Role of eosinophils in SIV infection

项目总结 慢性艾滋病毒感染与包括糖尿病在内的共病风险增加有关， 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障碍。此外，艾滋病毒还会导致肠道渗漏和肠道 感染患者胃肠道的炎症。嗜酸性粒细胞是一种重要的先天细胞 在小肠和大肠中高度丰富的具有肠道内稳态功能的亚群，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中(Jones等人， 2021；免疫学)，我们对恒河猴不同的粒细胞亚群进行了表型表征。 并发现非人类灵长类(NHP)嗜酸性粒细胞类似于人类嗜酸性粒细胞，并被 在空肠中发现丰富的嗜酸性粒细胞，这表明这些组织驻留的嗜酸性粒细胞处于良好的位置和 能够引起早期的抗病毒粘膜反应。然而，促炎症反应 嗜酸性粒细胞--细胞毒性、细胞因子分泌、活性氧的产生也可引起组织 损坏。此外，缺乏关于嗜酸性粒细胞在艾滋病毒感染中可能重新编程的知识。 这可能有助于清除病原体和/或病理表现。在这个新的 探索性建议，我们将测试嗜酸性粒细胞在抗病毒反应中的作用，从而导致 慢病毒感染中导致持续炎症的病毒清除或致病机制。 我们实现这一目标的两个具体目标是：(1)确定嗜酸性粒细胞的相对贡献 慢病毒的病理和控制以及(2)评估训练免疫的机制 恒河猴新感染SIV后的嗜酸性粒细胞。这项提议的结果是 将首次对任何病毒感染中的嗜酸性粒细胞耗尽的免疫系统进行详细分析 并在SIV感染的情况下对嗜酸性粒细胞进行重新编程。

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.