Plasmodium falciparum malaria causes more infant mortality and morbidity in sub-Saharan Africa than any other single infection. In areas where malaria transmission is stable over time, the bulk of malaria-related morbidity occurs within the first two to three years after birth; it declines thereafter as a consequence of acquisition of immunity to blood-stage infection. Pregnancy increases the susceptibility of partially immune women to malaria, such that African infants are often born of mothers infected with malaria during gestation. Thus infected red blood cells, soluble antigenic products, or maternal lymphocytes and antibodies may cross the placenta and expose the fetus. This could result in the fetal immune system becoming sensitized, or alternatively tolerant, to potentially protective blood-stage antigens (such as merozoite surface proteins involved in invasion of red blood cells). Our overall goal is to examine how prenatal exposure to malaria influences immunity to blood-stage infection. An immediate objective is to characterize fetal T cell (Tc) memory in reaction to the C-terminal 42 kD fragment of Merozoite Surface Protein-1 (MSP-142), a malaria antigen that looks promising as a vaccine candidate antigen. We seek to clarify how this pre-natal immunologic experience impacts upon the acquisition of T- and B-cell immunity to MSP-142 between birth and 3 years of age. Our central hypothesis is that heavy exposure of the fetus to malaria antigens will stimulate production of MSPl42-specific memory Tc in utero, as well as higher antibodies levels to the C-terminal portion of MSP 1, thereby inhibiting red cell invasion during infancy. Conversely, light exposure of the fetus to malaria will produce the opposite effect by development of Tc anergy or generation of T regulatory cells, resulting in reduced frequency of MSP-142-specific T helper cells and lower levels of invasion inhibitory Abs, consequently increasing the risk for malaria infection. These hypotheses will be evaluated in the following specific aims: (1) To determine the phenotype and frequency of malaria-specific T cells acquired in utero from newborns in a malaria endemic population. (2) To define the mechanisms of fetal exposure to MSP 142 and how this exposure regulates the phenotypes of malariaspecific T cells acquired in utero. (3) To evaluate whether the type of MSP 142-specific CD45RA- memory cells acquired in utero affects the frequencies and phenotype of MSP 1-specific T cells and levels of invasion inhibitory Abs to MSP 119 from birth to 3 years of age.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI064687-01
Application #
6911080
Study Section
Special Emphasis Panel (ZRG1-IHD (01))
Program Officer
Rao, Malla R
Project Start
2005-07-01
Project End
2010-03-31
Budget Start
2005-07-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$328,313
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Malhotra, Indu; LaBeaud, A Desiree; Morris, Nathan et al. (2018) Cord Blood Antiparasite Interleukin 10 as a Risk Marker for Compromised Vaccine Immunogenicity in Early Childhood. J Infect Dis 217:1426-1434
Fowkes, Freya J I; Moore, Kerryn A; Opi, D Herbert et al. (2018) Iron deficiency during pregnancy is associated with a reduced risk of adverse birth outcomes in a malaria-endemic area in a longitudinal cohort study. BMC Med 16:156
Pehrson, Caroline; Mathiesen, Line; Heno, Kristine K et al. (2016) Adhesion of Plasmodium falciparum infected erythrocytes in ex vivo perfused placental tissue: a novel model of placental malaria. Malar J 15:292
Atwell, Jessica E; Thumar, Bhagvanji; Robinson, Leanne J et al. (2016) Impact of Placental Malaria and Hypergammaglobulinemia on Transplacental Transfer of Respiratory Syncytial Virus Antibody in Papua New Guinea. J Infect Dis 213:423-31
Malhotra, Indu; McKibben, Maxim; Mungai, Peter et al. (2015) Effect of antenatal parasitic infections on anti-vaccine IgG levels in children: a prospective birth cohort study in Kenya. PLoS Negl Trop Dis 9:e0003466
LaBeaud, A Desiree; Nayakwadi Singer, Monica; McKibben, Maxim et al. (2015) Parasitism in Children Aged Three Years and Under: Relationship between Infection and Growth in Rural Coastal Kenya. PLoS Negl Trop Dis 9:e0003721
McClure, Elizabeth M; Meshnick, Steven R; Mungai, Peter et al. (2014) The association of parasitic infections in pregnancy and maternal and fetal anemia: a cohort study in coastal Kenya. PLoS Negl Trop Dis 8:e2724
McClure, Elizabeth M; Meshnick, Steven R; Lazebnik, Noam et al. (2014) A cohort study of Plasmodium falciparum malaria in pregnancy and associations with uteroplacental blood flow and fetal anthropometrics in Kenya. Int J Gynaecol Obstet 126:78-82
Wilson, Patrick T; Malhotra, Indu; Mungai, Peter et al. (2013) Transplacentally transferred functional antibodies against Plasmodium falciparum decrease with age. Acta Trop 128:149-53
Kalayjian, Benjamin C; Malhotra, Indu; Mungai, Peter et al. (2013) Marked decline in malaria prevalence among pregnant women and their offspring from 1996 to 2010 on the south Kenyan Coast. Am J Trop Med Hyg 89:1129-34

Showing the most recent 10 out of 18 publications