{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T02:18:55Z","timestamp":1785291535096,"version":"3.55.0"},"reference-count":60,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T00:00:00Z","timestamp":1680048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration (FDA) for HLN"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>No human vaccine is available for visceral leishmaniasis (VL). Live attenuated centrin gene-deleted L. donovani (LdCen\u2212\/\u2212) 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\u2212\/\u2212 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-\u03baB (NF-\u03baB). This process resulted in an increase in the DC\u2019s proinflammatory response, activation, and DC-mediated CD4+T cell proliferation. Further, LdCen\u2212\/\u2212 immunization in TLR-9\u2212\/\u2212 mice resulted in a significant loss of protective immunity. Thus, LdCen\u2212\/\u2212 vaccine naturally activates the TLR-9 signaling pathway to elicit protective immunity against virulent L. donovani challenge.<\/jats:p>","DOI":"10.3390\/pathogens12040534","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T02:23:46Z","timestamp":1680143026000},"page":"534","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Toll-like Receptor-9 (TLR-9) Signaling Is Crucial for Inducing Protective Immunity following Immunization with Genetically Modified Live Attenuated Leishmania Parasites"],"prefix":"10.3390","volume":"12","author":[{"given":"Parna","family":"Bhattacharya","sequence":"first","affiliation":[{"name":"Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6557-8220","authenticated-orcid":false,"given":"Sreenivas","family":"Gannavaram","sequence":"additional","affiliation":[{"name":"Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nevien","family":"Ismail","sequence":"additional","affiliation":[{"name":"Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankit","family":"Saxena","sequence":"additional","affiliation":[{"name":"Immune Monitoring Shared Resource, Rutgers, Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep K.","family":"Dagur","sequence":"additional","affiliation":[{"name":"Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adovi","family":"Akue","sequence":"additional","affiliation":[{"name":"Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"KuKuruga","sequence":"additional","affiliation":[{"name":"Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4941-1620","authenticated-orcid":false,"given":"Hira L.","family":"Nakhasi","sequence":"additional","affiliation":[{"name":"Division of Emerging and Transfusion Transmitted Disease, Center for Biologics Evaluation and Research Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,29]]},"reference":[{"key":"ref_1","first-page":"135","article-title":"Vulnerabilities to and the Socioeconomic and Psychosocial Impacts of the Leishmaniases: A Review","volume":"12","author":"Grifferty","year":"2021","journal-title":"Res. Rep. Trop. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"111671","DOI":"10.1016\/j.biopha.2021.111671","article-title":"Host immune response against leishmaniasis and parasite persistence strategies: A review and assessment of recent research","volume":"139","author":"Elmahallawy","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4604","DOI":"10.1128\/IAI.00975-15","article-title":"Toll-like receptor 9 signaling in dendritic cells regulates neutrophil recruitment to inflammatory foci following Leishmania infantum infection","volume":"83","author":"Sacramento","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.4049\/jimmunol.177.6.3515","article-title":"Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection","volume":"177","author":"Bafica","year":"2006","journal-title":"J. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"32987","DOI":"10.1074\/jbc.M304791200","article-title":"Roles of glycosylphosphatidylinositols of Toxoplasma gondii. Induction of tumor necrosis factor-alpha production in macrophages","volume":"278","author":"Azzouz","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1128\/IAI.69.4.2162-2171.2001","article-title":"DNA from protozoan parasites Babesia bovis, Trypanosoma cruzi, and T. brucei is mitogenic for B lymphocytes and stimulates macrophage expression of interleukin-12, tumor necrosis factor alpha, and nitric oxide","volume":"69","author":"Shoda","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"416","DOI":"10.4049\/jimmunol.167.1.416","article-title":"Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite","volume":"167","author":"Campos","year":"2001","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.intimp.2018.03.002","article-title":"Toll-like receptors in immunity and inflammatory diseases: Past, present, and future","volume":"59","author":"Vijay","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"461","DOI":"10.3389\/fimmu.2014.00461","article-title":"Toll-like receptor signaling