Abstract
Due to the high prevalence and economic impact of neosporosis, the development of safe and effective vaccines and therapies against this parasite has been a priority in the field and is crucial to limit horizontal and vertical transmission in natural hosts. Limited data is available regarding factors that regulate the immune response against this parasite and such knowledge is essential in order to understand Neospora caninum induced pathogenesis. Mitogen-activated protein kinases (MAPKs) govern diverse cellular processes, including growth, differentiation, apoptosis, and immune-mediated responses. In that sense, our goal was to understand the role of MAPKs during the infection by N. caninum. We found that p38 phosphorylation was quickly triggered in macrophages stimulated by live tachyzoites and antigen extracts, while its chemical inhibition resulted in upregulation of IL-12p40 production and augmented B7/MHC expression. In vivo blockade of p38 resulted in an amplified production of cytokines, which preceded a reduction in latent parasite burden and enhanced survival against the infection. Additionally, the experiments indicate that the p38 activation is induced by a mechanism that depends on GPCR, PI3K and AKT signaling pathways, and that the phenomena here observed is distinct that those induced by Toxoplasma gondii’s GRA24 protein. Altogether, these results showed that N. caninum manipulates p38 phosphorylation in its favor, in order to downregulate the host’s innate immune responses. Additionally, those results infer that active interference in this signaling pathway may be useful for the development of a new therapeutic strategy against neosporosis.
Highlights
Neospora caninum is an obligate intracellular protozoan from the phylum Apicomplexa, closely related to Toxoplasma gondii
To determine the effect of N. caninum infection on Mitogen-activated protein kinases (MAPKs) activation in macrophages, the phosphorylation of major MAPK signaling components was examined by cytometric bead array kit (CBA) and Western Blotting (Figure 1)
CBA experiments revealed that N. caninum induced strong phosphorylation of p38 MAPK (p-p38) between 15 and 30 min after contact with live parasites, with a tendency to reduce the reactivity after 60 min of infection
Summary
Neospora caninum is an obligate intracellular protozoan from the phylum Apicomplexa, closely related to Toxoplasma gondii. This parasite has a worldwide distribution and causes relevant economic impact in dairy and beef industries (Cardoso et al, 2011) due to negative effects such as abortion or reproductive disorders in cattle, in addition to neuromuscular disease in dogs. Infection may occur during gestation, due to the immune response regulation, which leads to the recrudescence of chronic infections into subsequent parasitemia (Mineo et al, 2010a; Pinheiro et al, 2010). The fetus may be infected by parasites that cross the placenta, causing abortions or congenital infections, depending on the period of gestation and parasite virulence (Eastick and Elsheikha, 2010). IL-12 is a key cytokine that links the innate and adaptive compartments of the immune system, and is triggered by microbial products during early host– pathogen interactions (Aliberti, 2005; Yarovinsky et al, 2005; Debierre-Grockiego et al, 2007; Jenkins et al, 2010; Donahoe et al, 2015)
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