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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12272004-131758 |
| Date | 14 June 2005 |
| Creators | Ochiel, Daniel Otieno |
| Contributors | Charles R. Rinaldo Jr., PhD, Robert E. Ferrell, PhD, Douglas J. Perkins, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12272004-131758/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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