pathways","volume":"5","author":"Kawasaki","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"930257","DOI":"10.1155\/2012\/930257","article-title":"Toll-like receptors in leishmania infections: Guardians or promoters?","volume":"2012","author":"Faria","year":"2012","journal-title":"J. Parasitol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.4049\/jimmunol.170.8.4237","article-title":"Genetically resistant mice lacking MyD88-adapter protein display a high susceptibility to Leishmania major infection associated with a polarized Th2 response","volume":"170","author":"Muraille","year":"2003","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1128\/IAI.72.2.824-832.2004","article-title":"Myd88-dependent in vivo maturation of splenic dendritic cells induced by Leishmania donovani and other Leishmania species","volume":"72","author":"Brait","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/eji.200535079","article-title":"RNA interference reveals a role for TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by interferon-gamma-primed macrophages","volume":"36","author":"Flandin","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1002\/eji.200324128","article-title":"MyD88 is essential for clearance of Leishmania major: Possible role for lipophosphoglycan and Toll-like receptor 2 signaling","volume":"33","author":"Curtis","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1016\/j.ajpath.2011.05.053","article-title":"Pathogen-derived oligosaccharides improve innate immune response to intracellular parasite infection","volume":"179","author":"Osanya","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1086\/653210","article-title":"Arabinosylated lipoarabinomannan-mediated protection in visceral leishmaniasis through up-regulation of toll-like receptor 2 signaling: An immunoprophylactic approach","volume":"202","author":"Bhattacharya","year":"2010","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1128\/IAI.72.4.1920-1928.2004","article-title":"Toll-like receptor 4 contributes to efficient control of infection with the protozoan parasite Leishmania major","volume":"72","author":"Kropf","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1189\/jlb.1003484","article-title":"Infection of C57BL\/10ScCr and C57BL\/10ScNCr mice with Leishmania major reveals a role for Toll-like receptor 4 in the control of parasite replication","volume":"76","author":"Kropf","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.4049\/jimmunol.182.3.1386","article-title":"TLR9-dependent activation of dendritic cells by DNA from Leishmania major favors Th1 cell development and the resolution of lesions","volume":"182","author":"Rachinel","year":"2009","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.imbio.2007.12.005","article-title":"The innate immune response against Leishmania parasites","volume":"213","author":"Liese","year":"2008","journal-title":"Immunobiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1084\/jem.20061293","article-title":"NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs","volume":"204","author":"Schleicher","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3389\/fimmu.2012.00144","article-title":"Adjuvants for Leishmania vaccines: From models to clinical application","volume":"3","author":"Raman","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_23","first-page":"74","article-title":"Vaccination with Live Attenuated L. Major and TLR4 Agonist Promotes a Th1 Immune Response and Induces Protection against L. Major Infection in BALB\/c Mice","volume":"15","author":"Farjadian","year":"2018","journal-title":"Iran. J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"134","DOI":"10.3389\/fimmu.2014.00134","article-title":"Live vaccination tactics: Possible approaches for controlling visceral leishmaniasis","volume":"5","author":"Saljoughian","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107849","DOI":"10.1016\/j.exppara.2020.107849","article-title":"The potential of live attenuated vaccines against Cutaneous Leishmaniasis","volume":"210","author":"Todd","year":"2020","journal-title":"Exp. Parasitol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3389\/fimmu.2014.00241","article-title":"Biomarkers of safety and immune protection for genetically modified live attenuated leishmania vaccines against visceral leishmaniasis\u2014Discovery and implications","volume":"5","author":"Gannavaram","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"25703","DOI":"10.1074\/jbc.M402794200","article-title":"Centrin gene disruption impairs stage-specific basal body duplication and cell cycle progression in Leishmania","volume":"279","author":"Selvapandiyan","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3513","DOI":"10.4049\/jimmunol.1303145","article-title":"Characterization of cross-protection by genetically modified live-attenuated Leishmania donovani parasites against Leishmania mexicana","volume":"193","author":"Dey","year":"2014","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3461","DOI":"10.1038\/s41467-020-17154-z","article-title":"A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing","volume":"11","author":"Zhang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gannavaram, S., Davey, S., Lakhal-Naouar, I., Duncan, R., and Nakhasi, H.L. (2014). Deletion of ubiquitin fold modifier protein Ufm1 processing peptidase Ufsp in L. donovani abolishes Ufm1 processing and alters pathogenesis. