?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F10456%2F&rft.title=ROLE+OF+CHEMOKINE-CHEMOKINE+RECEPTORS+IN+THE+PATHOGENESIS+OF+SEVERE+PLASMODIUM+FALCIPARUM+MALARIA+IN+CHILDREN%3A+IMPLICATIONS+FOR+MALARIA-HIV+INTERACTION&rft.creator=Ochiel%2C+Daniel+Otieno&rft.description=Molecular+determinants+of+malaria+pathogenesis+are+largely+undefined.+Chemokines+and+chemokine+receptors%2C+regulate+immune+responses%2C+may+thus+determine+malaria+severity.+Further%2C+by+regulating+HIV+pathogenesis%2C+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%2C+required+for+cellular+entry.+This+study+has+determined+circulating+levels+and+transcriptional+profiles+of+%CE%B2-chemokines+(MIP-1%CE%B1%2C+MIP-1%CE%B2%2C+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%2C+%CE%B2-chemokine+and+chemokine+receptor+(CCR5+and+CXCR4)+protein+expression+and+transcript+formation.+Plasma+MIP-1%CE%B1+and+MIP-1%CE%B2+levels+were+significantly+elevated+in+mild+and+severe+malaria%2C+while+RANTES+levels+decreased+with+increasing+disease+severity.+%CE%B2-chemokine+gene+expression+closely+matched+circulating+%CE%B2-chemokine+profile%2C+illustrating+that+PBMCs+are+a+primary+source+for+%CE%B2-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%2C+suggesting+inherent+differences+in+RANTES+production.+In+vitro+experiments+in+PBMCs+from+healthy+malaria-na%C3%AFve+donors+showed+that+Hz+and+sHz+promote+a+similar+pattern+of+%CE%B2-chemokine+protein+secretion+and+transcript+expression.+FACS+analysis+showed+that+Hz+and+sHz+induced+similar+patterns+of+cellular+surface+expression+of+CD4%2C+CCR5+and+CXCR4+on+PBMCs.+Hz+or+sHz-exerted+differential+effects+on+CD14%2B+and+CD3%2B+subsets%2C+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+%CE%B2-chemokine+expression+in+children+with+severe+malaria%2C+which+is+promoted+by+P.+falciparum+derived+hemozoin.+Further%2C+Hz+modulates+expression+of+surface+antigens+required+for+HIV-1+entry%2C+defining+a+possible+mechanism+for+HIV-malaria+interaction.&rft.date=2005-06-14&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F10456%2F1%2FOchielDETD2005.pdf&rft.identifier=++Ochiel%2C+Daniel+Otieno++(2005)+ROLE+OF+CHEMOKINE-CHEMOKINE+RECEPTORS+IN+THE+PATHOGENESIS+OF+SEVERE+PLASMODIUM+FALCIPARUM+MALARIA+IN+CHILDREN%3A+IMPLICATIONS+FOR+MALARIA-HIV+INTERACTION.++Master's+Thesis%2C+University+of+Pittsburgh.++++(Unpublished)++