Onchocerca volvulusMicrofilariae Avoid Complement Attack by Direct Binding of Factor H

Abstract

The filarial parasite Onchocerca volvulus is the causative agent of river blindness. The adult worms produce microfilariae (mf), which are responsible for the disease pathogenesis; mf activate the complement system, but the activation stops before the formation of terminal complement complexes. Because of the arrest of complement activation, this study analyzed binding of the main alternative pathway regulator, factor H (fH), to the mf. The mf bound fH after incubation in nonimmune human serum or with purified radiolabeled fH. In the presence of factor I, mf-bound fH promoted the cleavage of complement 3 molecule b (C3b) to iC3b. An analysis with recombinant constructs of fH showed that the C-terminal short consensus repeats (SCRs) 8-20 of fH bound to mf, whereas the N-terminal SCRs 1-7 containing the complement-regulatory domains in SCRs 1-5 did not. Thus, mf of the nematode O. volvulus may evade human complement by binding fH and by promoting inactivation of C3b into iC3b.

The liver proteome in a mouse model for Ascaris suum resistance and susceptibility: evidence for an altered innate immune response

“…Early granulocyte-mediated larval attrition of Nippostrongylus brasiliensis appears to be in part complement-driven as well, with the alternative pathway being activated during early invasion and a switch to the lectin pathway during late infection [36]. Similarly, Onchocerca volvulus microfilariae have been shown to bind factor H, which can cleave C3b to iC3b in the presence of factor I, therefore inactivating the central C3b protein [37]. This resistance to complement activation throughout maturation, with a switch to a different mechanism, has also been seen in O. volvulus and Dirofilaria immitis as the parasites mature into the next life cycle stages [38, 39].…”

Brugia malayi microfilariae adhere to human vascular endothelial cells in a C3-dependent manner

“…Indeed, iC3b deposition has been shown on the surface of Onchocerca volvulus Mf following incubation with human serum, and factor H deposition (which can lead to iC3b formation) has been seen on the surface of both O . volvulus and Loa loa Mf [68,69]. Interestingly, while IFN-γ moderately enhanced Mf binding to HUVEC, it did not alter the level of CR1 or CR4 expression on EC, suggesting that IFN-γ-increased Mf adherence either occurs by augmenting the levels of complement components secreted by HUVEC themselves, or by, an as yet undefined mechanism.…”

Inactivation of the complement anaphylatoxin C5a by secreted products of parasitic nematodes

“…Similar loss of complement fixation and/or cellular adherence is displayed by O. volvulus and Dirofilaria immitis as they make the transition from L3 to L4 stages, and this may represent an evasion mechanism to promote establishment (Abraham et al, 1988; Brattig et al, 1991). Onchocerca volvulus microfilariae utilise another method of inactivating complement by binding factor H which, in the presence of factor I, promotes the cleavage of C3b to iC3b, and restricts amplification of the alternative pathway (Meri et al, 2002). …”