Abstract
Neospora caninum is an apicomplexan parasite responsible for major economic losses due to abortions in cattle. Innate immune responses are crucial for host resistance against the infection, however the molecules involved in parasite recognition are still poorly understood. Nod2 is a cytosolic receptor that recognizes several pathogens and its role during N. caninum infection has not yet been described. In that sense, we evaluated the role of Nod2 in host response against this parasite. We found that infection of macrophages induced increased expression of Nod2, which colocalized with the parasites’ vacuoles. Nod2-deficient macrophages showed an impaired induction of pro-inflammatory cytokines, increased production of modulatory molecules, and failure to restrict parasite replication. In vivo, Nod2-knockout mice showed a reduction of MAPK phosphorylation and proinflammatory cytokines, followed by decreased inflammation in target organs and increment in parasite burden. Surprisingly, these mice were partially resistant to lethal doses of tachyzoites. In addition, these phenomena were not observed in Rip2−/− mice. In conclusion, our study indicates that Nod2-dependent responses account for N. caninum elimination. On the other hand, the inflammatory milieu induced by this innate receptor provoked pathogenesis and death in severe experimental neosporosis.
Highlights
Neospora caninum is an apicomplexan parasite responsible for major economic losses due to abortions in cattle
While Nod[1] is ubiquitously expressed, Nod[2] is expressed in hematopoietic cells, and both cooperate to signal via the adaptor molecule Receptor-Interacting Protein 2 (Rip2), a serine-threonine kinase required for activation of NF-κB and mitogen-activated protein kinase (MAPK) cascades that culminate with the upregulation of proinflammatory genes[18,19,20]
To assess the pattern of Nod[2] expression during the infection of macrophages, we evaluated the messenger RNA codifying this receptor in mouse bone marrow derived macrophages (BMDMs) during N. caninum infection in vitro
Summary
Neospora caninum is an apicomplexan parasite responsible for major economic losses due to abortions in cattle. N. caninum is an intracellular apicomplexan parasite capable of infecting a wide range of domestic and wild animals[1,2,3] This parasite is the etiological agent of neosporosis, a severe infectious illness responsible for neuromuscular disorders in canines and abortion, neonatal mortality and congenital infections, imposing a high economic burden in cattle raising farms and associated industry[1,4,5]. The pathogenesis of neosporosis is associated with the intracellular proliferation of N. caninum tachyzoites These parasite forms are disseminated through the blood stream and lymphatic system and can induce robust humoral and cellular immune responses, which are crucial to determine the development and severity of the disease[5,7]. It has been proposed that Nod[2] is necessary for generating protective Th1 immunity against T. gondii, a protozoan parasite closely related with N. caninum[22]
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