By now, we’re quite familiar with COVID-19’s respiratory symptoms: dry cough and shortness of breath, for instance, are among the most well-known early warning signs of infection. However, a significant number of COVID-19 patients with a severe infection also go on to develop serious liver-related symptoms. Until now, the underlying mechanisms driving this phenomenon have remained elusive, making the clinical management of these patients particularly challenging.
In search of answers, Ramanuj DasGupta and a team of scientists from A*STAR’s Genome Institute of Singapore (GIS) and Singapore Immunology Network (SIgN) turned to a comprehensive technology known as single-cell RNA sequencing to study SARS-CoV-2’s impact on the liver.
“Single-cell RNA sequencing allows high-throughput gene expression profiling of thousands of individual cells,” explained DasGupta, a Senior Group Leader at GIS. “The throughput and scale of this technology enable researchers to understand at the resolution of single-cells what genes are expressed, in what quantities and how they differ across thousands of cells within a heterogeneous tissue type.”
Using the technique, the researchers profiled around 300,000 individual liver cells, looking for cell populations that express both the ACE2 and TMPRSS2 genes. In the respiratory system, these genes are known to be abundantly expressed, with the TMPRSS2 enzyme priming SARS-CoV-2’s spike protein to latch on to the ACE2 receptor on host cells—two critical steps in the infection process.
From their analyses, the team found that these two genes are co-expressed in TROP2+ progenitor cells, a distinct subset of cells lining the bile duct that facilitate liver regeneration in response to damage. Interestingly, the scientists also observed that patients with liver cirrhosis had more of these ACE2 and TMPRSS2-expressing progenitor cells, suggesting that COVID-19 patients with existing liver damage may require more careful attention.
“Overall, our study suggests that COVID-19-associated liver dysfunction and co-morbidities in the clinic may be associated with infection of the liver progenitors that could impair their regenerative capacity in patients exhibiting liver damage,” explained DasGupta.
In the future, the researchers intend to use single-cell RNA sequencing to study progenitor cells from other organs that may be susceptible to SARS-CoV-2 infection, especially considering the systemic internal damage often observed in fatal cases of COVID-19.
“Our study paves the way for querying single-cell atlases for identifying cell types involved in viral entry and the impact of the virus on these cells,” added DasGupta. “The next line of investigation may lead to identifying novel ways of blocking viral entry in human tissue for better disease management.”
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS) and Singapore Immunology Network (SIgN).
