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 #
1R01AI051305-01
Application #
6455946
Study Section
Special Emphasis Panel (ZAI1-AM-M (J1))
Program Officer
Wali, Tonu M
Project Start
2002-09-01
Project End
2006-06-30
Budget Start
2002-09-01
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$403,504
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Public Health
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Raballah, Evans; Kempaiah, Prakasha; Karim, Zachary et al. (2017) CD4 T-cell expression of IFN-? and IL-17 in pediatric malarial anemia. PLoS One 12:e0175864
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
Davenport, Gregory C; Hittner, James B; Otieno, Vincent et al. (2016) Reduced Parasite Burden in Children with Falciparum Malaria and Bacteremia Coinfections: Role of Mediators of Inflammation. Mediators Inflamm 2016:4286576
Lalremruata, Albert; Magris, Magda; Vivas-Martínez, Sarai et al. (2015) Natural infection of Plasmodium brasilianum in humans: Man and monkey share quartan malaria parasites in the Venezuelan Amazon. EBioMedicine 2:1186-92
Rivas, Ariel L; Jankowski, Mark D; Piccinini, Renata et al. (2013) Feedback-based, system-level properties of vertebrate-microbial interactions. PLoS One 8:e53984
Anyona, Samuel B; Kempaiah, Prakasha; Davenport, Gregory C et al. (2013) Suppressed circulating bicyclo-PGE2 levels and leukocyte COX-2 transcripts in children co-infected with P. falciparum malaria and HIV-1 or bacteremia. Biochem Biophys Res Commun 436:585-90
Okeyo, Winnie A; Munde, Elly O; Okumu, Wilson et al. (2013) Interleukin (IL)-13 promoter polymorphisms (-7402 T/G and -4729G/A) condition susceptibility to pediatric severe malarial anemia but not circulating IL-13 levels. BMC Immunol 14:15
Anyona, Samuel B; Kempaiah, Prakasha; Raballah, Evans et al. (2012) Reduced systemic bicyclo-prostaglandin-E2 and cyclooxygenase-2 gene expression are associated with inefficient erythropoiesis and enhanced uptake of monocytic hemozoin in children with severe malarial anemia. Am J Hematol 87:782-9
Kempaiah, Prakasha; Anyona, Samuel B; Raballah, Evans et al. (2012) Reduced interferon (IFN)-? conditioned by IFNA2 (-173) and IFNA8 (-884) haplotypes is associated with enhanced susceptibility to severe malarial anemia and longitudinal all-cause mortality. Hum Genet 131:1375-91
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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