Publication Date:
2010-10-15
Description:
Herpes simplex virus-1 (HSV-1), the prototype of the alpha-herpesvirus family, causes life-long infections in humans. Although generally associated with various mucocutaneous diseases, HSV-1 is also involved in lethal encephalitis. HSV-1 entry into host cells requires cellular receptors for both envelope glycoproteins B (gB) and D (gD). However, the gB receptors responsible for its broad host range in vitro and infection of critical targets in vivo remain unknown. Here we show that non-muscle myosin heavy chain IIA (NMHC-IIA), a subunit of non-muscle myosin IIA (NM-IIA), functions as an HSV-1 entry receptor by interacting with gB. A cell line that is relatively resistant to HSV-1 infection became highly susceptible to infection by this virus when NMHC-IIA was overexpressed. Antibody to NMHC-IIA blocked HSV-1 infection in naturally permissive target cells. Furthermore, knockdown of NMHC-IIA in the permissive cells inhibited HSV-1 infection as well as cell-cell fusion when gB, gD, gH and gL were coexpressed. Cell-surface expression of NMHC-IIA was markedly and rapidly induced during the initiation of HSV-1 entry. A specific inhibitor of myosin light chain kinase, which regulates NM-IIA by phosphorylation, reduced the redistribution of NMHC-IIA as well as HSV-1 infection in cell culture and in a murine model for herpes stromal keratitis. NMHC-IIA is ubiquitously expressed in various human tissues and cell types and, therefore, is implicated as a functional gB receptor that mediates broad HSV-1 infectivity both in vitro and in vivo. The identification of NMHC-IIA as an HSV-1 entry receptor and the involvement of NM-IIA regulation in HSV-1 infection provide an insight into HSV-1 entry and identify new targets for antiviral drug development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arii, Jun -- Goto, Hideo -- Suenaga, Tadahiro -- Oyama, Masaaki -- Kozuka-Hata, Hiroko -- Imai, Takahiko -- Minowa, Atsuko -- Akashi, Hiroomi -- Arase, Hisashi -- Kawaoka, Yoshihiro -- Kawaguchi, Yasushi -- England -- Nature. 2010 Oct 14;467(7317):859-62. doi: 10.1038/nature09420.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944748" target="_blank"〉PubMed〈/a〉
Keywords:
Adsorption
;
Animals
;
Azepines/pharmacology
;
CHO Cells
;
Cell Fusion
;
Cercopithecus aethiops
;
Cricetinae
;
Cricetulus
;
Female
;
Gene Knockdown Techniques
;
HEK293 Cells
;
HL-60 Cells
;
Herpes Simplex/virology
;
Herpesvirus 1, Human/drug effects/metabolism/*physiology
;
Humans
;
Mice
;
Myosin-Light-Chain Kinase/antagonists & inhibitors
;
Naphthalenes/pharmacology
;
Nonmuscle Myosin Type IIA/deficiency/genetics/*metabolism
;
Receptors, Virus/*metabolism
;
Temperature
;
Up-Regulation
;
Vero Cells
;
Viral Envelope Proteins/metabolism
;
Virus Internalization/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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