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. Herpesviruses are supremely successful mammalian parasites. Yet their infections rarely present until well established, so how new hosts are first infected has been unclear. Understanding this is likely to be crucial for infection control. Using Murid Herpesvirus-4, a relative of the Kaposi's Sarcoma-associated Herpesvirus, we identified the olfactory neuroepithelium as a major portal of host entry. Heparan sulfate (HS) binding, which is common to many herpesviruses, played a key role. The HS of most epithelia is solely basolateral and therefore inaccessible to incoming, apical virions. The neuroepithelium, by contrast, also displayed HS on its apical surface. This comprises a dense meshwork of the neuronal cilia that mediate olfaction. Incoming virions bound to the cilia, as did a recombinant form of the virion glycoprotein H/L heterodimer. Some virions tracked down the cilia to infect neurons. Others were transferred to the microvilli of adjacent sustentacular cells. The central role of HS in this first detailed description of host entry by a mammalian herpesvirus, and the paucity of accessible HS on other epithelia, suggested that many HS-binding herpesviruses could follow a similar path.