A Heparan-Dependent Herpesvirus Targets the Olfactory Neuroepithelium for Host Entry

Abstract

Herpesviruses are ubiquitous pathogens that cause much disease. The difficulty of clearing their established infections makes host entry an important target for control. However, while herpesviruses have been studied extensively in vitro, how they cross differentiated mucus-covered epithelia in vivo is unclear. To establish general principles we tracked host entry by Murid Herpesvirus-4 (MuHV-4), a lymphotropic rhadinovirus related to the Kaposi's Sarcoma-associated Herpesvirus. Spontaneously acquired virions targeted the olfactory neuroepithelium. Like many herpesviruses, MuHV-4 binds to heparan sulfate (HS), and virions unable to bind HS showed poor host entry. While the respiratory epithelium expressed only basolateral HS and was bound poorly by incoming virions, the neuroepithelium also displayed HS on its apical neuronal cilia and was bound strongly. Incoming virions tracked down the neuronal cilia, and either infected neurons or reached the underlying microvilli of the adjacent glial (sustentacular) cells and infected them. Thus the olfactory neuroepithelium provides an important and complex site of HS-dependent herpesvirus uptake.

B Cell Response to Herpesvirus Infection of the Olfactory Neuroepithelium

“…Sialic acid-binding viruses, such as influenza virus, target the respiratory epithelium (2). Murid herpesvirus 4 (MuHV-4), a gammaherpesvirus of the genus Rhadinovirus, and herpes simplex virus 1 (HSV-1), an alphaherpesvirus, instead target the olfactory epithelium (3,4), where neuronal cilia are exposed directly to inhaled antigens. Borna disease virus (5), pseudorabies virus (6), and neurotropic murine coronaviruses (7) can spread along olfactory neurons to the brain and cause encephalitis, as can experimentally inoculated poliovirus (8), vesicular stomatitis virus (9), and highly virulent influenza virus (10).…”

“…MuHV-4 and HSV-1 both bind to heparan. The olfactory epithelium expresses heparan both apically and basolaterally (3); in most other sites, it is just basolateral (13). Therefore, many heparan-binding viruses may target the olfactory epithelium for host entry (14), making its immunology important to understand.…”

The Major Envelope Glycoprotein of Murid Herpesvirus 4 Promotes Sexual Transmission

“…Murine cytomegalovirus is transmitted via the upper respiratory tract (40). MuHV-4 also enters new hosts via the upper respiratory tract (22). However, it has not been shown to be transmitted spontaneously by this route.…”

“…One solution is to produce large numbers of infectious particles and cause widespread epithelial destruction. The modus operandi of herpesviruses, which are transmitted chronically, at a low level, and for the most part without symptoms, seems instead to center on entry and exit at different sites, for example, entry at the olfactory epithelium, where there is apical heparan, and exit from the oropharynx, where heparan is basolateral (22). Sexual transmission seems to go against this paradigm, as entry and exit then overlap.…”

“…However, the lungs and olfactory epithelium, which are efficiently targeted by MuHV-4, display heparan. Specifically, nonsulfated heparan, which is bound by gH/gL, is present on the apical cilia of olfactory neurons (22) and on type 1 alveolar epithelial cells (23). The genital tract is not known to express apical heparan, and here host entry may depend on sexual contact causing epithelial trauma, which exposes the abundant heparan of basolateral epithelial surfaces (24).…”