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ROLE OF CHEMOKINE-CHEMOKINE RECEPTORS IN THE PATHOGENESIS OF SEVERE PLASMODIUM FALCIPARUM MALARIA IN CHILDREN: IMPLICATIONS FOR MALARIA-HIV INTERACTION

Ochiel, Daniel Otieno (2005) ROLE OF CHEMOKINE-CHEMOKINE RECEPTORS IN THE PATHOGENESIS OF SEVERE PLASMODIUM FALCIPARUM MALARIA IN CHILDREN: IMPLICATIONS FOR MALARIA-HIV INTERACTION. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Molecular determinants of malaria pathogenesis are largely undefined. Chemokines and chemokine receptors, regulate immune responses, may thus determine malaria severity. Further, by regulating HIV pathogenesis, they may constitute a crucial link in malaria-HIV interaction. Understanding biologic mechanisms underlying malaria-HIV interaction has important public health utility in designing rational therapeutic and preventive strategies. Malaria could potentially modulate HIV-1 infection through alteration in expression of CD4 and chemokine receptors, required for cellular entry. This study has determined circulating levels and transcriptional profiles of β-chemokines (MIP-1α, MIP-1β, and RANTES) in ex vivo peripheral blood mononuclear cells (PBMCs) of children with varying degrees of malaria severity. Additional in vitro experiments assessed the effects of stimulation of PBMCs with crude hemozoin (Hz) or synthetic hemozoin (sHz) on CD4, β-chemokine and chemokine receptor (CCR5 and CXCR4) protein expression and transcript formation. Plasma MIP-1α and MIP-1β levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. β-chemokine gene expression closely matched circulating β-chemokine profile, illustrating that PBMCs are a primary source for β-chemokine production during malaria. Healthy children with a history of severe malaria had lower baseline RANTES production than children with a history of mild malaria, suggesting inherent differences in RANTES production. In vitro experiments in PBMCs from healthy malaria-naïve donors showed that Hz and sHz promote a similar pattern of β-chemokine protein secretion and transcript expression. FACS analysis showed that Hz and sHz induced similar patterns of cellular surface expression of CD4, CCR5 and CXCR4 on PBMCs. Hz or sHz-exerted differential effects on CD14+ and CD3+ subsets, and this modulatory effect part to transcriptional regulation based on gene expression profiles obtained for respective antigens. Additional studies showed that HIV-1 replicates differently in monoctye-derived macrophages (MDMs) stimulated with either Hz or sHz. sHz enhanced HIV-1 replication while Hz had an inhibitory effect. Results presented here demonstrate a distinct profile of β-chemokine expression in children with severe malaria, which is promoted by P. falciparum derived hemozoin. Further, Hz modulates expression of surface antigens required for HIV-1 entry, defining a possible mechanism for HIV-malaria interaction.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Ochiel, Daniel Otienodanielochiel@yahoo.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPerkins, Douglas Jdjp@pitt.eduDJP
Committee MemberRinaldo, Charles Rrinaldo@pitt.eduRINALDO
Committee MemberFerrell, Robert Erferrell@hgen.pitt.eduRFERRELL
Date: 14 June 2005
Date Type: Completion
Defense Date: 16 December 2004
Approval Date: 14 June 2005
Submission Date: 27 December 2004
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: CXCR4; CCR5; CD4; chemokine receptor; chemokines; MIP-1α; MIP-1β; RANTES; SDF-1; HIV; Malaria
Other ID: http://etd.library.pitt.edu/ETD/available/etd-12272004-131758/, etd-12272004-131758
Date Deposited: 10 Nov 2011 20:11
Last Modified: 15 Nov 2016 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/10456

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