ABSTRACT
SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis-related genes. Further, robust basal stem cell activation contributed to neuroepithelial regeneration and restored ACE2 expression postinfection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration after infection. The shifting characteristics of viral infection at the airway portal provide insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention.
Subject(s)
COVID-19 , Common Cold , Animals , Cricetinae , Humans , Aged , SARS-CoV-2/genetics , Post-Acute COVID-19 Syndrome , COVID-19/genetics , AxonsABSTRACT
BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a multifactorial inflammatory condition that remains poorly understood. Over the past decade, we have witnessed impressive scientific advancements that have allowed us to better understand the molecular and cellular mechanisms that underlie the inflammatory processes in mucosal diseases including asthma, allergic rhinitis, and CRSwNP. OBJECTIVE: The present review aims to summarize and highlight the most recent scientific advancements that have enriched our understanding of CRSwNP. METHODS: A comprehensive review of the available literature on the use of new scientific techniques in CRSwNP was performed. We evaluated the most recent evidence from studies using animal models, cell cultures, and genome sequencing techniques and their impact on our understanding of CRSwNP pathophysiology. RESULTS: Our understanding of CRSwNP has rapidly progressed with the development of newer scientific techniques to interrogate various pathways involved in its pathogenesis. Animal models remain powerful tools and have elucidated the mechanisms behind esinophilic inflammation in CRSwNP; however, animal models reproducing polyp formation are relatively sparse. 3D cell cultures have significant potential to better dissect the cellular interactions with the sinonasal epithelium and other cell types in CRS. Additionally, some groups are starting to utilize single-cell RNA sequencing to investigate RNA expression in individual cells with high resolution and on a genomic scale. CONCLUSION: These emerging scientific technologies represent outstanding opportunities to identify and develop more targeted therapeutics for different pathways that lead to CRSwNP. An additional understanding of these mechanisms will be critical for developing future therapies for CRSwNP.
