title: Characterization of cross-protection by genetically modified live-attenuated Leishmania donovani parasites against Leishmania mexicana.
abstract: Previously, we showed that genetically modified live-attenuated Leishmania donovani parasite cell lines (LdCen(-/-) and Ldp27(-/-)) induce a strong cellular immunity and provide protection against visceral leishmaniasis in mice. In this study, we explored the mechanism of cross-protection against cutaneous lesion-causing Leishmania mexicana. Upon challenge with wild-type L. mexicana, mice immunized either for short or long periods showed significant protection. Immunohistochemical analysis of ears from immunized/challenged mice exhibited significant influx of macrophages, as well as cells expressing MHC class II and inducible NO synthase, suggesting an induction of potent host-protective proinflammatory responses. In contrast, substantial inhibition of IL-10, IL-4, and IL-13 expression and the absence of degranulated mast cells and less influx of eosinophils within the ears of immunized/challenged mice suggested a controlled anti-inflammatory response. L. mexicana Ag-stimulated lymph node cell culture from the immunized/challenged mice revealed induction of IFN-γ secretion by the CD4 and CD8 T cells compared with non-immunized/challenged mice. We also observed suppression of Th2 cytokines in the culture supernatants of immunized/challenged lymph nodes compared with non-immunized/challenged mice. Adoptively transferred total T cells from immunized mice conferred strong protection in recipient mice against L. mexicana infection, suggesting that attenuated L. donovani can provide protection against heterologous L. mexicana parasites by induction of a strong T cell response. Furthermore, bone marrow-derived dendritic cells infected with LdCen(-/-) and Ldp27(-/-) parasites were capable of inducing a strong proinflammatory response leading to the proliferation of Th1 cells. These studies demonstrate the potential of live-attenuated L. donovani parasites as pan-Leishmania species vaccines.
authors.affiliation: Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Ranadhir
authors.initials: R
authors.lastname: Dey
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 42310;
authors.forename: Gayathri
authors.initials: G
authors.lastname: Natarajan
authors.affiliation: Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Parna
authors.initials: P
authors.lastname: Bhattacharya
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 42310;
authors.forename: Hannah
authors.initials: H
authors.lastname: Cummings
authors.affiliation: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Dagur
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 42310;
authors.forename: César
authors.initials: C
authors.lastname: Terrazas
authors.affiliation: Institute of Molecular Medicine, New Delhi 110020, India.
authors.forename: Angamuthu
authors.initials: A
authors.lastname: Selvapandiyan
authors.affiliation: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: John P
authors.initials: JP
authors.lastname: McCoy
authors.affiliation: Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993;
authors.forename: Robert
authors.initials: R
authors.lastname: Duncan
authors.affiliation: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 42310; Hira.Nakhasi@fda.hhs.gov Abhay.Satoskar@osumc.edu.
authors.forename: Abhay R
authors.initials: AR
authors.lastname: Satoskar
authors.affiliation: Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993; Hira.Nakhasi@fda.hhs.gov Abhay.Satoskar@osumc.edu.
authors.forename: Hira L
authors.initials: HL
authors.lastname: Nakhasi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003429:Cross Reactions / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects* / Q000235:genetics; D007893:Leishmania donovani / Q000235:genetics / Q000276:immunology*; D007894:Leishmania mexicana / Q000276:immunology*; D054332:Leishmaniasis Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D014613:Vaccines, Attenuated / Q000494:pharmacology
chemical_list: D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D054332:Leishmaniasis Vaccines; D014613:Vaccines, Attenuated