SOCS3-M2极化通路在HIV促进马尔尼菲蓝状菌感染的作用及机制研究

马尔尼菲蓝状菌（TM）是我国南方艾滋病人群的高发机会性感染，死亡率高，但艾滋病人易感TM的机制尚未阐明。我们前期发现HIV感染巨噬细胞导致SOCS3下调且促进细胞M2极化，而后者降低了细胞吞噬杀伤作用，促进TM感染发生。本项目旨在阐明其分子机制。首先通过人群研究明确HIV感染与巨噬细胞SOCS3表达、M2极化及通路、TM感染的相关性；采用体外巨噬细胞-HIV/TM模型，对SOCS3进行表达干预，阐明SOCS3在HIV诱导M2极化中的作用及其与降低细胞抗TM作用的因果关系，确定受影响的M2极化通路和关键极化因子；利用Co-IP、细胞共定位、缺失突变等鉴定作用于SOCS3的HIV蛋白，进一步利用SOCS3磷酸化/泛素化/类泛素位点突变研究HIV蛋白下调巨噬细胞SOCS3的分子机制。本项目首次从巨噬细胞极化角度揭示HIV感染者易感TM的新机制，为TM感染提供以巨噬细胞极化为导向的治疗新思路。

Talaromyces marneffei (TM, originally known as penicillium marneffei) is a regional high-risk opportunistic infection among HIV/AIDS population in southern China, which leads to a high death rate among AIDS patients. However, the mechanism(s) of TM susceptibility in HIV-infected patients has not been elucidated. Our preliminary study has showed that HIV infection of macrophages could inhibit cellular SOCS3 expression and induce M2 polarization of macrophages. It has been proved that macrophage M2 polarization leads to decreased phagocytosis and cell-killing effect and thus increases TM susceptibility in macrophages. The aim of this project is to elucidate the molecular mechanisms(s) involving in HIV enhancing TM infection in macrophages through inducing macrophage M2 polarization. Firstly, we will determine the associations among HIV infection, SOCS3 expression level in macrophages, M2 polarization and pathways, and TM infection via population research. Secondly, using in vitro macrophage-HIV/TM model, expression intervention on cellular SOCS3 will be used to determine the role of SOCS3 in HIV-induced M2 polarization and its causal relationship with decreased anti-TM activity of macrophages. Expression intervention on cellular SOCS3 will be also used to identify the M2 polarization pathway as well as the key M2 polarization factors affected by SOCS3. Finally, we will utilize Co-IP, cellular co-localization, deletion mutations, and so on to identify HIV viral protein(s) that acts on SOCS3 expression. Furthermore, point mutations of phosphorylation/ubiquitination/ubiquitin-like points of SOCS3 will be carried out to clarify the molecular mechanism of down-regulation SOCS3 expression by HIV protein. We expect that this project will reveal a novel mechanism(s) for the TM susceptibility in HIV-infected people from the perspective of macrophage M2 polarization. It is also expected to provide a new strategy for clinical TM treatment based on macrophage M2 polarization.