No abstract

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a newly emerged severe acute respiratory syndrome (SARS)-coronavirus-2 (SARS-CoV-2). COVID-19 presents a diverse clinical spectrum, ranging from an asymptomatic carrier state to patients with life-threatening multi-organ failure and death (Huang et al., 2020a). The greatest risk factor for severe disease is age, with higher morbidity and mortality rates in the elderly population, despite younger people shedding similar levels of virus (Yanez et al., 2020). The overall case fatality rate of COVID-19 is 2.3%, rising to 14.8% in patients over the age of 80, and 49% among the critically ill (Kang & Jung, 2020).Currently, therapeutics for COVID-19 are limited. To overcome this, it is important that we use physiologically relevant models to reproduce the pathology of infection and evaluate the efficacy of antiviral drugs. Models of airway infection, including the use of a human infection challenge model or well-defined, disease relevant in vitro systems can help determine the key components that perpetuate the severity of the disease. Here, we briefly review the human models that are currently being used in COVID-19 research and drug development.

Children infected with SARS-CoV-2 rarely progress to respiratory failure, but the risk of mortality in infected people over 85 years of age remains high, despite vaccination and improving treatment options. Here, we take a comprehensive, multidisciplinary approach to investigate differences in the cellular landscape and function of paediatric (<11y), adult (30-50y) and elderly (>70y) nasal epithelial cells experimentally infected with SARS-CoV-2. Our data reveal that nasal epithelial cell subtypes show different tropism to SARS-CoV-2, correlating with age, ACE2 and TMPRSS2 expression. Ciliated cells are a viral replication centre across all age groups, but a distinct goblet inflammatory subtype emerges in infected paediatric cultures, identifiable by high expression of interferon stimulated genes and truncated viral genomes. In contrast, infected elderly cultures show a proportional increase in ITGB6hi progenitors, which facilitate viral spread and are associated with dysfunctional epithelial repair pathways. A video explaining this work can be found here - https://youtu.be/uExP4bx6D_A .