在粘膜病毒感染中的作用大多被忽视。在我们最近的出版物（Jones等人， 2021; Immunology），我们对恒河猴中粒细胞的不同亚群进行了表型表征 猕猴和发现非人灵长类动物（NHP）嗜酸性粒细胞类似于人类嗜酸性粒细胞， 发现在空肠中富集，表明这些组织驻留的嗜酸性粒细胞位置良好， 能够引发早期抗病毒粘膜反应。然而， 嗜酸性粒细胞-细胞毒性、细胞因子分泌、活性氧物质产生也可引起组织 损害此外，对HIV感染中嗜酸性粒细胞的潜在重编程缺乏了解 这可能有助于清除病原体和/或病理表现。在这个新 探索性的建议，我们将测试嗜酸性粒细胞的作用，有助于抗病毒反应，导致 病毒清除或致病机制导致慢病毒感染中的持续炎症。 我们的两个具体目标是：（1）确定嗜酸性粒细胞的相对贡献 慢病毒病理学和控制和（2）评估训练免疫的机制， 嗜酸性粒细胞在恒河猴SIV从头感染。本提案的结果 将提供第一次详细分析嗜酸性粒细胞耗尽的免疫系统在任何病毒感染 和在SIV感染的情况下“训练”的重编程嗜酸性粒细胞。

PROJECT SUMMARY Chronic HIV infection is associated with increased risk of co-morbidities including diabetes mellitus, cardiovascular diseases, neuro-dysfunctions and cancer, due to the state of persistent inflammation and immune dysfunction induced by the virus. Further, HIV causes gut leakage and intestinal inflammation in the gastrointestinal tract of infected patients. Eosinophils are an important innate cell subset that are highly enriched in small and large intestines with gut homeostatic functions, but their role in mucosal viral infections have been mostly overlooked. In our recent publication (Jones et al, 2021; Immunology), we phenotypically characterized different subsets of granulocytes in rhesus macaques and found non-human primate (NHP) eosinophils analogous to human eosinophils and were found enriched in jejunum, suggesting that these tissue-resident eosinophils are well situated and capable of eliciting early antiviral mucosal responses. However, the pro-inflammatory responses of eosinophils- cytotoxicity, cytokine secretion, reactive oxygen species generation can also cause tissue damage. Further, there is a lack of knowledge of potential reprogramming of eosinophils in HIV infection that could contribute to clearance of pathogens and/or pathologic manifestations. In this new exploratory proposal, we will test the role of eosinophils contributing to antiviral responses that lead to viral clearance or pathogenic mechanisms that lead to persistent inflammation in lentivirus infection. Our two specific aims towards this goal are: (1) Determine the relative contribution of eosinophils to lentiviral pathology and control and (2) Evaluate mechanisms of trained immunity in eosinophils upon de novo infection with SIV in rhesus macaques. The outcomes of this proposal will provide first time detailed analysis of an eosinophil depleted immune system in any viral infection and reprogrammed eosinophils ‘trained’ in the context of SIV infection.