: Women living in high malaria endemic areas are at an increased risk for Plasmodial infection during pregnancy. The prevalence and density of parasitemia is highest among primigravidae, and commonly leads to maternal anemia and low birth weight. The placenta is especially susceptible to infection, with parasite densities being frequently higher than those in the peripheral blood. The underlying immunologic basis for the increased susceptibility of pregnant women (and their placentae) to malaria and the dependence of this susceptibility on gravidity are poorly understood. The objective of this application is to determine the cellular immune mechanisms that mediate resistance to placental malaria. The central hypothesis of this proposal is that the decreased susceptibility of multigravidae to placental infection is dependent on development of tissue-specific, T cell-mediated, memory immune responses against malaria in the placental blood.
The specific aims are to 1) to characterize cell-mediated immune memory in the placenta and identify the elements that contribute to protection against placental malaria, and 2) determine the role of chemokines in the regulation of memory immune responses against malarial infection in the placenta. Comparison of peripheral and placental blood collected at delivery using flow cytometry, ELISPOT, ELISA, and RNase protection assays, and examination of placental tissue using immunohistochemistry, will be used to 1) identify the phenotypic and functional components of placental cellular memory responses to malaria that distinguish multigravidae from primigravidae, susceptible women from resistant women, and pathogenic responses from protective responses, 2) determine the extent to which these placental responses are distinct from those in the peripheral blood, and 3) determine how differential, local chemokine expression patterns in the placenta influence memory immune responses to placental malaria. Expanded knowledge of protective, anti-malarial immune mechanisms that are developed and maintained in the immunomodulated state of pregnancy will facilitate application of immunologic tools, such as malaria vaccines when they become available, to the prevention and control of malaria in pregnant women. Preventing malaria in pregnant women will significantly reduce both the disease burden of women in the developing world and the loss of infants in their first few months of life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050240-03
Application #
6604961
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Naficy, Abdollah B
Project Start
2001-09-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$340,722
Indirect Cost
Name
University of Georgia
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Sarr, Demba; Cooper, Caitlin A; Bracken, Tara C et al. (2017) Oxidative Stress: A Potential Therapeutic Target in Placental Malaria. Immunohorizons 1:29-41
Cobb, David W; Florentin, Anat; Fierro, Manuel A et al. (2017) The Exported Chaperone PfHsp70x Is Dispensable for the Plasmodium falciparum Intraerythrocytic Life Cycle. mSphere 2:
Sarr, D; Bracken, T C; Owino, S O et al. (2015) Differential roles of inflammation and apoptosis in initiation of mid-gestational abortion in malaria-infected C57BL/6 and A/J mice. Placenta 36:738-49
Iriemenam, Nnaemeka C; Shah, Monica; Gatei, Wangeci et al. (2012) Temporal trends of sulphadoxine-pyrimethamine (SP) drug-resistance molecular markers in Plasmodium falciparum parasites from pregnant women in western Kenya. Malar J 11:134
Moore, Julie M; Avery, John W (2012) Defibrotide: a Swiss Army knife intervention in the battle against cerebral malaria. Arterioscler Thromb Vasc Biol 32:541-4
Avery, John W; Smith, Geoffrey M; Owino, Simon O et al. (2012) Maternal malaria induces a procoagulant and antifibrinolytic state that is embryotoxic but responsive to anticoagulant therapy. PLoS One 7:e31090
Talundzic, Eldin; Shah, Sheel; Fawole, Ope et al. (2012) Sequence polymorphism, segmental recombination and toggling amino acid residues within the DBL3X domain of the VAR2CSA placental malaria antigen. PLoS One 7:e31565
Lucchi, N W; Sarr, D; Owino, S O et al. (2011) Natural hemozoin stimulates syncytiotrophoblast to secrete chemokines and recruit peripheral blood mononuclear cells. Placenta 32:579-85
Perrault, Steven D; Hajek, Jan; Zhong, Kathleen et al. (2009) Human immunodeficiency virus co-infection increases placental parasite density and transplacental malaria transmission in Western Kenya. Am J Trop Med Hyg 80:119-25
Conroy, Andrea; Serghides, Lena; Finney, Constance et al. (2009) C5a enhances dysregulated inflammatory and angiogenic responses to malaria in vitro: potential implications for placental malaria. PLoS One 4:e4953

Showing the most recent 10 out of 21 publications