Neospora caninum Dense Granule Protein 7 Regulates the Pathogenesis of Neosporosis by Modulating Host Immune Response

is a protozoan parasite closely related to Neosporosis caused by is considered one of the main causes of abortion in cattle and nervous-system dysfunction in dogs, and identification of the virulence factors of this parasite is important for the development of control measures. Here, we used a lucif...

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Published in:	Applied and environmental microbiology Vol. 84; no. 18
Main Authors:	Nishikawa, Yoshifumi, Shimoda, Naomi, Fereig, Ragab M, Moritaka, Tomoya, Umeda, Kousuke, Nishimura, Maki, Ihara, Fumiaki, Kobayashi, Kaoru, Himori, Yuu, Suzuki, Yutaka, Furuoka, Hidefumi
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 15-09-2018
Subjects:	Ascites Calcineurin Calcium CRISPR CXCL10 protein Gene sequencing Genes Genetics and Molecular Biology Granular materials Immune response Immune system Infections Inflammation Inflammatory response Interferon Macrophages Mice Monocyte chemoattractant protein 1 Necrosis Neospora caninum Neosporosis NF-κB protein Parasites Pathogenesis Peritoneum Plasmids Protein kinase A Proteins Protozoa Ribonucleic acid RNA Spleen Virulence Virulence factors γ-Interferon NcGRA7 mouse macrophage CRISPR/Cas9 Neospora caninum
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Summary:	is a protozoan parasite closely related to Neosporosis caused by is considered one of the main causes of abortion in cattle and nervous-system dysfunction in dogs, and identification of the virulence factors of this parasite is important for the development of control measures. Here, we used a luciferase reporter assay to screen the dense granule proteins genes of , and we found that NcGRA6, NcGRA7, and NcGRA14 are involved in the activation of the NF-κB, calcium/calcineurin, and cAMP/PKA signals. To analyze the functions of these proteins and cyclophilin, we successfully knocked out their genes in the Nc1 strain using plasmids containing the CRISPR/Cas9 components. Among the deficient lines, the -deficient parasites showed reduced virulence in mice. An RNA sequencing analysis of infected macrophage cultures showed that NcGRA7 mainly regulates the host cytokine and chemokine production. The levels of gamma interferon in the ascites fluid, CXCL10 expression in the peritoneal cells, and CCL2 expression in the spleen were lower 5 days after infection with the -deficient parasite than after infection with the parental strain. The parasite burden and the degree of necrosis in the brains of mice infected with the -deficient parasite were also lower than in those of the parental strain. Collectively, our data suggest that both the NcGRA7-dependent activation of the inflammatory response and the parasite burden are important in virulence. invades and replicates in a broad range of host species and cells within those hosts. The effector proteins exported by induce its pathogenesis by modulating the host immunity. We show that most of the transcriptomic effects in -infected cells depend upon the activity of NcGRA7. A deficiency in NcGRA7 reduced the virulence of the parasite in mice. This study demonstrates the importance of NcGRA7 in the pathogenesis of neosporosis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Nishikawa Y, Shimoda N, Fereig RM, Moritaka T, Umeda K, Nishimura M, Ihara F, Kobayashi K, Himori Y, Suzuki Y, Furuoka H. 2018. Neospora caninum dense granule protein 7 regulates the pathogenesis of neosporosis by modulating host immune response. Appl Environ Microbiol 84:e01350-18. https://doi.org/10.1128/AEM.01350-18.
ISSN:	0099-2240 1098-5336
DOI:	10.1128/aem.01350-18