Abstract
BackgroundHuman 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 FindingsTo 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.ConclusionsThese 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.
Highlights
Infection with the pathogenic filariae, Loa loa, Brugia malayi, Wuchereria bancrofti, and Onchocerca volvulus, causes an enormous disease burden throughout tropical and sub-tropical regions of the world
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
Expatriates who acquire infection are not subject to many of the environmental and familial factors that affect those born in endemic regions, the most notable being the alteration of immune responses specific for filarial antigens that occurs early in life [7,8,9], and that can persist long-term [10] as a consequence of in utero exposure to filarial antigens
Summary
Infection with the pathogenic filariae, Loa loa, Brugia malayi, Wuchereria bancrofti, and Onchocerca volvulus, causes an enormous disease burden throughout tropical and sub-tropical regions of the world. The clinical manifestations of infection are often markedly different in those with lifelong exposure (i.e. those born in filarial-endemic regions) and those that acquire infection later in life through travel to or temporary residence in a filarial-endemic area [1,2]. Expatriates with loiasis, for example, are more likely to have Calabar swellings and other ‘‘allergic’’ phenomena – such as marked peripheral blood eosinophilia, elevated IgE levels, and urticaria – than is seen in the more chronically infected patients born and raised in endemic areas [5]. 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)
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