In addition to causing tremendous obstetric and neonatal morbidity, pregnancy-associated malaria may have lasting consequences for the development of immunity during childhood. It has long been known that the fetal immune system is predisposed toward development of tolerance upon exposure to foreign antigens. The biological mechanisms underlying this process are only beginning to be understood, but recent data support a novel model of "layered" immune development, wherein the fetal immune system is populated during development by two distinct waves of lymphoid progenitor cells that differ in their intrinsic properties and developmental potential: "fetal" T cells (Tf), which are tolerogenic, and "adult" T cells (Ta), which are poised to mount effector responses. We propose to test this hypothesis by examining the consequences of in utero exposure to malaria antigens among infants born to women participating in two randomized trials of chemoprevention during pregnancy in a highly malaria-endemic region of Uganda. We hypothesize that fetal exposure to malaria antigens in utero can induce immune tolerance, which interferes with the later development of antimalarial immunity. We further hypothesize that infants with a Tf-skewed (predominantly tolerogenic) T cell compartment at birth will develop less robust Th1 responses and be slower to acquire natural immunity to malaria. In three aims, we will assess the relationship between in utero exposure to malaria antigens, the proportion of "tolerogenic" fetal T cells present at birth (Tf:Ta ratio), and the frequency and function of malaria-specific effector T cells and FoxP3+ regulatory CD4 T cells in cord blood, and we will determine how these factors influence the T cell response to postnatal infection and the incidence of clinical malaria during the first 3 years of life. By performing longitudinal assessments of mother-infant pairs who are followed closely from mid-gestation through early childhood and differ only in their prenatal exposure to malaria antigens, the proposed investigations will test a novel paradigm for understanding human fetal immune ontogeny and will define the immune consequences of prenatal exposure to malaria, as well the potential of chemoprevention during pregnancy to enhance antimalarial immunity during childhood.

Public Health Relevance

The proposed studies will test the impact of enhanced chemoprevention during pregnancy on the development of antimalarial immunity during infancy, and will test a novel hypothesis for human fetal immune development. A better understanding of the mechanisms underlying fetal immune tolerance to malaria could lead to improved strategies to combat childhood malaria, and may also be of great importance for infant malaria vaccination strategies.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01HD059454-07
Application #
8706921
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
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
Boivin, Michael J; Sikorskii, Alla; Familiar-Lopez, Itziar et al. (2016) Malaria illness mediated by anaemia lessens cognitive development in younger Ugandan children. Malar J 15:210
Kakuru, Abel; Natureeba, Paul; Muhindo, Mary K et al. (2016) Malaria burden in a birth cohort of HIV-exposed uninfected Ugandan infants living in a high malaria transmission setting. Malar J 15:500
Achan, Jane; Kakuru, Abel; Ikilezi, Gloria et al. (2016) Growth Recovery Among HIV-infected Children Randomized to Lopinavir/Ritonavir or NNRTI-based Antiretroviral Therapy. Pediatr Infect Dis J 35:1329-1332
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
Marquez, Carina; Chamie, Gabriel; Achan, Jane et al. (2016) Tuberculosis Infection in Early Childhood and the Association with HIV-exposure in HIV-uninfected Children in Rural Uganda. Pediatr Infect Dis J 35:524-9
Odorizzi, Pamela M; Feeney, Margaret E (2016) Impact of In Utero Exposure to Malaria on Fetal T Cell Immunity. Trends Mol Med 22:877-888
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

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