Elevated Adaptive Immune Responses Are Associated with Latent Infections of Wuchereria bancrofti

Abstract

In order to guarantee the fulfillment of their complex lifecycle, adult filarial nematodes release millions of microfilariae (MF), which are taken up by mosquito vectors. The current strategy to eliminate lymphatic filariasis as a public health problem focuses upon interrupting this transmission through annual mass drug administration (MDA). It remains unclear however, how many rounds of MDA are required to achieve low enough levels of MF to cease transmission. Interestingly, with the development of further diagnostic tools a relatively neglected cohort of asymptomatic (non-lymphedema) amicrofilaremic (latent) individuals has become apparent. Indeed, epidemiological studies have suggested that there are equal numbers of patent (MF + ) and latent individuals. Since the latter represent a roadblock for transmission, we studied differences in immune responses of infected asymptomatic male individuals (n = 159) presenting either patent (n = 92 MF + ) or latent (n = 67 MF − ) manifestations of Wuchereria bancrofti . These individuals were selected on the basis of MF, circulating filarial antigen in plasma and detectable worm nests. Immunological profiles of either Th1/Th17, Th2, regulatory or innate responses were determined after stimulation of freshly isolated PBMCs with either filarial-specific extract or bystander stimuli. In addition, levels of total and filarial-specific antibodies, both IgG subclasses and IgE, were ascertained from plasma. Results from these individuals were compared with those from 22 healthy volunteers from the same endemic area. Interestingly, we observed that in contrast to MF + patients, latent infected individuals had lower numbers of worm nests and increased adaptive immune responses including antigen-specific IL-5. These data highlight the immunosuppressive status of MF + individuals, regardless of age or clinical hydrocele and reveal immunological profiles associated with latency and immune-mediated suppression of parasite transmission.

Helminth Infections and Host Immune Regulation

“…Conversely, those cases succumbing to lymphatic pathology have deficient numbers of a key cell type, the regulatory T cell (Treg), while expressing stronger Th1 and Th17 effector components (14); the latter may be responsible for lymphatic inflammation against resident adult worms. Th17 cells are also more numerous in patients who have cleared bloodstream Mf (10), raising an interesting question of whether Mf directly downregulate Th17 responses and extend their survival by doing so.…”

Differential tissular distribution ofLitomosoides sigmodontismicrofilariae between microfilaremic and amicrofilaremic mice following experimental infection

“…Microfilaremia is higher in infected IL-4 KO, IL-5 KO, and IFNγ-KO mice, and intravenously inoculated microfilariae remain longer in the blood circulation before being cleared (Volkmann et al , 2001; Volkmann et al , 2003; Saeftel et al , 2003). In lymphatic filariasis infected individuals, TGF-βsingle nucleotide polymorphism has been associated with microfilaremic/amicrofilaremic status (Debrah et al , 2011) and latent infection of Wuchereria bancrofti has been shown to be associated with an elevated adaptive immune response (Arndts et al , 2012). This amicrofilaremic/microfilaremic profile is elegantly mirrored by mice models of filarial disease.…”

Patency of Litomosoides sigmodontis infection depends on Toll‐like receptor 4 whereas Toll‐like receptor 2 signalling influences filarial‐specific CD4+ T‐cell responses

“…The release of Mf into the periphery signals the final stage of filarial nematode life cycles. Studies in individuals presenting asymptomatic W. bancrofti infections revealed that Mf + individuals had dampened immune responses following filarial‐specific activation when compared with Mf – cohorts . Infections in BALB/c mice with L. sigmodontis also results in Mf + and Mf – animals and this study shows that immune responses between these groups are different.…”

“…Interestingly, only 50% of asymptomatic Wuchereria bancrofti ‐infected individuals become Mf + and as the Mf – group showed no overt signs of pathology this cohort remained largely undetected for many years. Although the reasons behind this phenomenon remain unclear the immunological profiles of these two cohorts are distinct . For example, when compared with Mf – individuals, peripheral blood mononuclear cells (PBMC) isolated from Mf + individuals displayed decreased tumour necrosis factor‐ α (TNF‐ α ), IL‐10 and IL‐5 upon filarial‐specific re‐stimulation .…”