Professor Johns Hopkins School of Medicine Baltimore, Maryland
Background: SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. The prevalent loss of the sense of smell and the high levels of ACE2 expression by olfactory sustentacular cells suggest that the olfactory epithelium is a primary target of the virus. Intracranial spread of SARS-CoV-2 from the olfactory epithelium has been suggested, but remains controversial.
Methods: In vitro infection of human olfactory explants and in vivo intranasal infection of hamsters was performed with SARS-CoV-2. Olfactory tissue was examined by immunohistochemistry to characterize the pattern of infection and the inflammatory response.
Results: A striking tropism of SARS-CoV-2 for olfactory neuroepithelium was observed, as compared to nasal respiratory epithelium. In addition to primarily targeting sustentacular cells, SARS-CoV-2 infects a proportion of immature olfactory neurons in hamsters and human biopsies, gaining access to the hamster brain through axonal transport, resulting in a microglial response that is more pronounced in younger hosts. Viral infection induces a predominantly macrophage immune cell infiltration into the hamster olfactory mucosa. Viral clearance by macrophages was substantially compromised in older hamsters.
Discussion/Conclusion: Our observations identify the olfactory mucosa as a site of initial viral infection, propagation, and brain invasion. The evidence that brain infection may occur more readily in younger age hosts has implications for potential SARS-CoV-2-related neurological and psychological dysfunction in this population. Decreased olfactory epithelium macrophage function may underlie delayed viral clearance in aging.