Influence of SARS-CoV-2 on airway mucus production: A review and proposed model

Abstract

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has affected millions of lives. Individuals who survive severe COVID-19 can experience sustained respiratory symptoms that persist for months after initial infection. In other airway diseases, abnormal airway mucus contributes to sustained airway symptoms. However, the impact of SARS-CoV-2 on airway mucus has received limited attention. In the current review, we assess literature describing the impact of SARS-CoV-2 on airway pathophysiology with specific emphasis on mucus production. Accumulating evidence suggests that the 2 major secreted airway mucin glycoproteins, MUC5AC and MUC5B, are abnormal in some patients with COVID-19. Aberrations in MUC5AC or MUC5B in response to SARS-CoV-2 infection are likely due to inflammation, though the responsible mechanisms have yet to be determined. Thus, we also provide a proposed model highlighting mechanisms that can contribute to acute and sustained mucus abnormalities in SARS-CoV-2, with an emphasis on inflammatory cells and mediators, including mast cells and histamine. Last, we bring to light the challenges of studying abnormal mucus production in SARS-CoV-2 infections and discuss the strengths and limitations of model systems commonly used to study COVID-19. The evidence to date suggests that ferrets, nonhuman primates, and cats may have advantages over other models to investigate mucus in COVID-19.

Animal models for studying COVID-19, prevention, and therapy: Pathology and disease phenotypes

“…Limitations of COVID-19 animal models. 15,48,82 phenotypes andsequalae • Interspecies differences in anatomy and immune system understanding of chronic COVID-19 such as multisystem inflammatory syndrome and recently described long COVID (post-acute sequelae of SARS-CoV-2 infection), both of which involve damage to multiple organs. There are many ongoing efforts, including those led by NIH, 53 on identifying well-characterized small and large animal models for various COVID-19 manifestations (acute and chronic); many of these include grant opportunities in the academic setting.…”

“…Finally, efforts to develop COVID-19 animal models are hampered by enhanced (BSL-3) requirements (as explained in the previous section), increasingly restrictive but important ethical considerations, limited immunological and molecular research tools (particularly in species, such as hamster & ferrets), high demand for experimental animals during the pandemic which exceeds the capacity of commercial breeders, and interspecies anatomical and immune system differences. 48 …”

Special focus on SARS-CoV-2 and other zoonotic respiratory coronaviruses in animal models

“…The impact of SARS-CoV-2 on airway mucus production with emphasis on the contribution of inflammatory cells and mediators is reviewed by Meyerholz and Reznikov. 20 They expressed the challenges of studying abnormal mucus production in SARS-CoV-2 infections and argued that that ferrets, NHPs, and cats may have advantages over other models to investigate mucus in COVID-19.…”

“…Other SARS-CoV-2-focused papers in this issue review alternatives to animal models to study SARS-CoV-2 and other respiratory infectious pathogens; 26 influence of SARS-CoV-2 on airway mucus production; 20 SARS-CoV-2 infection in mustelids including ferrets 11 and in experimentally infected cats; 22 and natural SARS-CoV-2 infection in mink, 24 zoo, and companion animals. 25 These papers illustrate the wide species range of SARS-CoV-2 infection and disease, experimental or natural.…”

Mathematical modelling of respiratory viral infection and applications to SARS-CoV-2 progression

“…Moreover, mucus becomes more viscous in the infected tissue due to debris of viral particles and dead infected cells (Ref. [9]) and because more viscous mucus is produced due to infection and inflammation [8]. Furthermore, convective motion of ASL can influence infection spreading in the tissue.…”