Microfilariae of the filarial nematode Litomosoides sigmodontis exacerbate the course of 1 LPS - induced sepsis in mice

1 Helminths facilitate their own survival by actively modulating the immune systems of 2 their hosts. We investigated the impact different life-cycle stages of the rodent filaria 3 Litomosoides sigmodontis have on the inflammatory responses of mice injected with sub4 lethal doses of lipopolysaccharide (LPS). Mice infected with female adult worms from 5 prepatent infections, those which have not yet started to release microfilariae, developed 6 lower levels of pro-inflammatory cytokines in the peripheral blood after LPS-challenge 7 compared to sham treated controls, demonstrating that female adult worms can mitigate the 8 innate immune response. The presence of microfilariae in mice, however, through either direct 9 injection or implantation of microfilariae-releasing adult female worms, turned the LPS10 challenge fatal. This lethal outcome was characterized by increased plasma levels of IFNγ, 11 TNFα, IL-12, and IL-6, greater numbers of macrophages and granulocytes in the peripheral 12 blood, and decreased body temperatures in microfilariae-infected mice. Microfilariae-infected 13 mice deficient in IFNγR (interferon-gamma-receptor) and TNFR1 (tumor necrosis factor 14 receptor 1) had an increased survival rate after LPS challenge compared to immune competent 15 mice, suggesting that microfilariae worsen LPS-induced sepsis through actions of IFNγ and 16 TNFα. In summary, we have demonstrated that infection of mice with L. sigmodontis female 17 adult worms from prepatent infections protect mice injected with LPS whereas microfilariae 18 worsen LPS-induced sepsis through the induction of pro-inflammatory cytokines and 19 upregulation of granulocytes, NK cells, and monocytes in the peripheral blood. 20 AC CE PT ED on S etem er 3, 2017 by gest http/iai.asm .rg/ D ow nladed fom