Regulation of global gene expression in human loa loa infection is a function of chronicity

Background: human filarial infection is characterized by downregulated parasite-antigen specific t cell responses but distinct differences exist between patients with longstanding infection (endemics) and those who acquired infection through temporary residency or visits to filarial-endemic regions (expatriates). methods and findings: to characterize mechanisms underlying differences in t cells,analysis of global gene expression using human spotted microarrays was conducted on cd4 + and cd8 + t cells from microfilaremic loa loa-infected endemic and expatriate patients. assessment of unstimulated cells showed overexpression of genes linked to inflammation and caspase-associated cell death,particularly in endemics,and enrichment of the th1/th2 canonical pathway in endemic cd4 + cells. however,pathways within cd8 + unstimulated cells were most significantly enriched in both patient groups. antigen (ag)-driven gene expression was assessed to microfilarial ag (mfag) and to the nonparasite ag streptolysin o (slo). for mfag-driven cells,the number of genes differing significantly from unstimulated cells was greater in endemics compared to expatriates (p<0.0001). functional analysis showed a differential increase in genes associated with nfkb (both groups) and caspase activation (endemics). while the expatriate response to mfag was primarily a cd4 + pro-inflammatory one,the endemic response included cd4 + and cd8 + cells and was linked to insulin signaling,histone complexes,and ubiquitination. unlike the enrichment of canonical pathways in cd8 + unstimulated cells,both groups showed pathway enrichment in cd4 + cells to mfag. contrasting with the divergent responses to mfag seen between endemics and expatriates,the cd4 + response to slo was similar; however,cd8 + cells differed strongly in the nature and numbers (156 [endemics] vs 36 [expatriates]) of genes with differential expression. conclusions: these data suggest several important pathways are responsible for the different outcomes seen among filarial-infected patients with varying levels of chronicity and imply an important role for cd8 + cells in some of the global changes seen with lifelong exposure.