Wolbachia and river blindness

Abstract

The filarial nematode Onchocerca volvulus is the causative agent of river blindness. Onchocerca volvulus can result in a range of disease states, one of which is eye disease, but the aetiology of this eye disease is unclear. It has been thought that microfilariae (the first larval stage progeny of adult worms) can enter the host eye and (perhaps following microfilarial death) generate immune responses which can cause eye disease. Other work has suggested that the immunological cross-reaction between O. volvulus antigens and human eye antigens are the reason for this immune damage.Recently, it has been found that O. volvulus and a range of other filarial nematodes (all transmitted by arthropods) have obligate bacterial endosymbionts, Wolbachia. Similar endosymbionts are known from arthropods, where they can have one of several effects on their host, ranging from generating cytoplasmic incompatibility at mating to the induction of parthenogenetic reproduction. Endosymbionts can be eliminated from infected animals by treatment with antibiotics. When filarial nematodes are treated with antibiotics, the nematodes appear stunted and they become sterile suggesting that the endosymbiont in filarial nematodes has become an obligate part of the nematode's ‘normal’ biology.Andre et al. have investigated the role of Wolbachia in the pathology of onchocerciasis using a murine model of corneal inflammation in which worm extracts are injected into the corneal stroma [1xThe role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Andre et al. Science. 2002; 295: 1892–1895Crossref | PubMed | Scopus (260)See all References][1]. When extracts from O. volvulus are used in this model, there is an increase in the thickness of the corneal stoma, greater stromal haze and neutrophil infiltration, compared with the controls, all of which are measures of eye pathology. However, when extracts of O. volvulus treated with antibiotics (therefore free of Wolbachia) are used, there is no eye pathology when using these measures. These results suggest that immune responses against the Wolbachia component of O. volvulus might be responsible for the eye disease in onchocerciasis. Andre et al. extended this study to two other species of filarial nematodes, one with Wolbachia endosymbionts (Brugia malayi) and one without (Acanthocheilonema viteae). This showed that B. malayi extracts induced eye pathology, whereas A. viteae did not, as would be predicated if the Wolbachia component of the filarial nematodes is responsible for the induction of the eye pathology.Immunological responses to bacterial lipopolysaccharide (LPS) require a host Toll-like receptor (TLR4). Immune responses to Wolbachia are likely to involve this receptor, whereas those against nematode antigens per se will not. Mice hypo- or hyper-responsive to LPS (as a result of mutations in TLR4) were compared in their responses to O. volvulus. These results showed that mice hyper-responsive to LPS had greater eye pathology compared with hypo-responsive mice, further suggesting that immune responses against Wolbachia are responsible for the observed eye disease.Antibiotic therapy reduces the reproduction of these filarial worms and therefore reduces host microfilaraemia. The disease, due to this microfilaraemia, might therefore be susceptible to treatment simply by the administration of antibiotics. The discovery that the eye pathology of river blindness could similarly be due to the bacterial endosymbiont raises the prospect that this aspect of the disease might also be susceptible to such treatment.