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.