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. Project Narrative 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.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23AI100949-01
Application #
8353165
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Rao, Malla R
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$131,490
Indirect Cost
$9,740
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Sullivan, Richard T; Ssewanyana, Isaac; Wamala, Samuel et al. (2016) B cell sub-types following acute malaria and associations with clinical immunity. Malar J 15:139
Kakuru, Abel; Jagannathan, Prasanna; Muhindo, Mary K et al. (2016) Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med 374:928-39
Farrington, Lila A; Jagannathan, Prasanna; McIntyre, Tara I et al. (2016) Frequent Malaria Drives Progressive Vδ2 T-Cell Loss, Dysfunction, and CD16 Up-regulation During Early Childhood. J Infect Dis 213:1483-90
Rodriguez-Barraquer, Isabel; Arinaitwe, Emmanuel; Jagannathan, Prasanna et al. (2016) Quantifying Heterogeneous Malaria Exposure and Clinical Protection in a Cohort of Ugandan Children. J Infect Dis 214:1072-80
Muhindo, Mary K; Kakuru, Abel; Natureeba, Paul et al. (2016) Reductions in malaria in pregnancy and adverse birth outcomes following indoor residual spraying of insecticide in Uganda. Malar J 15:437
Prahl, Mary; Jagannathan, Prasanna; McIntyre, Tara I et al. (2016) Timing of in utero malaria exposure influences fetal CD4 T cell regulatory versus effector differentiation. Malar J 15:497
Rek, John; Katrak, Shereen; Obasi, Hannah et al. (2016) Characterizing microscopic and submicroscopic malaria parasitaemia at three sites with varied transmission intensity in Uganda. Malar J 15:470
Jagannathan, Prasanna; Bowen, Katherine; Nankya, Felistas et al. (2016) Effective Antimalarial Chemoprevention in Childhood Enhances the Quality of CD4+ T Cells and Limits Their Production of Immunoregulatory Interleukin 10. J Infect Dis 214:329-38
Sundell, Kerstin; Jagannathan, Prasanna; Huang, Liusheng et al. (2015) Variable piperaquine exposure significantly impacts protective efficacy of monthly dihydroartemisinin-piperaquine for the prevention of malaria in Ugandan children. Malar J 14:368
Boyle, Michelle J; Jagannathan, Prasanna; Bowen, Katherine et al. (2015) Effector Phenotype of Plasmodium falciparum-Specific CD4+ T Cells Is Influenced by Both Age and Transmission Intensity in Naturally Exposed Populations. J Infect Dis 212:416-25

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