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.
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