Project 3: Immune regulation in visceral leishmaniasis will continue to study the immunologic defects associated with human visceral leishmaniasis with a view toward developing immune based therapies that will reverse the immunosuppression associated with active disease. The studies will continue to focus on the nature and mode of action of regulatory cells and suppressive cytokines that are present in lesional tissue and peripheral blood during active disease.
Four specific aims are proposed:
Aim 1 will undertake comprehensive immune response profiling of peripheral, whole blood cells from active and clinically cured VL patients at the transcriptional and protein levels to identify correlates of immunity or progressive disease.
Aim 2 will test the effect of immune-modulation on parasite survival ex vivo. Splenic aspirate cells obtained for diagnostic purposes will be used to reveal a direct effect of endogenous IL-10 as well as other activating and deactivating cytokines on parasite growth or killing in a target organ by taking advantage of the fact that the aspirate contains infected macrophages as well as the regulatory and effector cells thought to be relevant to the infection outcome.
Aim 3 will explore in detail the regulation of IL-10 production by T cells in human VL, focusing on IL-27 and lL-21 signaling in the induction and amplification of the T cell IL-10 response. Elevated IL-10 is associated with many chronic infections in humans, including HIV, TB, and malaria, yet no studies on the regulation of human IL-10 in an infectious disease setting have been reported.
Aim 4 will investigate the role of CD8+ T cells in human VL to determine if they contribute a suppressive or pathologic function. Splenic CD8+ T cells from VL patients have been found to be enriched in IL-10 and in inhibitory signaling molecules, PD-1 and CTLA-4. No CD8 functional studies in VL have been previously described.

Public Health Relevance

Project 3. The studies proposed in Project 3 may reveal immunosuppressive pathways that account for the severe progression and fatal outcome of untreated VL, and may identify novel targets of immune based therapies to enhance current treatments for VL.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center (P50)
Project #
5P50AI074321-09
Application #
8896403
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Banaras Hindu University
Department
Type
DUNS #
650330558
City
Varanasi
State
Country
India
Zip Code
221005
Sundar, Shyam; Singh, Anup (2018) Chemotherapeutics of visceral leishmaniasis: present and future developments. Parasitology 145:481-489
Sundar, Shyam; Singh, Bhawana (2018) Emerging therapeutic targets for treatment of leishmaniasis. Expert Opin Ther Targets 22:467-486
Sundar, Shyam; Singh, Bhawana (2018) Understanding Leishmania parasites through proteomics and implications for the clinic. Expert Rev Proteomics 15:371-390
Sundar, Shyam; Agarwal, Dipti (2018) Visceral Leishmaniasis-Optimum Treatment Options in Children. Pediatr Infect Dis J 37:492-494
Singh, Neetu; Sundar, Shyam (2018) Combined neutralization of interferon gamma and tumor necrosis factor alpha induces IL-4 production but has no direct additive impact on parasite burden in splenic cultures of human visceral leishmaniasis. PLoS One 13:e0199817
Singh, Neetu; Kumar, Rajiv; Chauhan, Shashi Bhushan et al. (2018) Peripheral Blood Monocytes With an Antiinflammatory Phenotype Display Limited Phagocytosis and Oxidative Burst in Patients With Visceral Leishmaniasis. J Infect Dis 218:1130-1141
Singh, Toolika; Fakiola, Michaela; Oommen, Joyce et al. (2018) Epitope-Binding Characteristics for Risk versus Protective DRB1 Alleles for Visceral Leishmaniasis. J Immunol 200:2727-2737
Kelly, Patrick H; Bahr, Sarah M; Serafim, Tiago D et al. (2017) The Gut Microbiome of the Vector Lutzomyia longipalpis Is Essential for Survival of Leishmania infantum. MBio 8:
Sharma, Smriti; Srivastva, Shweta; Davis, Richard E et al. (2017) The Phenotype of Circulating Neutrophils during Visceral Leishmaniasis. Am J Trop Med Hyg 97:767-770
Kansal, S; Chakravarty, J; Kumar, A et al. (2017) Risk Factors associated with defaulting from visceral leishmaniasis treatment: analysis under routine programme conditions in Bihar, India. Trop Med Int Health 22:1037-1042

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