Microfilariae of the Filarial NematodeLitomosoides sigmodontisExacerbate 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 shamtreated 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 microfilariareleasing adult female worms, turned the LPS challenge fatal. This lethal outcome was characterized by increased plasma levels of gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), 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-␥ 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-␥ and TNF-␣. 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.Infections with helminths often cause chronic disease with a wide spectrum of clinical manifestations, ranging from asymptomatic to severe pathology. By actively suppressing the inflammatory responses of their hosts, helminths facilitate their own survival (26). This suppression will not only permit parasite persistence at high infection levels but also avoid pathological changes to the host. Amazingly, the presence of only one female adult worm of the rodent filarial nematode Litomosoides sigmodontis, an animal model for human filariasis (1, 18), is sufficient to prolong the viability of their progeny, the microfilariae, in the host (19). Although microfilariae given alone provoke a Th1 response in their hosts (25), adult filarial worms typically induce a Th2 immune response characterized by high levels of interleukin 4 (IL-4), IL-5, IL-10, IL-13, and immunoglobulin E as well as an augmentation of mast cells, eosinophils, and basophils (26).In addition, helminths induce a stage of hyporesponsiveness in their hosts (14), likely due to a targeted immune suppression by IL-10, transforming growth factor ␤, regulatory T cells, and alternatively activated macrophages (12,16,23,33,36,37). Recently, this immunomodulatory capacity of parasitic worms or their excretory/secretory products has been effectively utilized for therapeutic purposes in patients with inf...

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

“…Surgical implantation of L. sigmodontis adults into BALB/c mice reduced induced allergic airway inflammation and hyperreactivity in a model for OVA-induced asthma (30). Also, onset of type 1 diabetes was prevented by injection of L3 and implantation of adults (31), and LPS-induced sepsis was slightly mitigated by adult implantation (22). Finally, it was shown that a preexisting natural L. sigmodontis infection prevented the development of cerebral malaria in C57BL/6 mice coinfected with Plasmodium berghei ANKA (32).…”

“…L. sigmodontis third-stage larvae (L3) are transmitted to their natural host, the cotton rat (Sigmodon hispidus), by the bite of infected mites (Ornithonyssus bacoti). Laboratory mice may be infected naturally by the bite of infected mites (19,20) or artificially by injection of L3 (21) or implantation of different stages such as L3, adults, and first-stage larvae, socalled microfilariae (MF) (22). After infection, L3 migrate during the first 3 d via the lymphatic system to the thoracic cavity (23).…”

Urticaria as Symptom of Parasite Migration Through the Biological Barriers

“…We share the opinion that Th2 deviation may permit parasites to invade the host organism, and to select specific organs or host cell types as predilection site to reside, maturate or even proliferate [11,28,29]. While many microparasites escape immune attack by antigenic variation or sequestration in specialized niches, helminths appear to thrive in exposed extracellular locations, such as the lymphatics, bloodstream, or gastrointestinal tract [29,30].…”

Tropical Medicine at the University of Tübingen

“…Wolfgang Hoff mann is starting a group looking into immunological and pathological variables of coinfections in animal experiments [52].…”