Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated <i>Leishmania</i> Parasites
No human vaccine is available for visceral leishmaniasis (VL). Live attenuated centrin gene-deleted <i>L. donovani</i> (<i>LdCen<sup>−/−</sup></i>) parasite vaccine has been shown to induce robust innate immunity and provide protection in animal models. Toll-like...
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MDPI AG
2023-03-01
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| Series: | Pathogens |
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| Online Access: | https://www.mdpi.com/2076-0817/12/4/534 |
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| author | Parna Bhattacharya Sreenivas Gannavaram Nevien Ismail Ankit Saxena Pradeep K. Dagur Adovi Akue Mark KuKuruga Hira L. Nakhasi |
| author_facet | Parna Bhattacharya Sreenivas Gannavaram Nevien Ismail Ankit Saxena Pradeep K. Dagur Adovi Akue Mark KuKuruga Hira L. Nakhasi |
| author_sort | Parna Bhattacharya |
| collection | DOAJ |
| description | No human vaccine is available for visceral leishmaniasis (VL). Live attenuated centrin gene-deleted <i>L. donovani</i> (<i>LdCen<sup>−/−</sup></i>) 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 <i>Leishmania</i> infection. Among TLRs, TLR-9 signaling has been reported to induce host protection during <i>Leishmania</i> 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 <i>Leishmania</i> vaccines remains unknown. In this study, we investigated the function of TLR-9 during <i>LdCen<sup>−/−</sup></i> 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<sup>+</sup>T cell proliferation. Further, <i>LdCen<sup>−/−</sup></i> immunization in TLR-9<sup>−/−</sup> mice resulted in a significant loss of protective immunity. Thus, <i>LdCen<sup>−/−</sup></i> vaccine naturally activates the TLR-9 signaling pathway to elicit protective immunity against virulent <i>L. donovani</i> challenge. |
| first_indexed | 2024-03-11T04:39:42Z |
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| id | doaj.art-ce954f59d47649aeac64fc072e4e623b |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-11T04:39:42Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-ce954f59d47649aeac64fc072e4e623b2023-11-17T20:48:05ZengMDPI AGPathogens2076-08172023-03-0112453410.3390/pathogens12040534Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated <i>Leishmania</i> ParasitesParna Bhattacharya0Sreenivas Gannavaram1Nevien Ismail2Ankit Saxena3Pradeep K. Dagur4Adovi Akue5Mark KuKuruga6Hira L. Nakhasi7Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USADivision of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USADivision of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USAImmune Monitoring Shared Resource, Rutgers, Cancer Institute of New Jersey, New Brunswick, NJ 08901, USAFlow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USADivision of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USADivision of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USADivision of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USANo human vaccine is available for visceral leishmaniasis (VL). Live attenuated centrin gene-deleted <i>L. donovani</i> (<i>LdCen<sup>−/−</sup></i>) 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 <i>Leishmania</i> infection. Among TLRs, TLR-9 signaling has been reported to induce host protection during <i>Leishmania</i> 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 <i>Leishmania</i> vaccines remains unknown. In this study, we investigated the function of TLR-9 during <i>LdCen<sup>−/−</sup></i> 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<sup>+</sup>T cell proliferation. Further, <i>LdCen<sup>−/−</sup></i> immunization in TLR-9<sup>−/−</sup> mice resulted in a significant loss of protective immunity. Thus, <i>LdCen<sup>−/−</sup></i> vaccine naturally activates the TLR-9 signaling pathway to elicit protective immunity against virulent <i>L. donovani</i> challenge.https://www.mdpi.com/2076-0817/12/4/534visceral leishmaniasisdendritic cellsmyeloid differentiation primary response 88nuclear factor-kappa Bcytokinescostimulatory molecules |
| spellingShingle | Parna Bhattacharya Sreenivas Gannavaram Nevien Ismail Ankit Saxena Pradeep K. Dagur Adovi Akue Mark KuKuruga Hira L. Nakhasi Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated <i>Leishmania</i> Parasites Pathogens visceral leishmaniasis dendritic cells myeloid differentiation primary response 88 nuclear factor-kappa B cytokines costimulatory molecules |
| title | Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated <i>Leishmania</i> Parasites |
| title_full | Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated <i>Leishmania</i> Parasites |
| title_fullStr | Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated <i>Leishmania</i> Parasites |
| title_full_unstemmed | Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated <i>Leishmania</i> Parasites |
| title_short | Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated <i>Leishmania</i> Parasites |
| title_sort | toll like receptor 9 tlr 9 signaling is crucial for inducing protective immunity following immunization with genetically modified live attenuated i leishmania i parasites |
| topic | visceral leishmaniasis dendritic cells myeloid differentiation primary response 88 nuclear factor-kappa B cytokines costimulatory molecules |
| url | https://www.mdpi.com/2076-0817/12/4/534 |
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