Severe malarial anemia (SMA) is the most common clinical manifestation of severe malaria in infants and young children and causes ~ 20% mortality in children <3 years in areas holoendemic for P. falciparum. SMA is a multifactorial disease involving increased erythrocyte destruction as well as decreased erythrocyte production. Although the etiology of these mechanisms likely involves dysregulation in inflammatory mediators, the underlying molecular basis of SMA remains largely undefined. The current application is a competing continuation of a previously funded proposal in response to an RFA to meet this challenge. To gain improved understanding of the factors that regulate SMA, we have taken a genetic-based approach that investigates the role of innate inflammatory mediators in conditioning the development and outcomes of SMA in children residing in a holoendemic area of malaria transmission in western Kenya. Our previous application focused on defining the complex phenotype of SMA by performing extensive clinical evaluations so that the underlying genes responsible for the varied outcomes could be established. These investigations identified a number of novel inflammatory mediators and polymorphisms within immune response genes associated with susceptibility to SMA. These studies further revealed that HIV-1 exposure significantly enhanced the development of SMA during acute malaria. This finding has important public health implications since 20% of the study participants were exposed to HIV-1, a rate comparable to that throughout much of sub-Saharan Africa. Although we successfully defined factors that promote SMA, these studies were limited due to small sample volumes available from severely anemic children. Recent advances in biotechnology now allow for cost-effective, high-throughput genetic and immunological analyses that overcome these limitations. Since malaria is a polygenic disease, exploration of a larger panel of genes is required to successfully identify those variants that condition clinical outcomes. As such, in the competing continuation, we will investigate a comprehensive, but focused panel of innate immune response genes we hypothesize to be important in conditioning acute and longitudinal outcomes of SMA. This will allow for construction of haplotypes which appear to be better predictors of complex disease outcomes than individual polymorphisms. The primary goals of this proposal are: 1) to determine the genotypic profiles and haplotypic structures that condition the development and outcomes of SMA in children with malaria as a single disease and in children exposed to HIV-1, and 2) to identify innate immune response genes that mediate protective immunity against SMA following repeated episodes of malaria. The overall goal of this proposal is to identify critical genes that underlie susceptibility to SMA. Successful accomplishment of this goal will aid in identifying those children in which targeted therapeutic interventions are required.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051305-08
Application #
7778268
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Rao, Malla R
Project Start
2002-09-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
8
Fiscal Year
2010
Total Cost
$557,423
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
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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
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
Kempaiah, Prakasha; Dokladny, Karol; Karim, Zachary et al. (2016) Reduced Hsp70 and Glutamine in Pediatric Severe Malaria Anemia: Role of Hemozoin in Suppressing Hsp70 and NF-?B activation. Mol Med :
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
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; 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
Rivas, Ariel L; Fasina, Folorunso O; Hoogesteyn, Almira L et al. (2012) Connecting network properties of rapidly disseminating epizoonotics. PLoS One 7:e39778
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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