Neospora caninum Activates p38 MAPK as an Evasion Mechanism against Innate Immunity

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.

Rhoptry protein 5 (ROP5) Is a Key Virulence Factor in Neospora caninum

“…However, related research reports about functions of proteins in N. caninum are limited to epidemiological studies, the expression and localization of cloned genes, and immunogenicity (Liu et al, 2013; Li et al, 2014; Hecker et al, 2015; Pastor-Fernández et al, 2016). The overexpression of some genes and addition of labeling with biotin in N. caninum have been reported (Tao et al, 2014; Mota et al, 2016). Few reports on N. caninum have investigated the loss of one or more genes and their effects on gene functions (Mota et al, 2016).…”

“…The overexpression of some genes and addition of labeling with biotin in N. caninum have been reported (Tao et al, 2014; Mota et al, 2016). Few reports on N. caninum have investigated the loss of one or more genes and their effects on gene functions (Mota et al, 2016). …”

Estimulação de vias inatas em células uterinas e ensaios de imunoprofilaxia em modelo murino visando o controle da neosporose bovina

“…caninum uses p38 phosphorylation in its favor, in order to down-regulate innate immune responses of the host (MOTA et al, 2016). In contrast, a study inhibiting ERK in mouse peritoneal macrophages infected with N. caninum showed a reduction in IL-12 production using the UO126 inhibitor (JIN et al, 2017).…”

“…Adicionalmente, p38 é induzido por um mecanismo que depende das vias de sinalização GPCR, PI3K e AKT. Portanto, N. caninum utiliza da fosforilação de p38 em seu favor, a fim de regular negativamente as respostas imunitárias inatas do hospedeiro (MOTA et al, 2016).…”

“…The study of innate immunity against N. caninum has shown the importance of PRRs for the control or resistance to the infection through the induction or inhibition of several chemical mediators such as cytokines (MINEO et al, 2009;MINEO et al, 2010, MOTA et al, 2016SILVA et al, 2017). Here we showed that both TLR3 and MyD88 molecules with siRNA silencing led to reduce the IFNγ production and increased the IL-10, IL-6 and IL-8 production during infection in the endometrial cells studied.…”