Prenatal exposure to microbial antigens can alter neonatal immunity to pathogens, modulate responses to pediatric vaccines, and increase infant susceptibility to infections. Infants born to mothers with P. falciparum infection during pregnancy are at increased risk of developing malaria during infancy, when symptoms are most severe and the risk of dying from the infection is highest. V?2V?2 lymphocytes, a subset of ?? T cells, mount rapid responses to a broad array of infectious agents, including plasmodia and mycobacteria. Numerous observations suggest the involvement of V?2V?2 lymphocytes in controlling malaria infection, and P. falciparum infection perturbs their homeostasis in adults contracting malaria for the first time. V?2V?2 lymphocytes take part in responses to Bacille Calmette-Gu?rin (BCG), the vaccine against tuberculosis, which is routinely administered to neonates in Sub-Saharan Africa. V?2V?2 T cell responses are antigen specific, yet MHC unrestricted, so all individuals recognize the same antigens independently of HLA haplotypes. Our preliminary results suggest that placental malaria affects fetal V?2V?2 lymphocyte phenotype, proliferation and repertoire maturation, attenuating the selection of neonatal pathogen-reactive V?2V?2 lymphocytes. We hypothesize that strong prenatal antigen stimulation, occurring in particular during placental malaria, induces deletion of pathogen-reactive V?2V?2 lymphocytes, affecting their repertoire and reactivity in neonates. This might have clinical impacts, contributing to increased malaria morbidity and lower responses to BCG vaccination during infancy. In this perspective, we seek to address two key problems concerning the impact of maternal malaria on fetal immunity and newborn responses to pathogens or pediatric vaccines. First, we want to define the impact of placental malaria on fetal immunity by quantifying changes among ?? T cells. Second, knowing that V?2V?2 T cells respond both to P. falciparum and BCG, we will test whether changes among V?2V?2 T cells link placental malaria directly to impaired BCG reactivity in newborn. To achieve these goals, we will compare V?2V?2 lymphocyte repertoire and responses to P. falciparum and BCG in three exposure groups of neonates and infants: no prenatal exposure to malaria, prenatal exposure to maternal peripheral infection with no placental involvement, and prenatal exposure to placental infection. Our long-term goal is to capitalize on our understanding of immune mechanisms at the fetal-maternal interface for developing intervention strategies to improve responses to pediatric vaccinations.

Public Health Relevance

In utero exposure to P. falciparum antigens causes priming of the fetal immune system, and can have negative consequences on infant immunity and health. Our goal is to define the impact of prenatal exposure to P. falciparum on neonatal and infant immunity by measuring changes in the T cells, which play important roles in antimicrobial immunity and participate in responses to Bacille Calmette-Gurin (BCG), the vaccine against tuberculosis. We seek to test whether dysfunction of newborn T cells may have clinical impacts, contributing to increased malaria morbidity and linking placental malaria to impaired BCG reactivity in infants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI104702-02
Application #
8608480
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Rao, Malla R
Project Start
2013-02-01
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$336,924
Indirect Cost
$110,255
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Cairo, Cristiana; Longinaker, Nyaradzo; Cappelli, Giulia et al. (2014) Cord blood Výý2Výý2 T cells provide a molecular marker for the influence of pregnancy-associated malaria on neonatal immunity. J Infect Dis 209:1653-62