Semaphorin 7A contributes to West Nile virus pathogenesis through TGF-β1/Smad6 signaling.
Semaphorin 7A (Sema7A) is a membrane-associated/secreted protein that plays an essential role in connecting the vertebrate neuronal and immune systems. However, the role of Sema7A has not been elucidated in viral pathogenesis. 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.
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. hameeda.sultana@yale.edu
Hameeda
H
Sultana
Girish
G
Neelakanta
Harald G
HG
Foellmer
Ruth R
RR
Montgomery
John F
JF
Anderson
Raymond A
RA
Koski
Ruslan M
RM
Medzhitov
Erol
E
Fikrig
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000276:immunology / Q000378:metabolism / Q000821:virology; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039961:Semaphorins / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D051905:Smad6 Protein / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D014779:Virus Replication / Q000276:immunology; D014902:West Nile virus / Q000276:immunology* / Q000472:pathogenicity*
D015703:Antigens, CD; C485571:Sema7a protein, mouse; D039961:Semaphorins; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D053773:Transforming Growth Factor beta1