1 year ago
30
Pathogens, Vol. 12, Pages 534: Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated Leishmania Parasites
Pathogens doi: 10.3390/pathogens12040534
Authors: Parna Bhattacharya Sreenivas Gannavaram Nevien Ismail Ankit Saxena Pradeep K. Dagur Adovi Akue Mark KuKuruga Hira L. Nakhasi
No human vaccine is available for visceral leishmaniasis (VL). Live attenuated centrin gene-deleted L. donovani (LdCen−/−) 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 Leishmania infection. Among TLRs, TLR-9 signaling has been reported to induce host protection during Leishmania 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 Leishmania vaccines remains unknown. In this study, we investigated the function of TLR-9 during LdCen−/− 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 CD4+T cell proliferation. Further, LdCen−/− immunization in TLR-9−/− mice resulted in a significant loss of protective immunity. Thus, LdCen−/− vaccine naturally activates the TLR-9 signaling pathway to elicit protective immunity against virulent L. donovani challenge.
