Current Research and Scholarly Interests
Working with the Infectious Diseases Research Collaboration in Uganda, we have studied the development of naturally acquired antimalarial immunity in infants, young children, and pregnant women. In birth cohorts of infants in Eastern Uganda, the incidence of malaria is very high, and there is a high prevalence of asymptomatic parasitemia in young infants. We have reported that both infant sex (PMID 33272281) and sickle cell trait status (PMID 33738485) modify malaria immune phenotypes in infancy.
Following repeated Pf infections, children eventually gain the ability to tolerate parasitemia at low levels without developing symptoms. We have been studying how repeated Pf infections impact the innate immune response in children, and identified an atypical, CD56-negative NK cell subset that expands following repeated parasite exposure and correlated with protection against symptomatic malaria. These cells were functional, displaying capacity to perform antibody-dependent cellular cytotoxicity, but were rapidly lost in the absence of continuous exposure. These data suggest that continued exposure to Pf parasites is required to maintain this atypical subset of cells (PMID 36696483.) We also recently utilized EpiTOF, a single-cell epigenetic profiling technique developed at Stanford, and found that repeated exposure to Pf was associated with epigenetic changes across a number of innate immune cells that regulate excessive inflammation and contribute to naturally acquired immunity to malaria (PNAS Nexus, in Press). To further study the innate immune response to Pf, we are longitudinally profiling the innate and adaptive immune response to Pf infection in young children across single and repeated infections by utilizing broad, longitudinal, multiomic assessments of host immunity, along with computational approaches.
We also hypothesize that clinical tolerance to Pf infection is driven by expansion of malaria-specific regulatory CD4+ T cell populations. We have been studying malaria-specific CD4+ populations in children using single cell genomic approaches. We have found that clonal populations of Plasmodium-specific type 1 regulatory T cells expand following single and repeated Plasmodium infections, and are currently studying the impact of repeated Plasmodium infections on T cell populations in children and in mice through a collaboration with Dr. Ashraful Haque of the University of Melbourne.
We have also been studying malaria-specific immune responses in pregnancy. With successive pregnancies, women gain protection against malaria in pregnancy and adverse birth outcomes, but cellular correlates of both protection against malaria in pregnancy have not been identified and would assist with vaccine design. We reported that Plasmodium-specific Tr1 cells were highly prevalent in primigravid Ugandan women, and their presence correlated with a higher risk of malaria in pregnancy. (PMID 37634385).
Finally, we are evaluating novel, artemisinin-based chemoprevention to prevent malaria in high transmission settings in children and during pregnancy, and are interested in how strategies to prevent malaria might alter the development of protective immune responses. In a preliminary trial, we previously reported that prevention of malaria in infancy with chemoprevention may enhance subsequent protective immunity to malaria (PMID 31307883.) We are now conducting a Phase 3, placebo-controlled, randomized controlled trial, “Modifying immunity in children with dihydroartemisinin-piperaquine (MIC-DroP, NCT 04978272). In this trial, 924 Ugandan infants are being randomized to receive monthly dihydroartemisinin-piperaquine chemoprevention or placebo from 8 weeks to 2 years of age, then followed up to 4 years of age. Here, we are testing the hypothesis that effective prevention of malaria in infants infancy enhances protective immunity to malaria by limiting malaria-induced immunoregulatory mechanisms.
