Deciphering mechanisms of CD4+ T cell-dependent clinical immunity to repeated Plasmodium infections

With repeated Plasmodium infections, children eventually gain the ability to tolerate Plasmodium parasitemia without developing symptoms. However, preventing malaria with effective chemoprevention may delay development of this clinical immunity, such that children are at increased risk of more severe disease following cessation. Although mechanisms controlling development of clinical immunity remain unclear, effector and regulatory CD4+ T cells play a critical role in orchestrating a coordinated immune response to pathogens including malaria. Plasmodium-specific Type 1 regulatory CD4+ T cells (Tr1) are a specialized, tolerogenic CD4 subset that expand following Plasmodium infection in humans and mice, although genetic mechanisms that support Tr1 differentiation and maintenance remain unresolved. It also remains unclear whether these represent clonal expansions, contribute to a stable memory pool, and/or play a role in mediating clinical immunity to subsequent Plasmodium infections. The hypothesis is that clonal populations of Plasmodium– specific Tr1 cells expand following Plasmodium infection, are critical mediators of clinical immunity to repeated infection, and are limited by effective chemoprevention. To test the hypotheses, two extraordinary and complementary cohorts will be leveraged to longitudinally and comprehensively analyze the CD4+ T cell response in children. Aim 1 will analyze samples already obtained from children enrolled in the Ugandan International Centers of Excellence in Malaria cohorts before, during, and at multiple time points following a single and repeated malaria infection. CD4+ T cell population dynamics will be studied within the same child over time using innovative single cell transcriptomic and epigenomic approaches that we have optimized. The study will predict genes and other genetic loci that support or suppress Tr1 responses in children, and determine associations with antibody responses and clinical phenotypes of infection. Aim 2 will analyze samples collected as part of the Modifying Immunity in Children with Dihydroartemisin-Piperaquine (MIC-DroP) clinical trial, in which 924 infants are being randomized to receive artemisinin-based chemoprevention vs. placebo from birth to 2 years of age, then followed to 4 years of age. It will determine whether preventing repeated infection interferes with Tr1 development, and whether specific malaria-specific CD4+ T cell populations correlate with clinical outcomes following the cessation of chemoprevention. Finally, to complement the pediatric studies, Aim 3 will perform studies of experimental re-infection and chemoprevention in mice, since these systems permit detailed analysis of CD4+ T cell dynamics in the first few hours and days after a reinfection event, and can assess organ-specific CD4+ responses in both the spleen and liver. This study of Plasmodium-specific CD4+ T cell dynamics in humans and mice will provide critical insight into how the adaptive immune system tolerates foreign antigens, and lay the foundation for the development of therapeutic strategies aimed at reducing disease severity and/or enhancing parasite clearance.

NIH Project details

Asymptomatic Reservoir
Basic Science

Mar 2024 — Jan 2029

$616,546

United States