Neutrophils initiate the destruction of the olfactory epithelium during SARS-CoV-2 infection in hamsters

Abstract

The loss of smell related to SARS-CoV-2 infection is one of the most prevalent symptoms of COVID-19. It is now clear that this symptom is related to the massive infection by SARS-CoV-2 of the olfactory epithelium leading to its desquamation. However, the molecular mechanism behind the destabilization of the olfactory epithelium is less clear. Using golden Syrian hamster, we show here that while apoptosis remains at a low level in damaged infected epithelium, the latter is invaded by innate immunity cells. By depleting the neutrophil population or blocking the activity of neutrophil elastase-like proteinases, we reduced the damage induced by the SARS-CoV-2 infection. Surprisingly, the impairment of neutrophil activity led to a decrease of SARS-CoV-2 infection levels in the nasal cavity. Our results indicate a counterproductive role of neutrophils leading to the release of infected cells in the lumen of the nasal cavity and thereby enhanced spreading of the virus.

Reduced Olfactory Bulb Volume Accompanies Olfactory Dysfunction After Mild SARS-CoV-2 Infection

“…How OSN are affected by SARS-CoV-2 is controversial. Discussed mechanisms are neurotropism, affection by an impaired support system and damage caused by the immune response to the virus (12,36,37). As the OB serves as a relay for projections from the OSN, volumetric reductions might occur as an indirect effect of OSN affection.…”

“…How OSN are affected by SARS-CoV-2 is controversial. Discussed mechanisms are neurotropism, affection by an impaired support system and damage caused by the immune response to the virus (12,36,37).…”

The nervous system during COVID‐19: Caught in the crossfire

“…This robust macrophage response in the olfactory neuroepithelium is consistent with the high levels of Macrophage Inflammatory Protein‐1 Alpha (MIP‐1a) detected in the ethmoid turbinates of SARS‐CoV‐2 (A‐D) ‐infected hamsters. 177 The increased presence of granulocytes in the human nasal cavity 217 and myeloperoxidase‐containing cells in the hamster ethmoid turbinates has also been detected during acute infection 216 (Figure 4 ). Elevated CD4 + cell counts in the nasopharyngeal swabs of COVID‐19 patients 217 and increased gene expression of CD3, CD4, and CD86 in the ethmoid turbinates of SARS‐CoV‐2‐infected hamsters suggests that activated CD4 + T cells flood the ethmoid turbinates to aid in the clearance of SARS‐CoV‐2.…”

“… 214 In the incipient stages of SARS‐CoV‐2 (A‐D) infection, levels of macrophage chemoattractants, including CCL5 and CXCL10, become elevated in the ethmoid turbinates of hamsters 177 , 211 (Figure 3 ). As the infection of the ethmoid turbinates progresses, an increasing number of Iba1 + macrophages infiltrate the neuroepithelium and swarm the sites of SARS‐CoV‐2 infection 172 , 175 , 215 , 216 (Figure 4 ). This robust macrophage response in the olfactory neuroepithelium is consistent with the high levels of Macrophage Inflammatory Protein‐1 Alpha (MIP‐1a) detected in the ethmoid turbinates of SARS‐CoV‐2 (A‐D) ‐infected hamsters.…”

“… 175 , 216 This sloughing of the olfactory neuroepithelium occurs through an unknown mechanism that appears to be neutrophil‐mediated. 216 Treatment with a Cathepsin C inhibitor reduced the amount of cells expulsed into the nasal lumen following SARS‐CoV‐2 (Beta) intranasal inoculation of Syrian golden hamsters. 216 It seems likely that the sloughing of the olfactory neuroepithelium is a protective mechanism to clear pathogens from the ethmoid turbinates.…”