Molecular Pathogenesis and Immune Evasion of Vesicular Stomatitis Virus Inferred from Genes Expression Changes in Ex Vivo Porcine Macrophages after Infection

Authors: Zhu, James; VELAZQUEZ-SALINAS, LAURO - University Of Kansas; CANTER, JESSICA - Oak Ridge Institute For Science And Education (ORISE); Rodriguez, Luis

Submitted to: Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/31/2021
Publication Date: 9/3/2021
Citation: Zhu, J.J., Velazquez-Salinas, L., Canter, J., Rodriguez, L.L. 2021. Molecular Pathogenesis and Immune Evasion of Vesicular Stomatitis Virus Inferred from Genes Expression Changes in Ex Vivo Porcine Macrophages after Infection. Pathogens. https://doi.org/10.3390/pathogens10091134.
DOI: https://doi.org/10.3390/pathogens10091134

Interpretive Summary: Vesicular stomatitis virus (VSV) infection causes fever and vesicular stomatitis, one of four clinically indistinguishable viral vesicular diseases. VSV is the cause of most cases of vesicular diseases reported in livestock resulting in drastic economic losses partly due to these infections frequently being mistaken for foot and mouth disease virus due to its similar clinical presentation. Molecular mechanisms of how VSV causes fever and vesicular lesion are not clear. VSV infects and replicates in epithelial cells and macrophages. In this study, ex vivo VSV-infected porcine macrophages were used as model cells to extrapolate the mechanisms involved because of the wide tissue distribution and important roles in inflammation of the cells. The objective of this study is to understand how VSV causes the disease. We identify new mechanisms involved in the pathogenesis of vesicular stomatitis. This study provides novel insights into VSV molecular pathogenesis and immune evasion for further investigation.

Technical Abstract: Vesicular stomatitis virus (VSV) causes fever and vesicular lesions in specific tissues of a wide range of mammals including livestock such as cattle, horses, and pigs. VSV displays a wide cell and host tropism primarily due to conserved VSV receptors ubiquitously expressed on host cells. Molecular mechanisms of VSV pathogenesis are not clear. VSV can infect and replicate in macrophages. In this study, ex vivo VSV-infected porcine macrophages were used as model cells to extrapolate the mechanisms involved because of the wide tissue distribution and important roles in inflammation of the cells. The objective of this study is to infer the mechanisms of VSV pathogenesis and immune evasion based on transcriptomic changes after virus infection. The infection of virulent wildtype NJ epidemic strain VSV induced massive expression (>10-fold) of anorexic, pyrogenic and/or proinflammatory genes (CCL4, CCL20, CXCL2, IL1A, LIF, PTGS2 and TNF) and immunosuppressive IL10. IFNß expression was induced by 6.2-fold, but the expression of an IFNA and IFNa and IFN' receptors were downregulated. Six genes (AHR, ATF3, DUSP1, FOS, HES1, and PRDM1) known to negatively regulate IFNB expression, and no interferon-stimulated genes (ISG) were induced after infection, indicating that VSV infection suppresses IFNB expression and signaling. There was not significantly differential gene expression between two wildtype VSV infections. Other differential gene expression also indicated that (1) IL-1, RIG-I, TLR, and TNF signaling pathways, (2) biological processes of apoptosis, autophagy and unfolded protein response, (3) M1 macrophage activation, (4) transcription, cap-methylation, and stability of host mRNA, and (5) eIF2a-phosphorylation-mediated inhibition in protein translation were suppressed in the infected cells. This study provides novel insights into VSV molecular pathogenesis and immune evasion for further investigation.