Bhattacharya Parna, Gannavaram Sreenivas, Ismail Nevien, Saxena Ankit, Dagur Pradeep K, Akue Adovi, KuKuruga Mark, Nakhasi Hira L
Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USA.
Immune Monitoring Shared Resource, Rutgers, Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
Pathogens. 2023 Mar 29;12(4):534. doi: 10.3390/pathogens12040534.
No human vaccine is available for visceral leishmaniasis (VL). Live attenuated centrin gene-deleted () parasite vaccine has been shown to induce robust innate immunity and provide protection in animal models. Toll-like receptors (TLRs) are expressed in innate immune cells and are essential for the early stages of infection. Among TLRs, TLR-9 signaling has been reported to induce host protection during infection. Importantly, TLR-9 ligands have been used as immune enhancers for non-live vaccination strategies against leishmaniasis. However, the function of TLR-9 in the generation of a protective immune response in live attenuated vaccines remains unknown. In this study, we investigated the function of TLR-9 during infection and found that it increased the expression of TLR-9 on DCs and macrophages from ear-draining lymph nodes and spleen. The increase in TLR-9 expression resulted in changes in downstream signaling in DCs mediated through signaling protein myeloid differentiation primary response 88 (MyD88), resulting in activation and nuclear translocation of nuclear factor-κB (NF-κB). This process resulted in an increase in the DC's proinflammatory response, activation, and DC-mediated CD4T cell proliferation. Further, immunization in TLR-9 mice resulted in a significant loss of protective immunity. Thus, vaccine naturally activates the TLR-9 signaling pathway to elicit protective immunity against virulent challenge.
目前尚无用于内脏利什曼病（VL）的人用疫苗。减毒活的中心体基因缺失（）寄生虫疫苗已被证明可诱导强大的先天免疫并在动物模型中提供保护。Toll样受体（TLR）在先天免疫细胞中表达，对利什曼原虫感染的早期阶段至关重要。在TLR中，据报道TLR-9信号在利什曼原虫感染期间可诱导宿主保护。重要的是，TLR-9配体已被用作针对利什曼病的非活疫苗接种策略的免疫增强剂。然而，TLR-9在减毒活疫苗产生保护性免疫反应中的作用仍然未知。在本研究中，我们研究了TLR-9在利什曼原虫感染期间的功能，发现它增加了来自耳引流淋巴结和脾脏的DC和巨噬细胞上TLR-9的表达。TLR-9表达的增加导致通过信号蛋白髓样分化初级反应88（MyD88）介导的DC下游信号变化，导致核因子κB（NF-κB）的激活和核转位。这一过程导致DC的促炎反应增加、激活以及DC介导的CD4T细胞增殖。此外，在TLR-9缺陷小鼠中进行利什曼原虫免疫导致保护性免疫显著丧失。因此，利什曼原虫疫苗自然激活TLR-9信号通路以引发针对强毒利什曼原虫攻击的保护性免疫。
