This is an application for a K23 award for Dr. Prasanna Jagannathan, a fellow in infectious diseases at the University of California at San Francisco who is establishing himself as a young investigator in patient-oriented, field-based studies of antimalarial immunity. This K23 award will provide Dr. Jagannathan with the support necessary to accomplish the following goals: (1) to study the impact of antimalarial chemoprevention on the development of IL-10-specific counterregulatory mechanisms and malaria-specific T cell responses in children living in high endemicity settings, and (2) to determine whether these responses correlate with protection from subsequent malaria. To achieve these goals, Dr. Jagannathan has assembled a mentoring team comprised of a primary mentor, Dr. Margaret Feeney, an expert in pediatric translational immunologic research in infectious diseases, and three co-mentors: Dr. Grant Dorsey, a malaria epidemiologist and PI of the parent clinical trial from which samples for this K23 will be obtained;Dr. Philip Rosenthal, a expert in malaria parasitology and antimalarial drug resistance;and Dr. Diane Havlir, an international leader of clinical research in HIV, TB, and malaria. Antimalarial chemoprevention is an emerging modality to prevent deaths and morbidity from malaria in children living in highly endemic areas, but there are concerns that it will delay the acquisition of antimalarial immunity. Recent studies in mice and humans have challenged this paradigm, and suggest that selective blockade of blood stage infection with antimalarial drugs may paradoxically enhance the development of sterilizing antimalarial immunity. Leveraging samples from an ongoing, NIH-funded randomized clinical trial of antimalarial chemoprevention in African children, Dr. Jagannathan will test the central hypothesis that chemoprevention suppresses the generation of IL-10 mediated counterregulatory mechanisms and allows for the development of polyfunctional malaria-specific CD4+ T cell responses. Specifically, he will compare IL-10 production by T cells and other immune cell populations (Aim 1) and malaria-specific T cell responses to whole parasite antigens using multiparameter flow cytometry (Aim 2) in children randomized to receive effective malaria chemoprevention or no chemoprevention. In the third aim, he will conduct a within-group analysis of the association between IL-10 production and malaria-specific T cell responses, and whether these responses are subsequently associated with reductions in the future incidence of malaria. Through a focused program of mentored training and coursework, the candidate will develop advanced skills in translational immunology, clinical research design, and the conduct of translational studies of malaria in resource-limited settings. At the completion of this award, Dr. Jagannathan will be well positioned to develop an R01 application to further define correlates and mechanisms of protective immunity to malaria.

Public Health Relevance

Malaria is responsible for nearly 1 million deaths/year, mostly among African infants and children. Antimalarial chemoprevention for children in endemic settings is a promising strategy, but concerns remain about its effect on the acquisition of antimalarial immunity. Through studying correlates of effective immunity to malaria in children utilizing samples collected as part of a field-based, randomized trial of chemoprevention, this proposal has the potential to inform the design of future strategies for antimalarial chemoprevention, vaccines, and other immunomodulatory approaches.

National Institute of Health (NIH)
Mentored Patient-Oriented Research Career Development Award (K23)
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Microbiology and Infectious Diseases Research Committee (MID)
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Rao, Malla R
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Jagannathan, Prasanna; Nankya, Felistas; Stoyanov, Cristina et al. (2015) IFN? Responses to Pre-erythrocytic and Blood-stage Malaria Antigens Exhibit Differential Associations With Past Exposure and Subsequent Protection. J Infect Dis 211:1987-96
Kamya, Moses R; Kapisi, James; Bigira, Victor et al. (2014) Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial. AIDS 28:2701-9
Jagannathan, Prasanna; Kim, Charlie C; Greenhouse, Bryan et al. (2014) Loss and dysfunction of V?2? ?? T cells are associated with clinical tolerance to malaria. Sci Transl Med 6:251ra117
Muhindo, Mary K; Kakuru, Abel; Jagannathan, Prasanna et al. (2014) Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated Plasmodium falciparum malaria. Malar J 13:32
Jagannathan, Prasanna; Eccles-James, Ijeoma; Bowen, Katherine et al. (2014) IFN?/IL-10 co-producing cells dominate the CD4 response to malaria in highly exposed children. PLoS Pathog 10:e1003864