Review of studies of severe acute respiratory syndrome related coronavirus-2 pathogenesis in human organoid models

Abstract

Severe acute respiratory syndrome related coronavirus-2 (SARS-CoV-2) is the cause of Covid-19 which was classified as a global pandemic in March 2020. The increasing global health and economic burden of SARS-CoV-2 has necessitated urgent investigations into the pathogenesis of disease and development of therapeutic and vaccination regimens. Human trials of vaccine and antiviral candidates have been undertaken, but basic pathogenetic studies are still required to inform these trials. Gaps in understanding of cellular infection by, and immunity to, SARS-CoV-2 mean additional models are required to assist in improved design of these therapeutics. Human organoids are three-dimensional models that contain multiple cell types and mimic human organs in ex vivo culture conditions. The SARS-CoV-2 virus has been implicated in causing not only respiratory injury but also injury to other organs such as the brain, liver and kidneys. Consequently, a variety of different organoid models have been employed to investigate the pathogenic mechanisms of disease due to SARS-CoV-2. Data on these models have not been systematically assembled. In this review, we highlight key findings from studies that have utilised different human organoid types to investigate the expression of SARS-CoV-2 receptors, permissiveness, immune response, dysregulation of cellular functions, and potential antiviral therapeutics.

Keywords: Covid-19; SARS-CoV-2; antivirals; immune response; organoids; pathogenesis.

FIGURE 1

Severe acute respiratory syndrome related coronavirus‐2 (SARS‐CoV‐2) and host cell receptors. (a) Viral attachment and cellular entry is mediated by the SARS‐CoV‐2 spike (S) protein. The N‐terminal subunit, S1 binds to the receptor, angiotensin I converting enzyme 2 (ACE2)., , Hoffmann et al. suggest the S protein is primed by the transmembrane serine protease 2 (TMPRSS2), inducing host cell fusion. (b) Using single cell RNA sequencing datasets, various human organs have been identified as expressing the target receptors for SARS‐CoV‐2 infection, ACE2 and TMPRSS2., , Subsequently, numerous organoid models have been utilised to detect ACE2 and TMPRSS2., , , , , , , , , , , ,