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.
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.
|Wallender, Erika; Vucicevic, Katarina; Jagannathan, Prasanna et al. (2018) Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz. J Infect Dis 217:964-972|
|Harrington, Whitney E; Kakuru, Abel; Jagannathan, Prasanna (2018) Malaria in pregnancy shapes the development of foetal and infant immunity. Parasite Immunol :e12573|
|Savic, Rada M; Jagannathan, Prasanna; Kajubi, Richard et al. (2018) Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine. Clin Infect Dis 67:1079-1088|
|Jagannathan, Prasanna; Kakuru, Abel; Okiring, Jaffer et al. (2018) Dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria during pregnancy and risk of malaria in early childhood: A randomized controlled trial. PLoS Med 15:e1002606|
|Jagannathan, Prasanna; Kajubi, Richard; Aweeka, Francesca T (2018) Response to ""Antiretroviral Therapy With Efavirenz in HIV-Infected Pregnant Women: Understanding the Possible Mechanisms for Drug-Drug Interaction"". Clin Pharmacol Ther 103:571|
|Kapisi, James; Kakuru, Abel; Jagannathan, Prasanna et al. (2017) Relationships between infection with Plasmodium falciparum during pregnancy, measures of placental malaria, and adverse birth outcomes. Malar J 16:400|
|Prahl, Mary; Jagannathan, Prasanna; McIntyre, Tara I et al. (2017) Sex Disparity in Cord Blood FoxP3+ CD4 T Regulatory Cells in Infants Exposed to Malaria In Utero. Open Forum Infect Dis 4:ofx022|
|Kajubi, R; Huang, L; Jagannathan, P et al. (2017) Antiretroviral Therapy With Efavirenz Accentuates Pregnancy-Associated Reduction of Dihydroartemisinin-Piperaquine Exposure During Malaria Chemoprevention. Clin Pharmacol Ther 102:520-528|
|Conrad, Melissa D; Mota, Daniel; Foster, Marissa et al. (2017) Impact of Intermittent Preventive Treatment During Pregnancy on Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Uganda. J Infect Dis 216:1008-1017|
|Jagannathan, Prasanna; Lutwama, Fredrick; Boyle, Michelle J et al. (2017) V?2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure. Sci Rep 7:11487|
Showing the most recent 10 out of 33 publications