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0002707"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.4049\/jimmunol.0900276","article-title":"Intracellular replication-deficient Leishmania donovani induces long lasting protective immunity against visceral leishmaniasis","volume":"183","author":"Selvapandiyan","year":"2009","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1016\/j.vaccine.2013.01.048","article-title":"Induction of immunogenicity by live attenuated Leishmania donovani centrin deleted parasites in dogs","volume":"31","author":"Fiuza","year":"2013","journal-title":"Vaccine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.vaccine.2014.11.039","article-title":"Vaccination using live attenuated Leishmania donovani centrin deleted parasites induces protection in dogs against Leishmania infantum","volume":"33","author":"Fiuza","year":"2015","journal-title":"Vaccine"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Fiuza, J.A., Dey, R., Davenport, D., Abdeladhim, M., Meneses, C., Oliveira, F., Kamhawi, S., Valenzuela, J.G., Gannavaram, S., and Nakhasi, H.L. (2016). Intradermal Immunization of Leishmania donovani Centrin Knock-Out Parasites in Combination with Salivary Protein LJM19 from Sand Fly Vector Induces a Durable Protective Immune Response in Hamsters. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004322"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3333","DOI":"10.4049\/jimmunol.2000829","article-title":"Essential Role of Neutrophils in the Protective Immune Response Induced by a Live Attenuated Leishmania Vaccine","volume":"205","author":"Bhattacharya","year":"2020","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3800","DOI":"10.1128\/IAI.00184-15","article-title":"Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice","volume":"83","author":"Bhattacharya","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bhattacharya, P., Ismail, N., Saxena, A., Gannavaram, S., Dey, R., Oljuskin, T., Akue, A., Takeda, K., Yu, J., and Karmakar, S. (2022). Neutrophil-dendritic cell interaction plays an important role in live attenuated Leishmania vaccine induced immunity. PLoS Negl. Trop. Dis., 16.","DOI":"10.1371\/journal.pntd.0010224"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1128\/CMR.00046-08","article-title":"Pathogen recognition and inflammatory signaling in innate immune defenses","volume":"22","author":"Mogensen","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.exppara.2012.05.002","article-title":"Leishmania donovani recombinant iron superoxide dismutase B1 protein in the presence of TLR-based adjuvants induces partial protection of BALB\/c mice against Leishmania major infection","volume":"131","author":"Daifalla","year":"2012","journal-title":"Exp. Parasitol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1084\/jem.20020147","article-title":"Vaccination with heat-killed leishmania antigen or recombinant leishmanial protein and CpG oligodeoxynucleotides induces long-term memory CD4+ and CD8+ T cell responses and protection against leishmania major infection","volume":"195","author":"Rhee","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.femsim.2004.05.008","article-title":"Vaccination with Leishmania soluble antigen and immunostimulatory oligodeoxynucleotides induces specific immunity and protection against Leishmania donovani infection","volume":"42","author":"Tewary","year":"2004","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1016\/j.vaccine.2004.02.007","article-title":"Immunostimulatory oligodeoxynucleotides are potent enhancers of protective immunity in mice immunized with recombinant ORFF leishmanial antigen","volume":"22","author":"Tewary","year":"2004","journal-title":"Vaccine"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"119390","DOI":"10.1016\/j.ijpharm.2020.119390","article-title":"A TLR9-adjuvanted vaccine formulated into dissolvable microneedle patches or cationic liposomes protects against leishmaniasis after skin or subcutaneous immunization","volume":"586","author":"Lanza","year":"2020","journal-title":"Int. J. