The Microvillar and Solitary Chemosensory Cells as the Novel Targets of Infection of SARS-CoV-2 in Syrian Golden Hamsters

Abstract

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019, suffer from respiratory and non-respiratory symptoms. Among these symptoms, the loss of smell has attracted considerable attention. The objectives of this study were to determine which cells are infected, what happens in the olfactory system after viral infection, and how these pathologic changes contribute to olfactory loss. For this purpose, Syrian golden hamsters were used. First, we verified the olfactory structures in the nasal cavity of Syrian golden hamsters, namely the main olfactory epithelium, the vomeronasal organ, and their cellular components. Second, we found angiotensin-converting enzyme 2 expression, a receptor protein of SARS-CoV-2, in both structures and infections of supporting, microvillar, and solitary chemosensory cells. Third, we observed pathological changes in the infected epithelium, including reduced thickness of the mucus layer, detached epithelia, indistinct layers of epithelia, infiltration of inflammatory cells, and apoptotic cells in the overall layers. We concluded that a structurally and functionally altered microenvironment influences olfactory function. We observed the regeneration of the damaged epithelium, and found multilayers of basal cells, indicating that they were activated and proliferating to reconstitute the injured epithelium.

Oral SARS-CoV-2 Inoculation Causes Nasal Viral Infection Leading to Olfactory Bulb Infection: an Experimental Study

“…Considering that in ammatory cell in ltration is not as abundant in the OM, it is presumed that the OE damage was induced by direct cell damage caused by the virus rather than by the effects of in ammatory cell in ltration. In the previously reported transnasal infection model of SARS-CoV-2, SARS-CoV-2 mainly infected the sustentacular cells, not the ORNs, and most of their cilia were lost early after infection 19,22 . It was also reported that SARS-CoV-2 could only be identi ed in the nasal septum of intranasal infected hamsters up to 3 days after infection 20 , which is consistent with our results.…”

“…Many studies have examined which OE cells are susceptible to infection by SARS-CoV-2, and it is now considered that the virus primarily infects the olfactory cilia and supporting cells but can also infect some basal ORN progenitors 9,19,21,22 . However, SARS-CoV-2 can also affect olfactory neurons, albeit slightly 21 .…”

“…As several cells negative for SOX2, GAP43, and OMP were found in the middle layer of the OE, it is possible that SARS-CoV-2 impaired the function of mature ORNs and prevented normal ORN protein expression. Taken together, the possible effects of SARS-CoV-2 infection on the ORNs are as follows: (1) sustentacular cells cannot support the ORNs because of viral infection, resulting in di culty in maintaining the epithelial morphology and reduced function of mature ORNs 9,19,21,22 ; (2) SARS-CoV-2 directly infects the ONRs and reduces their function, although the percentage may be small 21 ; and (3) SARS-CoV-2 may inhibit the maturation and differentiation of immature ORNs into mature ORNs.…”

“…In contrast, the Syrian hamster ACE2 is highly homologous to human ACE2 and e ciently binds to the SARS-CoV-2 receptor binding domain; therefore, the Syrian hamster is recognized as a good small animal model for SARS-CoV-2 infection 23,24 . In Syrian hamsters, the olfactory epithelium (OE) is extensively disrupted in the rst few days after SARS-CoV-2 infection, and the loss of microvilli becomes signi cant on days 2-7 20,22 . The virus mainly infects the sustentacular and microvillar cells and not the ORNs in the OE 19,22 .…”

“…In Syrian hamsters, the olfactory epithelium (OE) is extensively disrupted in the rst few days after SARS-CoV-2 infection, and the loss of microvilli becomes signi cant on days 2-7 20,22 . The virus mainly infects the sustentacular and microvillar cells and not the ORNs in the OE 19,22 . Subsequently, immune cells are recruited and in ltrate the OE and lamina propria of the olfactory mucosa (OM) 19,21 .…”