title: Microfilariae of the filarial nematode Litomosoides sigmodontis exacerbate the course of lipopolysaccharide-induced sepsis in mice.
abstract: Helminths facilitate their own survival by actively modulating the immune systems of their hosts. We investigated the impacts that different life cycle stages of the rodent filaria Litomosoides sigmodontis have on the inflammatory responses of mice injected with sublethal doses of lipopolysaccharide (LPS). Mice infected with female adult worms from prepatent infections, worms which have not yet started to release microfilariae, developed lower levels of proinflammatory cytokines in the peripheral blood after LPS challenge than sham-treated controls, demonstrating that female adult worms can mitigate the innate immune response. The presence of microfilariae in mice, however, through either direct injection or implantation of microfilaria-releasing adult female worms, turned the LPS challenge fatal. This lethal outcome was characterized by increased plasma levels of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin 12 (IL-12), and IL-6, greater numbers of macrophages and granulocytes in the peripheral blood, and decreased body temperatures in microfilaria-infected mice. Microfilaria-infected mice deficient in IFN-gamma receptor and TNF receptor 1 had increased survival rates after LPS challenge compared to immune-competent mice, suggesting that microfilariae worsen LPS-induced sepsis through actions of IFN-gamma and TNF-alpha. In summary, we have demonstrated that infection of mice with L. sigmodontis female adult worms from prepatent infections protects mice injected with LPS whereas microfilariae worsen LPS-induced sepsis through the induction of proinflammatory cytokines and upregulation of granulocytes, NK cells, and monocytes in the peripheral blood.
authors.affiliation: Institute of Tropical Medicine, University of Tübingen, 72074 Tübingen, Germany. mhubner@usuhs.mil
authors.forename: Marc P
authors.initials: MP
authors.lastname: Hübner
authors.forename: Bastian
authors.initials: B
authors.lastname: Pasche
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Kalaydjiev
authors.forename: Peter T
authors.initials: PT
authors.lastname: Soboslay
authors.forename: Andreas
authors.initials: A
authors.lastname: Lengeling
authors.forename: Hartwig
authors.initials: H
authors.lastname: Schulz-Key
authors.forename: Edward
authors.initials: E
authors.lastname: Mitre
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D001831:Body Temperature; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005370:Filarioidea / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006098:Granulocytes / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008842:Microfilariae / Q000502:physiology*; D009000:Monocytes / Q000502:physiology; D018512:Parasitemia / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D018805:Sepsis / Q000139:chemically induced* / Q000469:parasitology*; D000096743:Interferon gamma Receptor
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D017471:Receptors, Interferon; D018124:Receptors, Tumor Necrosis Factor; D000096743:Interferon gamma Receptor