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1084\/jem.20030645","article-title":"Dendritic cells are responsible for the capacity of CpG oligodeoxynucleotides to act as an adjuvant for protective vaccine immunity against Leishmania major in mice","volume":"198","author":"Shah","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1006\/expr.2001.4656","article-title":"A lipophosphoglycan-independent method for isolation of infective Leishmania metacyclic promastigotes by density gradient centrifugation","volume":"99","author":"Spath","year":"2001","journal-title":"Exp. Parasitol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Campos, M.B., Lima, L., de Lima, A.C.S., Vasconcelos Dos Santos, T., Ramos, P.K.S., Gomes, C.M.C., and Silveira, F.T. (2018). Toll-like receptors 2, 4, and 9 expressions over the entire clinical and immunopathological spectrum of American cutaneous leishmaniasis due to Leishmania (V.) braziliensis and Leishmania (L.) amazonensis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0194383"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"227","DOI":"10.3389\/fimmu.2019.00227","article-title":"Molecular Aspects of Dendritic Cell Activation in Leishmaniasis: An Immunobiological View","volume":"10","author":"Tiburcio","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.ijmm.2012.07.006","article-title":"The role of NF-kappaB activation during protection against Leishmania infection","volume":"302","author":"Reinhard","year":"2012","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_49","first-page":"5693736","article-title":"Cytokine Effect of TLR3, TLR4, and TLR7 Agonists Alone or Associated with Leishmania infantum Antigen on Blood from Dogs","volume":"2018","author":"Gonzalez","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.exppara.2011.07.001","article-title":"Immunogenicity of Leishmania donovani iron superoxide dismutase B1 and peroxidoxin 4 in BALB\/c mice: The contribution of Toll-like receptor agonists as adjuvant","volume":"129","author":"Daifalla","year":"2011","journal-title":"Exp. Parasitol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Pratti, J.E.S., da Fonseca Martins, A.M., da Silva, J.P., Ramos, T.D., Pereira, J.C., Firmino-Cruz, L., Oliveira-Maciel, D., Vieira, T.S.S., Lacerda, L.L., and Vale, A.M. (2019). The role of TLR9 on Leishmania amazonensis infection and its influence on intranasal LaAg vaccine efficacy. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007146"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/pim.12145","article-title":"Enhanced expression of Toll-like receptors 2 and 4, but not 9, in spleen tissue from patients with visceral leishmaniasis","volume":"36","author":"Kumar","year":"2014","journal-title":"Parasite Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1111\/pim.12202","article-title":"Leishmania donovani influenced cytokines and Toll-like receptors expression among Sudanese visceral leishmaniasis patients","volume":"37","author":"Babiker","year":"2015","journal-title":"Parasite Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.bbrc.2015.02.121","article-title":"Cross talk between Leishmania donovani CpG DNA and Toll-like receptor 9: An immunoinformatics approach","volume":"459","author":"Gupta","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e12910","DOI":"10.1111\/pim.12910","article-title":"Paradoxical immune response in leishmaniasis: The role of toll-like receptors in disease progression","volume":"44","author":"Bamigbola","year":"2022","journal-title":"Parasite Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.intimp.2012.02.002","article-title":"Miltefosine triggers a strong proinflammatory cytokine response during visceral leishmaniasis: Role of TLR4 and TLR9","volume":"12","author":"Mukherjee","year":"2012","journal-title":"Int. Immunopharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Ives, A., Masina, S., Castiglioni, P., Prevel, F., Revaz-Breton, M., Hartley, M.A., Launois, P., Fasel, N., and Ronet, C. (2014). MyD88 and TLR9 dependent immune responses mediate resistance to Leishmania guyanensis infections, irrespective of Leishmania RNA virus burden. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096766"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/cei.12074","article-title":"Leishmania expressed lipophosphoglycan interacts with Toll-like receptor (TLR)-2 to decrease TLR-9 expression and reduce anti-leishmanial responses","volume":"172","author":"Srivastava","year":"2013","journal-title":"Clin. Exp. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2318","DOI":"10.1128\/IAI.01468-12","article-title":"Regulatory actions of Toll-like receptor 2 (TLR2) and TLR4 in Leishmania donovani infection in the liver","volume":"81","author":"Murray","year":"2013","journal-title":"Infect. Immun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1002\/ddr.21662","article-title":"Impelling TLR9: Road to perspective vaccine for visceral leishmaniasis","volume":"83","author":"Tiwari","year":"2022","journal-title":"Drug Dev. Res."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/12\/4\/534\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:06:14Z","timestamp":1760123174000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/12\/4\/534"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,29]]},"references-count":60,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["pathogens12040534"],"URL":"https:\/\/doi.org\/10.3390\/pathogens12040534","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,29]]}}}