Xinchen Wang and David Goldstein: Transcriptional inhibition of viral entry proteins as a therapeutic strategy SARS CoV 2
Summary by: Arooba Ahmed (CC '23)
Drs. Wang and Goldstein are working on transcriptional inhibition to knock down host proteins that are essential for virus entry into cells. A lot of work has been done on the ACE2 receptor, but they are also looking at other proteins needed for viruses to enter the cell. They focus on TMPRSS2, a protein necessary to cleave the virus’ spike protein and facilitate entry. Since ACE2 and TMPRSS2 are indispensable to entry, both genes are potential targets for transcriptional inhibition. However, ACE2 is not a good target as loss of function is strongly selected against in humans. In studies of SARS-CoV-1 (the original SARS virus), TMPRSS2 allele loss has been tolerated, and mice seem viable when this gene is also knocked out. This makes it a good target for transcriptional inhibition.
The group conducted a literature wide screening for studies in which drug treatment changed the expression of TMPRSS2. They found many of the treatments which downregulate or upregulate TMPRSS2 involve the estrogen/androgen pathway. The estrogen related compounds such as estradiol consistently downregulate TMPRSS2 while testosterone derivatives seem to upregulate it. They also noticed a time dependent effect: it seemed that longer treatments with estrogen decreases TMPRSS2 expression
But all the studies were done in either breast or prostate cancer cell lines, so had to determine whether the trend was relevant to lung tissue. And in fact, in the human lung, the genes correlated with TMPRSS2 expression seem to follow the same expression patterns following estrogen treatment. Therefore, based on the expression patterns, they think TMPRSS2 expression can be regulated by androgen or estrogen related compounds in the human lung.
Because estrogen and testosterone are also sex hormones, they wondered if this would match with epidemiological data for the difference in male and female expression, but didnt seem much difference.
Even though there was no difference in median expression across their data, there was a large difference in variances. Both genes have very large skews where most of the expression was low, but in select groups was very high (varying by two orders of magnitude, which was relatively unusual). TMPRSS2 shows more skewing in older individuals, which makes it possible that its gene expression causes COVID-19 severity. For this reason, the group wants to look at TMPRSS2 before and after infection to create profile expressions from existing nasal swabs.