The Major Surface Protein of Wolbachia Endosymbionts in Filarial Nematodes Elicits Immune Responses through TLR2 and TLR4

Abstract

More than 150 million humans in tropical countries are infected by filarial nematodes which harbor intracellular bacterial endosymbionts of the genus Wolbachia (Rickettsiales). These bacteria have been implicated in adverse effects of drug treatment in filariasis. The present study provides evidence that purified major Wolbachia surface protein (rWSP) acts as an inducer of the innate immune system through TLR2 and TLR4: 1) recombinant, stringently purified rWSP elicited the release of TNF-α, IL-12, and IL-8 from cultured blood cells of both Onchocerca volvulus-infected and uninfected people; 2) the inflammatory response to rWSP challenge was TLR2- and TLR4-dependent as demonstrated with TLR-transfected fibroblastoid cells, as well as macrophages and dendritic cells from functional TLR-deficient mice; 3) blood cells of onchocerciasis patients exposed to rWSP also generated down-regulating mediators IL-10 and PGE2 after 6 days of culture; 4) furthermore, rWSP-reactive IgG1 Abs were present in sera of O. volvulus-infected people but not in those of uninfected Europeans. The lack of rWSP-reactive IgE and IgG4 in serum indicated a bias toward a Th1-type adaptive immune response. Abs against rWSP stained endobacteria in living and degenerating adult O. volvulus filariae, tissue microfilariae and host tissue macrophages that apparently had engulfed microfilariae. Thus, filarial helminths, through products of their endobacteria such as WSP, acquire characteristics of a typical microbial pathogen inducing immune responses via TLR2 and TLR4.

Analysis of gene expression from theWolbachiagenome of a filarial nematode supports both metabolic and defensive roles within the symbiosis

“…A much larger body of data exists pertaining to the immunogenicity of WSP. This molecule is a ligand for TLR-2 and -4 (Brattig et al 2004) and stimulates production of the pro-inflammatory cytokine IL-8 in neutrophils (Bazzocchi et al 2003) while inhibiting apoptosis in these cells (Bazzocchi et al 2007). Moreover, in common with GroEL, antibody levels against WSP are correlated with the disease manifestations of LF (Punkosdy et al 2003).…”

Wolbachia Endosymbiotic Bacteria of Brugia malayi Mediate Macrophage Tolerance to TLR- and CD40-Specific Stimuli in a MyD88/TLR2-Dependent Manner

“…On release from the worm, the endosymbionts or their products induce innate inflammatory responses of macrophages (14) and neutrophils (15). In addition, a recombinant form of the major surface protein of nematode Wolbachia (WSP) activates macrophages and DC via signaling through TLR2 and TLR4 (16). In this study, we tested the hypothesis that Wolbachia bacteria of B. malayi would induce homotolerance and heterotolerance toward multiple TLR ligands in macrophages and drive the tolerization of innate immunity in filarial infection.…”

Differential induction of Th2- And Th1-associated responses by filarial antigens and endosymbioticWolbachiain a murine model of river blindness

“…This is unexpected as the production of IL-5 was previously found to be TLR2 independent and thus thought to be Wolbachia independent [13]. This finding might indicate that Wolbachia is not only activating the immune system via TLR2, but other Toll-like receptors like TLR4 that have been previously implicated in the pathogenesis of filariasis might also be involved [7,26].…”