HIV-1感染人群中马尔尼菲蓝状菌从定植转化为感染的流行病学研究

As the cART (combined antiretroviral therapy) were extensively developed, and the harm of opportunistic infection gradually exceeded the primary human immunodeficiency virus (HIV) infection with the virus was effectively suppressed. T. marneffei (TM) is an emerging opportunistic pathogen endemic in Southeast Asia and Southern China, especially for those with impaired cellular immunity such as HIV-infected persons. However, there is little evidence that TM may colonize in HIV-1 infected with asymptomatic. Progression from colonization to infection was clearly established as well as formal description of the colonization is the first step of potential contribution of fungal subsequent infection. Therefore, improved knowledge of exposure to risk factors and infection development of invasive TM should promote better use of prophylaxis in the evaluation of patients who could truly benefit from early antifungal therapy. This study will use a cohort of HIV-infected prospectively investigate the correlation of TM colonization and infection in Guangxi province. On the basis of this cohort, then we design a nested case-control study, combined with the molecular epidemiology investigation to explore infection development of invasive TM. Lastly, to explore into the mechanism of TM colonization and infection, we study the difference of fungi spectrum (group) among HIV-1 infected with TM colonization and invasive. The results will help to clarify the TM susceptibility and disease process, and likely to benefit from early diagnosis and empirical antifungal treatment in HIV-1 infected.

随着联合抗逆转录病毒疗法（cART）的广泛开展，HIV病毒被有效抑制后，机会性感染的危害性逐渐超过了原发HIV感染。马尔尼菲蓝状菌（T. marneffei）病是东南亚和我国南方地区HIV-1感染人群高发的地方性、机会性感染性真菌病。研究已表明真菌的定植与感染发展有密切关系，其是转化为真菌感染和疾病发生、发展的第一步。因此，阐明TM定植与感染关系的研究将有助于明确影响TM易感的关键因素及正确指导临床预防和诊疗。本课题通过队列研究分析广西HIV-1感染人群中TM定植与感染的关联性；基于队列，按照巢式病例对照设计，结合分子流行病学调查定植与否、定植与感染的影响因素，分析TM定植与感染的真菌谱分布的差异，以此阐明定植转化为感染的过程。课题首次在HIV-1人群中从定植的角度研究与TM感染的影响，有助于明确TM的易感性和疾病进程，并有望据此提出预防和早期诊治HIV-1人群中TM机会性感染的新策略。

随着联合抗逆转录病毒疗法（cART）的广泛开展，HIV病毒被有效抑制后，机会性感染的危害性逐渐超过了原发HIV感染。马尔尼菲篮状菌（TM）病是东南亚和我国南方地区HIV-1感染人群高发的地方性、机会性感染性真菌病。该病起病隐匿，易漏诊、误诊，病原学培养确诊耗时长，病情进展迅速且严重，未经治疗的HIV/TM患者病死率极高，即使接受抗真菌治疗，病死率仍高达20.7%。研究显示HIV/TM重症者肝损伤发生率极高。因此，阐明TM定植与感染关系的研究将有助于明确影响TM易感的关键因素及正确指导临床预防和诊疗，探究马尔尼菲篮状菌感染能否通过细胞焦亡导致肝细胞损伤具有重要意义。本课题通过队列研究分析广西HIV-1感染人群中TM定植与感染的关联性，建立了符合标准的HIV-1患者前瞻性研究队列，收集研究对象的全血（或骨髓）、痰液、咽拭子和肺泡灌洗液；根据所采集到的样本信息，构建马尔尼菲篮状菌定植-感染评分模型（TMCDS），对纳入人群进行定植-感染状态初筛，进行流行病学调查，血液及相关样本采集，成功构建了构建马尔尼菲篮状菌早期快速诊断机器学习模型；通过检测乳酸脱氢酶含量，确定细胞发生损伤，成功构建肝细胞和脾细胞感染TM的细胞模型；通过流式细胞术分析细胞损伤所占比例，明确细胞焦亡相关因子AIM2、Caspase-1/4、IL-1β、IL-18、TNF-α和GSDMD等的表达上调，成功构建TM感染模型。该研究可为临床寻找感染后缓解内脏损伤的药物治疗靶点提供参考依据，也可为TM在宿主内休眠、肉芽肿形成和潜伏感染的研究奠定基础。