Children residing in holoendemic regions of malaria transmission, such as western Kenya, are at an increased risk for developing life-threatening complications due to severe malarial anemia (SMA). Our recent findings in this area illustrate that the highest rates of SMA-associated morbidity and mortality occur in children between birth and 2 years of age. Therefore, we will investigate the genetic and immunologic mechanisms of SMA in young children residing in Kisumu, Kenya. Since effective cell-mediated immunity is required for controlling malaria infection, we will focus on defining the role of cytokines [interleukin (IL )-12, tumor necrosis factor (TNF)-alpha, macrophage migration inhibitory factor (MIF), IL-10 and transforming growth factor (TGF)-beta1], and effector molecules [nitric oxide (NO) and prostaglandin (PG)-E2] in the immunopathogenesis of SMA. The goals of this proposal are: 1) to identify unique profiles of cytokine and effector molecule gene expression associated with the development and outcome of SMA, 2) to determine if polymorphisms in the cytokine and effector molecule genes lead to disequilibrium in the cytokine balance that affects the clinical course and outcome of SMA, and 3) to identify novel patterns of gene expression associated with the immunopathogenesis of SMA. The overall goal of this proposal is to identify the immunomodulatory genes, whose critical patterns of expression underlie disease susceptibility to SMA. Successful completion of this project, that takes into account the complex genetic, inflammatory, and clinical factors that promote malarial anemia, will offer important information for the future development and testing of malaria vaccine candidates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051305-02
Application #
6651607
Study Section
Special Emphasis Panel (ZAI1-AM-M (J1))
Program Officer
Rao, Malla R
Project Start
2002-09-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
2
Fiscal Year
2003
Total Cost
$465,352
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Munde, Elly O; Okeyo, Winnie A; Raballah, Evans et al. (2017) Association between Fc? receptor IIA, IIIA and IIIB genetic polymorphisms and susceptibility to severe malaria anemia in children in western Kenya. BMC Infect Dis 17:289
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Ouma, Collins; Davenport, Gregory C; Garcia, Steven et al. (2012) Functional haplotypes of Fc gamma (Fc?) receptor (Fc?RIIA and Fc?RIIIB) predict risk to repeated episodes of severe malarial anemia and mortality in Kenyan children. Hum Genet 131:289-99
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Davenport, Gregory C; Hittner, James B; Were, Tom et al. (2012) Relationship between inflammatory mediator patterns and anemia in HIV-1 positive and exposed children with Plasmodium falciparum malaria. Am J Hematol 87:652-8

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