TNF-TNFR1 Signaling Enhances the Protection Against Neospora caninum Infection

Flávia Batista Ferreira França,Tiago Wilson Patriarca Mineo,Mariana Ferreira Silva,Fernanda Maria Santiago,Vanessa Dos Santos Miranda,José Roberto Mineo,Eliézer Lucas Pires Ramos,Caroline Martins Mota,Murilo Vieira Silva

doi:10.3389/fcimb.2021.789398

Flávia Batista Ferreira França, Tiago Wilson Patriarca Mineo + Show 7 more

Open Access

https://doi.org/10.3389/fcimb.2021.789398

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Abstract

Neospora caninum is a protozoan associated with abortions in ruminants and neuromuscular disease in dogs. Classically, the immune response against apicomplexan parasites is characterized by the production of proinflammatory cytokines, such as IL-12, IFN-γ and TNF. TNF is mainly produced during the acute phases of the infections and binds to TNF receptor 1 (CD120a, p55, TNFR1) activating a variety of cells, hence playing an important role in the induction of the inflammatory process against diverse pathogens. Thus, in this study, we aimed to evaluate the role of TNF in cellular and humoral immune responses during N. caninum infection. For this purpose, we used a mouse model of infection based on wildtype (WT) and genetically deficient C57BL/6 mice in TNFR1 (Tnfr1 -/-). We observed that Tnfr1 -/- mice presented higher mortality associated with inflammatory lesions and increased parasite burden in the brain after the infection with N. caninum tachyzoites. Moreover, Tnfr1 -/- mice showed a reduction in nitric oxide (NO) levels in vivo. We also observed that Tnfr1 -/- mice showed enhanced serum concentration of antigen-specific IgG2 subclass, while IgG1 production was significantly reduced compared to WT mice, suggesting that TNFR1 is required for regular IgG subclass production and antigen recognition. Based on our results, we conclude that the TNF-TNFR1 complex is crucial for mediating host resistance during the infection by N. caninum.

Highlights

Neosporosis is an infectious disease caused by the parasite Neospora caninum which was first described as the causative of neurological disorders in dogs (Bjerkas et al, 1984)
Due to the lack of information regarding this key cytokine in the context of the infection, we aimed to evaluate the role of tumor necrosis factor (TNF) in the regulation of cellular and humoral immune responses against N. caninum, using genetically deficient mice in its main receptor - TNF receptor I (TNFR1) - as a model
In order to evaluate whether the parasite burden profile was altered in the absence of TNF receptor 1 (TNFR1), we determined the amount of parasite genomic DNA in tissues of both groups infected with a sublethal dose of N. caninum tachyzoites (1x106 parasites/mice)

Summary

Introduction

Neosporosis is an infectious disease caused by the parasite Neospora caninum which was first described as the causative of neurological disorders in dogs (Bjerkas et al, 1984). Classified in 1988, N. caninum is an obligatory intracellular parasite that belongs to Apicomplexa phylum (Dubey et al, 1988), a group composed by a range of parasites with great importance in human and veterinary medicine (Cowper et al, 2012). N. caninum has been reported to infect varied species of animals, including dogs, cattle, sheep, goat, among others. This infection occurs mainly through ingestion of food and/or water contaminated with oocysts eliminated in feces of canids, which are its definitive hosts (Almeria et al, 2017). The transplacental transmission is considered an important transmission route, especially in cattle (Marugan-Hernandez, 2017), causing abortions and generating significant economic impacts in dairy and beef production (Dubey and Schares, 2011; Reichel et al, 2014; Mansilla et al, 2015)

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