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Previously, we have shown that genetically modified<jats:named-content content-type=\"genus-species\">Leishmania donovani<\/jats:named-content>parasites, here described as live attenuated parasites, induce a host protective adaptive immune response in various animal models. In this study, we demonstrate an innate immune response upon infection with live attenuated parasites in macrophages from BALB\/c mice both<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo. In vitro<\/jats:italic>infection of macrophages with live attenuated parasites (compared to that with wild-type [WT]<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>parasites) induced significantly higher production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-\u03b1], interleukin-12 [IL-12], gamma interferon [IFN-\u03b3], and IL-6), chemokines (monocyte chemoattractant protein 1\/CCL-2, macrophage inflammatory protein 1\u03b1\/CCL-3, and IP-10), reactive oxygen species (ROS), and nitric oxide, while concomitantly reducing anti-inflammatory cytokine IL-10 and arginase-1 activities, suggesting a dominant classically activated\/M1 macrophage response. The classically activated response in turn helps in presenting antigen to T cells, as observed with robust CD4<jats:sup>+<\/jats:sup>T cell activation<jats:italic>in vitro<\/jats:italic>. Similarly, parasitized splenic macrophages from live attenuated parasite-infected mice also demonstrated induction of an M1 macrophage phenotype, indicated by upregulation of IL-1\u03b2, TNF-\u03b1, IL-12, and inducible nitric oxide synthase 2 and downregulation of genes associated with the M2 phenotype, i.e., the IL-10, YM1, Arg-1, and MRC-1 genes, compared to WT<jats:named-content content-type=\"genus-species\">L. donovani<\/jats:named-content>-infected mice. Furthermore, an<jats:italic>ex vivo<\/jats:italic>antigen presentation assay showed macrophages from live attenuated parasite-infected mice induced higher IFN-\u03b3 and IL-2 but significantly less IL-10 production by ovalbumin-specific CD4<jats:sup>+<\/jats:sup>T cells, resulting in proliferation of Th1 cells. These data suggest that infection with live attenuated parasites promotes a state of classical activation (M1 dominant) in macrophages that leads to the generation of protective Th1 responses in BALB\/c mice.<\/jats:p>","DOI":"10.1128\/iai.00184-15","type":"journal-article","created":{"date-parts":[[2015,7,14]],"date-time":"2015-07-14T02:20:04Z","timestamp":1436840404000},"page":"3800-3815","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":63,"title":["Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice"],"prefix":"10.1128","volume":"83","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, Maryland, 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