神经干祖细胞通过分泌piRNA-PIWIL2复合物抵御脑内病毒感染的机制研究

许多流行病毒（新冠、艾滋、流感病毒等）可导致脑内感染，但目前对脑内抗病毒机制知之甚少。我们前期发现相较于其它类型细胞，成体神经干祖细胞（NSC）不易被多种工具病毒感染，进而发现NSC含有识别多种病毒的piRNA序列，且表达其依赖的剪切蛋白PIWIL2，可发挥抗病毒作用；细胞实验进一步表明，NSC可通过外泌体内piRNA-PIWIL2有效阻止其它细胞感染病毒。据此提出假说：NSC是脑内抗病毒的重要细胞，通过分泌和转移含piRNA-PIWIL2的外泌体至其它神经细胞中剪切病毒基因组，实现其广泛的抗病毒作用。本研究拟利用新冠假病毒和HIV-1型慢病毒脑内感染的小鼠模型，通过NSC移植、基因工具干预、病毒毒力测试等手段，探讨1）NSC在脑内的抗病毒作用；2）NSC表达和分泌piRNA-PIWIL2在脑内的抗病毒机制。本研究将揭示成体NSC在脑免疫中的全新作用，为开发脑内病毒感染治疗方法提供新思路。

Some viruses (SARS-COV-2, HIV, pathogenic influenza virus etc.) can move into the brain where they cause acute or persistent infections. However, little is known about how the brain fights against viral infection. Our previous study found that compare to other types of cells, adult neural stem and progenitor cells (NSC) are less susceptible to the infection of multiple types of tool viruses. Starting from this phenomenon, we found that mouse adult NSCs contain a large number of virus-recognizing Piwi-interacting RNA (piRNA) sequences and highly expressed the splicing machinery protein PIWIL2, which were involved in the anti-viral infection effects of NSCs. Furthermore, in vitro study indicated that NSCs could protect other cells from viral infections through exosomal piRNA-PIWIL2 complex secretion. Therefore, I hypothesize that adult NSC is an important cellular component of brain immunity, and can protect brain against virus infection through producing and secreting exosomal piRNA-PIWIL2 complex. This project will employ rVSV-SARS-CoV-2 and HIV-1 lentivirus infected mice as animal models, and use genetic interventions, virulence test etc. to achieve the following goals. 1) Verification the anti-viral effects of adult NSC in brain viral infections. 2) Uncovering the underlying exosomal piRNA-PIWIL2 mechanisms of the NSC-mediated anti-viral effects. This project will reveal the new role of NSC-mediated anti-viral effects in brain immunity and provide a new theoretical possibility and experimental evidence for the treatment of brain viral infection.