Suppression of annexin A1 reduces the lethality induced by herpes simplex virus

Abstract

Herpes simplex virus (HSV)-induced encephalitis is the most common cause of sporadic fatal encephalitis with a mortality rate as high as 70% in patients without treatment Even treated with anti-herpetic drugs only 3% survivors recover to normal neurological functions Moreover it remains elusive regarding why some individuals develop diseases in human population with more than 90% infected Viruses rely on cellular proteins to complete their replication However little is known about these cellular factors and their mechanism In our study we found that annexin A1 (Anx-A1) a cellular protein was expressed on cell surface HSV-1 infection further enhanced Anx-A1 expression on cell surface Enhanced surface Anx-A1 expression induced by HSV-1 infection is not specific to a particular virus strain or cell type Furthermore surface Anx-A1 co-localized with HSV-1 virion during virus attachment and antiserum against Anx-A1 neutralized HSV-1 infection in cells Using embryonic fibroblasts and cortical neurons cultured from wild-type or Anx-A1-deficient mice we found that Anx-A1 increased HSV-1 replication in vitro via increasing the numbers of HSV-1-infected cells and virus binding on cells To study the mechanism mediated by Anx-A1 to enhance HSV-1 infection we found that Anx-A1 interacted with HSV-1 virions and Anx-A1 interacted with more than one viral structural protiens The strongest two interacting proteins were identified as viral glycoprotein (g) D and gE by matrix-assisted laser desorption inoization-time of flight (MALDI-TOF) mass spectrometry analysis We further demonstrated that gE but not gD interacted with Anx-A1 via co-immunoprecipitation assay These results indicate that Anx-A1 interacts with gE on HSV-1 virions to enhance virus binding on cells To study the effect of Anx-A1 in HSV-1 infection in vivo mice were infected with HSV-1 via scarified cornea which mimics virus infection in humans Anx-A1 was detected in the HSV-1 target cells (epithelial cells and neurons) and tissues (eyes trigeminal ganglia and brains) of mock- and HSV-1-infecte mice HSV-1 infection increased the expression of Anx-A1 in infected mouse brains Mice deficient in Anx-A1 were significantly more resistant to HSV infection as demonstrated by lower tissue viral loads and a higher survival rate when compared with those of wild-type mice Furthermore knockdown of Anx-A1 expression in mice by an antisense oligodeoxynucleotide specific to Anx-A1 reduced the mortality in a dose dependent manner and inhibited viral replication in infected tissues In conclusion we found that Anx-A1 acts as an accessory protein that interacts with gE to enhance HSV-1 infection Knockout or knockdown of Anx-A1 expression in mice reduces the lethality of HSV-1-infected mice Furthermore glucocorticoids enhance Anx-A1 externalization and expression These results provide a new insight of how glucocorticoid treatment increases HSV-1 infection in vitro and in vivo and suggest that Anx-A1 is a risk factor that regulates the susceptibility of hosts to HSV-1 infection especially in those who are under psychological stress or glucocorticoid treatment

Date of Award	2015 Jan 27
Original language	English
Supervisor	Shun-hua Chen (Supervisor)