Olfactory host entry supports herpesvirus recombination

Abstract

Herpesvirus genomes record abundant recombination. Its impact on infection remains ill-defined. When co-infecting mice by the natural olfactory route, individually incapacitated Murid Herpesvirus-4 (MuHV-4) mutants routinely recombined to restore normal host colonization. Lung infection rescued much less well. Murine cytomegalovirus mutants deficient in salivary gland colonization also showed rescue via the nose but not the lungs. As nose and lung infections show similar spread, efficient recombination seemed specific to olfactory entry. Rescue of replication-deficient MuHV-4 implied co-infection of the first encountered cells, and this worked also with asynchronous inoculation, suggesting that latent virus could lie in wait for later reactivation. Inhaled MuHV-4 is commonly caught on respiratory mucus, which epithelial cilia push back towards the olfactory surface, and infection was correspondingly frequent at the anterior olfactory edge. Thus olfactory entry provides a general means for herpesviruses to meet. Author summaryInter-strain recombination allows viruses to optimise infection in diverse hosts. Many herpesviruses show past recombination. Yet they are ancient pathogens, so this past may be remote and recombination rare. Diverse herpesviruses enter new hosts via olfactory cells. We show that such entry routinely allows recombination between co-infecting virus strains, even when one strain cannot spread. Recombination was contrastingly rare after lung infection. Thus, entry via olfactory cells specifically supports frequent herpesvirus recombination.