Herpes Simplex Virus 1 Targets the Murine Olfactory Neuroepithelium for Host Entry

Herpes simplex virus 1 (HSV-1) is a ubiquitous and important human pathogen. It is known to persist in trigeminal ganglia (TG), but how it reaches this site has been difficult to determine, as viral transmission is sporadic, pathogenesis is complicated, and early infection is largely asymptomatic. We usedmice to compare the most likely natural HSV-1 host entry routes: oral and nasal. Intranasal infection was 100-fold more efficient than oral and targeted predominantly the olfactory neuroepithelium. Live imaging of HSV-1-expressed luciferase showed infection progressing from the nose to the TG and then reemerging in the facial skin. The brain remained largely luciferase negative throughout. Infected cell tagging by viral Cre recombinase expression in floxed reporter gene mice showed nasal virus routinely reaching the TG and only rarely reaching the olfactory bulbs. Thus, HSV-1 spread from the olfactory neuroepithelium to the TG and reemerged peripherally without causing significant neurologi-cal disease. This recapitulation of typical clinical infection suggests that HSV-1 might sometimes also enter humans via the respi-ratory tract. Herpes simplex virus 1 (HSV-1) persists in at least 70 % of hu-mans. Infection is mostly mild but can cause repeated ulcer-ation, keratitis, and encephalitis (1). Better control would there-fore greatly benefit human health. Established, latent infections are difficult if not impossible to clear, so host entry offers perhaps the best opportunity to break the viral infection cycle. Under