Project 4: "Molecular and cellular action of HLA class II molecules, the major genetic risk factors for VL" The studies will build on observations made during the current TMRC, in collaboration with Phase 2 of the Welcome Trust Case Control Consortium (WTCCC2), that HLA DR_DQ class 11 region contains the major genetic risk factor for visceral leishmaniasis in India (and Brazil).
Four specific aims are proposed: 1. To determine transcriptional signatures in whole blood and/or splenic aspirates from active and past cases, and Quantiferon and/or antibody positive asymptomatic infected donors (Project 1), carrying risk versus protective HLA DRB1 allele groups. 2. To determine at mRNA and protein levels ex vivo, and following stimulation/infection of cells in vitro, whether cis-acting regulatory polymorphisms are functional correlates of risk and protective HLA DRB1 allele groups. 3. To purify, and identify using mass spectrometry, naturally processed leishmanial peptides from EBV transformed B cells prepared from HLA DRB1*13/*14 versus HLA DRB1*15 donors stimulated with whole crude parasite lysate prepared from a local Indian strain of L. donovani, compare with in silico predictions of epitopes and binding affinity, and develop a strategy to subvert the immune response by vaccination 4. To validate results of aim 3 by measuring antigen presenting cell function and immune response to naturally processed and predicted peptide epitopes in exposed individuals, including active and past cases, and asymptomatic infected donors.

Public Health Relevance

Project 4. These studies will contribute to understanding of the molecular and cellular basis of HLA class genes as the major genetic risk factors for disease, and have implications for therapeutics and vaccine design and delivery.

National Institute of Health (NIH)
Specialized Center (P50)
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Special Emphasis Panel (ZAI1)
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Banaras Hindu University
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Sundar, Shyam; Chakravarty, Jaya (2015) An update on pharmacotherapy for leishmaniasis. Expert Opin Pharmacother 16:237-52
Malaviya, Paritosh; Picado, Albert; Hasker, Epco et al. (2014) Health & Demographic Surveillance System profile: the Muzaffarpur-TMRC Health and Demographic Surveillance System. Int J Epidemiol 43:1450-7
Mudavath, Shyam Lal; Talat, Mahe; Rai, Madhukar et al. (2014) Characterization and evaluation of amine-modified graphene amphotericin B for the treatment of visceral leishmaniasis: in vivo and in vitro studies. Drug Des Devel Ther 8:1235-47
Hasker, Epco; Malaviya, Paritosh; Gidwani, Kamlesh et al. (2014) Strong association between serological status and probability of progression to clinical visceral leishmaniasis in prospective cohort studies in India and Nepal. PLoS Negl Trop Dis 8:e2657
Singh, Om Prakash; Hasker, Epco; Sacks, David et al. (2014) Asymptomatic Leishmania infection: a new challenge for Leishmania control. Clin Infect Dis 58:1424-9
Kumar, R; Singh, O P; Gautam, S et al. (2014) Enhanced expression of Toll-like receptors 2 and 4, but not 9, in spleen tissue from patients with visceral leishmaniasis. Parasite Immunol 36:721-5
Kumar, Dinesh; Tiwary, Puja; Chakravarty, Jaya et al. (2014) Association of interleukin-18 gene polymorphism with susceptibility to visceral leishmaniasis in endemic area of Bihar, an Indian population. ScientificWorldJournal 2014:852104
Singh, Om Prakash; Sundar, Shyam (2014) Whole blood assay and visceral leishmaniasis: Challenges and promises. Immunobiology 219:323-8
Sudarshan, Medhavi; Sundar, Shyam (2014) Parasite load estimation by qPCR differentiates between asymptomatic and symptomatic infection in Indian visceral leishmaniasis. Diagn Microbiol Infect Dis 80:40-2
Gautam, Shalini; Kumar, Rajiv; Singh, Neetu et al. (2014) CD8 T cell exhaustion in human visceral leishmaniasis. J Infect Dis 209:290-9

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