Determinants for resistance and susceptibility to microfilaraemia in Litomosoides sigmodontis filariasis

Filarial infections of humans are chronic diseases. Despite an ongoing immu ne response, adult filariae continuously produce their offspring, the micro filariae (Mf), which are able to persist in sufficient numbers to ensure tr ansmission. In this study, host- and parasite-derived factors, which contri bute to persistence of Mf, were investigated using the filariasis model of Litomosoides sigmodontis in mice. Different strains of mice were found to d iffer widely in their capability to eliminate circulating Mf. Studies of co ngenic mouse strains showed that early and rapid clearance of Mf nas mediat ed by activation pathways relevant to innate immunity, whereas late or dela yed clearance of Mf nas pre-determined by MHC-related factors. Genetic knoc k-out of genes for the MHC class-II molecules totally abrogated resistance. Most interestingly, the presence of only 1 adult female, but not male worm s, renders all mice susceptible, irrespective of the genetic background, en abling Mf to circulate for extended periods of time. Such prolonged microfi laraemia was also observed in L. sigmodontis-infected animals challenged wi th heterologous Mf of Acanthocheilonema viteae. The use of cytokine gene kn ock-out mice showed that persistence of L. sigmodontis Mf was facilitated b y IL-10, but not by IL-4 or IFN-gamma. In conclusion, irrespective of a res istant or susceptible host genetic background, survival of Mf of L. sigmodo ntis in mice is decisively regulated by the presence of adult female L. sig modontis which will skew and exploit immune responses to facilitate the sur vival and persistence of their offspring in the infected host.