Non-muscle myosin IIA is a functional entry receptor for herpes simplex virus-1

Abstract

Herpes simplex virus-1 (HSV-1), the prototype of the α-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.

Modulation of T cell signaling by the actin cytoskeleton

“…Actin retrograde motion is likely to be driven by the polymerization of its filaments (Henson et al, 1999). Additionally, the actin-associated molecular motor myosin II has been found to contribute to actin flow by exerting contractile forces on actin filaments (Vicente-Manzanares et al, 2009;Betapudi, 2010;Arii et al, 2010;Bhuwania et al, 2012). Nonmuscle myosin IIA is the dominantly expressed isoform of myosin II in T cells (Jacobelli et al, 2004).…”

Update On Emerging Antivirals For The Management Of Herpes Simplex Virus Infections: A Patenting Perspective

“…gC and gB can also bind to C-type lectin dendritic cell-specific ICAM3-grabbing nonintegrin (DC-SIGN), facilitating dendritic cell infection. Apart from HS and DC-SIGN, gB can bind to paired immunoglobulin-like type 2 receptor-α (PILRα), non-muscle myosin heavy chain IIA (NMMHCIIA) and myelinassociated glycoprotein (MAG) [34][35][36][37]. Initial tethering followed by viral fusion is facilitated by binding of gD to second receptors such as herpesvirus entry mediator (HVEM/ HveA) (member of the tumor necrosis factor superfamily); nectin-1 (HveC) and nectin -2 (HveB) (cell adhesion molecules of the immunoglobulin superfamily); and 3-O-sulphated HS [38][39][40][41][42][43].…”

Rapid Screening by Cell-Based Fusion Assay for Identifying Novel Antivirals of Glycoprotein B-Mediated Herpes Simplex Virus Type 1 Infection

“…17) Specifically, gB plays a critical role for entry into the target cells. 18,19) Entry consists of a multistep process involving several cellular receptors, paired immunoglobulin-like type 2 receptor alpha (PILRα), 20) as well as non-muscle myosin IIA (NM-IIA) 21) and myelin associated glycoprotein (MAG), 22) which have been shown to interact with gB. Since PILRα is an inhibitory receptor, and its binding to gB could induce immune suppression followed by acceleration of immune evasion by HSV-1, inhibition of the gB-PILRα interaction could be a promising target to reduce the spread of viruses in vivo.…”