https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496209/
Semaphorin 7A Contributes to West Nile Virus Pathogenesis through TGF-β1/Smad6 Signaling
* - DNA viruses that infect humans, such as vaccinia and alcelaphine herpesvirus, encode secreted semaphorin A39R and Alcelaphine herpes virus (AHV)-sema (16, 26, 27). These viral semaphorins show high similarity to vertebrate Sema7A (16, 26, 27). Similarly to Sema7A, these semaphorins bind plexin-like receptors (32). Upon vaccinia and AHV infection, A39R and AHV-sema are believed to play immunomodulatory role(s) by mimicking Sema7A (16, 26, 27).
- Indeed, A39R induces CD54 expression and stimulates production of IL-6 and IL-8 by cultured monocytes (16, 33). No study has reported the presence of Sema7A homologs in RNA viral genomes. Therefore, we postulated that RNA viruses may use vertebrate Sema7A during infection and assessed the role of vertebrate Sema7A using the murine model of WNV infection.
- In this study, we show that abrogation of Sema7A protects mice from lethal West Nile virus (WNV) infection. Mice lacking Sema7A showed increased survival, reduced viral burden, and less blood–brain barrier permeability upon WNV infection. Increased Sema7A levels were evident in murine tissues, as well as in murine cortical neurons and primary human macrophages upon WNV infection. Treatment with Sema7A Ab blocked WNV infection in both of these cell types. Furthermore, Sema7A positively regulates the production of TGF-β1 and Smad6 to facilitate WNV pathogenesis in mice.
- Collectively, these data elucidate the role of Sema7A in shared signaling pathways used by the immune and nervous systems during viral pathogenesis that may lead to the development of Sema7A-blocking therapies for WNV and possibly other flaviviral infections.
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