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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900276v1 183/3/1813    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Selvapandiyan, A. Articles by Nakhasi, H. L. PubMed PubMed Citation Articles by Selvapandiyan, A. Articles by Nakhasi, H. L.

Intracellular Replication-Deficient Leishmania donovani Induces Long Lasting Protective Immunity against Visceral Leishmaniasis

Angamuthu Selvapandiyan^*, Ranadhir Dey^*, Susanne Nylen, Robert Duncan^*, David Sacks and Hira L. Nakhasi^1,*

^* Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, 20892; and Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

No vaccine is currently available for visceral leishmaniasis (VL) caused by Leishmania donovani. This study addresses whether a live attenuated centrin gene-deleted L. donovani (LdCen1^–/–) parasite can persist and be both safe and protective in animals. LdCen1^–/– has a defect in amastigote replication both in vitro and ex vivo in human macrophages. Safety was shown by the lack of parasites in spleen and liver in susceptible BALB/c mice, immune compromised SCID mice, and human VL model hamsters 10 wk after infection. Mice immunized with LdCen1^–/– showed early clearance of virulent parasite challenge not seen in mice immunized with heat killed parasites. Upon virulent challenge, the immunized mice displayed in the CD4⁺ T cell population a significant increase of single and multiple cytokine (IFN-, IL-2, and TNF) producing cells and IFN-/IL10 ratio. Immunized mice also showed increased IgG2a immunoglobulins and NO production in macrophages. These features indicated a protective Th1-type immune response. The Th1 response correlated with a significantly reduced parasite burden in the spleen and no parasites in the liver compared with naive mice 10 wk post challenge. Protection was observed, when challenged even after 16 wk post immunization, signifying a sustained immunity. Protection by immunization with attenuated parasites was also seen in hamsters. Immunization with LdCen1^–/– also cross-protected mice against infection with L. braziliensis that causes mucocutaneous leishmaniasis. Results indicate that LdCen1^–/– can be a safe and effective vaccine candidate against VL as well as mucocutaneous leishmaniasis causing parasites.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Hira Nakhasi, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892. E-mail address: hira.nakhasi{at}fda.hhs.gov

² Abbreviations used in this paper: CL, cutaneous leishmaniasis; MCL, mucocutaneous leishmaniasis; VL, visceral leishmaniasis; Wt, wild type; FTAg, freeze-thaw Ag; WI, week immunized; WPC, week post challenge.

³ The online version of this article contains supplemental material.