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ROLE OF MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) AND MIF PROMOTER POLYMORPHISMS IN THE PATHOGENESIS OF SEVERE MALARIAL ANEMIA

Awandare, Gordon Akanzuwine (2007) ROLE OF MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) AND MIF PROMOTER POLYMORPHISMS IN THE PATHOGENESIS OF SEVERE MALARIAL ANEMIA. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Severe malarial anemia (SMA), caused by infections with Plasmodium falciparum, is one of the leading causes of childhood mortality in sub-Saharan Africa. Although the molecular determinants of SMA are largely undefined, dysregulation in host-derived inflammatory mediators influences disease severity. Macrophage migration inhibitory factor (MIF) is an important regulator of innate inflammatory responses that has recently been shown to suppress erythropoiesis and promote pathogenesis of SMA in murine models. The role of MIF in childhood malarial pathogenesis was investigated by examining peripheral blood MIF production in children residing in a hyperendemic area of Gabon, and a holoendemic region of western Kenya. The relationship between MIF concentrations and monocytic acquisition of hemozoin, and the effects of MIF on erythropoiesis in vivo and in vitro were investigated. In addition, the influence of genetic variation at MIF -173 (G/C) and -794 (CATT5-8) on MIF production and susceptibility to SMA and high-density parasitemia (HDP) was examined. Circulating MIF concentrations and peripheral blood mononuclear cells (PBMC) MIF production progressively declined with increasing anemia severity and increasing levels of hemozoin-containing monocytes. However, circulating MIF concentrations were not significantly associated with reticulocyte production in children with acute malaria. Additional experiments in malaria-naïve individuals demonstrated that hemozoin caused both increased and decreased MIF production in cultured PBMC based on genetic differences. In addiiton, a novel in vitro model of erythropoiesis was developed and used to demonstrate that treatment with exogenous MIF or blocking endogenous MIF did not signifcantly impact on the efficiency of erythropoiesis. Genetic analyses revealed that the MIF -173 CC genotype was associated with an increased risk of HDP compared to MIF -173 GG. In addition, individuals with the MIF -794CATT6/-173G haplotype were significantly protected from SMA while those with -794CATT7/8/-173C haplotypes were at an increased risk of developing SMA. Taken together, our findings demonstrate that SMA is associated with decreased MIF production and that individuals with high MIF-producing genetic variants are less susceptible to severe malaria. The public health significance of this study is that investigations presented here increase our understanding of protective inflammatory responses to childhood malaria, which is critical in the formulation of an effective malarial vaccine.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Awandare, Gordon Akanzuwinegawandare@hotmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPerkins, Douglas Jaydjp@pitt.eduDJP
Committee MemberMartinson, Jeremy Jjmartins@pitt.eduJMARTINS
Committee MemberFerrell, Robert Erferrell@hgen.pitt.eduRFERRELL
Committee MemberBarratt-Boyes, Simonsmbb@pitt.eduSMBB
Date: 26 September 2007
Date Type: Completion
Defense Date: 8 June 2007
Approval Date: 26 September 2007
Submission Date: 5 June 2007
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 237
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: anemia; cytokines; hemozoin; macrophage migration inhibitory factor; polymorphisms; Severe malaria
Other ID: http://etd.library.pitt.edu/ETD/available/etd-06052007-111045/, etd-06052007-111045
Date Deposited: 10 Nov 2011 19:46
Last Modified: 15 Nov 2016 13:44
URI: http://d-scholarship.pitt.edu/id/eprint/8013

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