As the COVID-19 pandemic appears to be weakening its grip on the world, scientists are learning more about what makes the new coronavirus tick. Three different research groups independently discovered, to their surprise, that SARS-CoV-2 infects human cells only if the cells express the lysosomal receptor TMEM106B. Its gene is a known factor in dementia, but whether the dementia risk variants affect Covid-19 remain to be seen.
The researchers used genome-wide CRISPR knockout screens to assess which genes are required for Sars-CoV-2 to be able to infect human liver cell lines. They exposed cell libraries to SARS-CoV-2, and looked for knockout cells that failed to churn out virus as an indication that the missing gene is important to establish a full cycle of infection. The three groups converged on the same lysosomal receptor, TMEM106B, a genetic risk factor for frontotemporal dementia and Alzheimer’s disease (Sep 2020 news; Mar 2020 news; Feb 2021 news; Jun 2020 news).
Researchers led by Dirk Daelemans, KU Leuven, Belgium, reported their findings in the March 8 Nature Genetics. The other two papers had appeared back-to-back in the January 7 Cell. Andreas Puschnik, Chan Zuckerberg Biohub, and Melanie Ott, Gladstone Institutes, both in San Francisco, were senior authors on one. The other came from the labs of John Poirier, NYU Grossman School of Medicine, and Charles Rice, Rockefeller University, both in New York.
Exactly what makes TMEM106B essential for SARS-CoV-2 infection remains a mystery, but Markus Damme, University of Kiel, Germany, noted that related coronaviruses hitch a ride on lysosomes to get out of the cell. “Future work is needed to determine if SARS-CoV-2 is hijacking TMEM106B for binding in lysosomes after being released from ACE2 upon endocytosis,” Damme wrote to Alzforum (full comment below).
Whether carriers of TMEM106B risk variants are more or less likely to get COVID-19 is unclear. “Major differences in disease severity in COVID-19 are well-known, and it might be interesting to figure out if there is any direct correlation between the SNPs and disease severity. It might also be interesting to see if FTD patients are more prone to a severe course of the disease,” wrote Damme.—Chelsea Weidman Burke
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