: Malaria kills 1 million African children each year. However, although all infants in holoendemic areas develop parasitemia frequently, only 10 percent develop severe anemia, the commonest cause of death. We previously showed that parasite adhesion and anti-adhesion antibodies explain susceptibility and resistance to pregnancy malaria. Because the parasites infecting children have binding phenotypes distinct from those infecting adults, we hypothesize that a similar paradigm explains the pathogenesis of infancy malaria. We propose a longitudinal study of infants from birth through age 3. We will examine samples for: 1) P. falciparum adhesion phenotype; 2) anti-adhesion antibodies; 3) presence of parasites in hemoglobin (Hb)Fvs HbA-containing (i.e., fetal vs. maternal) red cells; 4) levels of p-amino benzoic acid (PABA), HbF, and antibodies. We will test our primary hypothesis that parasite binding and anti-adhesion antibodies predict severe infancy malaria. In addition, we will examine a secondary hypothesis that neonates are resistant to malaria because their vasculature does not support parasite binding. Based on our hypotheses, we expect the following results: 1) parasite adhesion phenotypes change with host age; 2) anti-adhesion antibodies protect infants from parasites with the corresponding adhesion phenotype; 3) parasite binding patterns and specific anti-adhesion antibodies predict protection from severe anemia; 4) cord blood parasites will bind CSA, and parasites will appear exclusively in HbA-containing red cells of neonates; 5) the genotype and binding phenotype will differ between cord blood isolates and isolates obtained at the time of an infant's first infection. We will examine other factors for their effect on malaria, including transpiacentally transferred maternal antibodies, HbF, and PABA levels, and we will determine HIV status as a potential confounder in these studies. If breastfeeding confers resistance to malaria by limiting PABA intake, this will influence the debate on whether HIV-infected women in tropical areas should breastteed. These studies will establish the roles of parasite adhesion and anti-adhesion antibodies in the pathogenesis of infancy malaria, and may identify new targets for antimalarial therapies in children. Identifying new therapies for children is an urgent public health goal, but is not a funding priority for the United States Department of Defense.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052059-02
Application #
6532906
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rao, Malla R
Project Start
2001-09-30
Project End
2005-05-31
Budget Start
2002-08-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$642,061
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109
Harrington, Whitney E; Kanaan, Sami B; Muehlenbachs, Atis et al. (2017) Maternal Microchimerism Predicts Increased Infection but Decreased Disease due to Plasmodium falciparum During Early Childhood. J Infect Dis 215:1445-1451
Nixon, Christina E; Park, Sangshin; Pond-Tor, Sunthorn et al. (2017) Identification of Protective B-Cell Epitopes within the Novel Malaria Vaccine Candidate Plasmodium falciparum Schizont Egress Antigen 1. Clin Vaccine Immunol 24:
Nash, Scott D; Prevots, D Rebecca; Kabyemela, Edward et al. (2017) A Malaria-Resistant Phenotype with Immunological Correlates in a Tanzanian Birth Cohort Exposed to Intense Malaria Transmission. Am J Trop Med Hyg 96:1190-1196
Gonçalves, Bronner P; Prevots, D Rebecca; Kabyemela, Edward et al. (2016) Preparing for future efficacy trials of severe malaria vaccines. Vaccine 34:1865-7
Brickley, Elizabeth B; Wood, Angela M; Kabyemela, Edward et al. (2015) Fetal origins of malarial disease: cord blood cytokines as risk markers for pediatric severe malarial anemia. J Infect Dis 211:436-44
Gadalla, Nahla B; Tavera, Gloria; Mu, Jianbing et al. (2015) Prevalence of Plasmodium falciparum anti-malarial resistance-associated polymorphisms in pfcrt, pfmdr1 and pfnhe1 in Muheza, Tanzania, prior to introduction of artemisinin combination therapy. Malar J 14:129
Raj, Dipak K; Nixon, Christian P; Nixon, Christina E et al. (2014) Antibodies to PfSEA-1 block parasite egress from RBCs and protect against malaria infection. Science 344:871-7
Gonçalves, Bronner P; Huang, Chiung-Yu; Morrison, Robert et al. (2014) Parasite burden and severity of malaria in Tanzanian children. N Engl J Med 370:1799-808
Kabyemela, Edward; Gonçalves, Bronner P; Prevots, D Rebecca et al. (2013) Cytokine profiles at birth predict malaria severity during infancy. PLoS One 8:e77214
Harrington, Whitney E; Morrison, Robert; Fried, Michal et al. (2013) Intermittent preventive treatment in pregnant women is associated with increased risk of severe malaria in their offspring. PLoS One 8:e56183

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