Department of Pathogenic Biology, Army Medical University, Chongqing, China.
The Institute of Immunology, Army Medical University, Chongqing, China.
Front Immunol. 2022 Feb 9;13:815936. doi: 10.3389/fimmu.2022.815936. eCollection 2022.
Although exo-erythrocytic forms (EEFs) of liver stage malaria parasite in the parasitophorous vacuole (PV) are encountered with robust host innate immunity, EEFs can still survive and successfully complete the infection of hepatocytes, and the underlying mechanism is largely unknown. Here, we showed that sporozoite circumsporozoite protein (CSP) translocated from the parasitophorous vacuole into the hepatocyte cytoplasm significantly mediated the resistance to the killing of EEFs by interferon-gamma (IFN-γ). Attenuation of IFN-γ-mediated killing of EEFs by CSP was dependent on its ability to reduce the levels of autophagy-related genes (ATGs) in hepatocytes. The ATGs downregulation occurred through its enhanced ubiquitination mediated by E3 ligase NEDD4, an enzyme that was upregulated by CSP when it translocated from the cytoplasm into the nucleus of hepatocytes its nuclear localization signal (NLS) domain. Thus, we have revealed an unrecognized role of CSP in subverting host innate immunity and shed new light for a prophylaxis strategy against liver-stage infection.
虽然肝期疟原虫的红细胞外期（EEF）在滋养液泡（PV）中遇到强大的宿主固有免疫，但 EEF 仍能存活并成功完成对肝细胞的感染，其潜在机制在很大程度上尚不清楚。在这里，我们表明，从滋养液泡转运到肝细胞细胞质中的孢子环子孢子蛋白（CSP）显著介导了干扰素-γ（IFN-γ）对 EEF 杀伤的抗性。CSP 通过降低肝细胞中自噬相关基因（ATGs）的水平来减弱 IFN-γ介导的 EEF 杀伤作用。ATGs 的下调是通过其增强的泛素化介导的，E3 连接酶 NEDD4 通过这种泛素化作用介导，该酶在 CSP 从细胞质转运到肝细胞的核内时被上调，其核定位信号（NLS）域。因此，我们揭示了 CSP 在颠覆宿主固有免疫方面的一个未被认识的作用，并为预防肝期感染的策略提供了新的思路。
