Researchers identify human-cell proteins required for coronavirus infections

January 19, 2021

Cells without certain proteins might be incapable of being infected by COVID-19. (NIAID-RML via AP)

The novel coronavirus is incapable of infecting human cells that do not produce certain molecules, including some related to cholesterol, researchers found in a paper published in Cell, opening the door for possible COVID-19 drug treatments.

The study is the latest to screen human cells to learn how their components are being co-opted for infection by the novel coronavirus. It also tested two other coronavirus strains, both of which cause the common cold, to discover any similarities within the virus family that may help in mitigating the outbreak of a new coronavirus.

A team of California scientists used gene editing to individually disable the roughly 20,000 protein-coding human genes across across many liver cancer cells — a cell line particularly susceptible to COVID-19 — before exposing them to one of the three coronavirus strains. If the infection rate in a cell decreased, it meant the knocked-out gene and its associated protein were likely important to that virus’ infection process.

The screens across 120 million cells turned up many proteins found to be crucial for at least one of the viruses, but only proteins related to two intracellular systems affected all three.

“The surprising thing was really that these pathways popped up in all three screens, so this is really a feature of ourselves that is hijacked by viruses,” said Andreas Puschnik, a lead author of the study and a virology and immunology researcher at the Chan Zuckerberg Biohub in San Francisco.

One of the two pathways was cholesterol creation and regulation. A group of five proteins responsible for the lipid’s uptake and upkeep collectively slowed the spread of COVID-19 and both common colds when removed, possibly because the cholesterol is required for the viruses to enter the cell.

The drugs already approved to manage cholesterol levels and could be promising COVID-19 treatments, according to Puschnik.

“The exciting thing is that there are already cholesterol-lowering drugs on the market like statins,” he said. “There are some studies that see correlations that certain patients on statins do better when they come to the hospital than people without statins.”

The other system crucial to the three coronaviruses are phosphatidylinositol kinases, a family of enzymes that play many roles in the cell. Puschnik said viruses could also be using it to enter the cell, or to travel from the cell membrane to deeper within.

The knocked-out gene that impeded COVID-19 infection most was TMEM106B, a poorly understood protein connected to lysosome function and dementia. It had little effect on the common-cold viruses.

The work of Puschnik’s team strongly aligned with the results of other research published as preprints while their paper was being reviewed for publication. Some cholesterol and phosphatidylinositol kinase regulators, as well as TMEM106B, were identified in a range of different cells using similar screening methods. One study, published in Cell earlier this month, used a closely related line of liver cancer cells and reproduced similar results for a majority of the identified crucial proteins.

Identifying the components of a successful coronavirus infection could be the first step in developing treatments, not only of COVID-19 but all diseases caused by coronaviruses.

“It's advantageous if you have something that is used by coronavirus because if you're now able to design a drug that inhibits this pathway,” Puschnik said. “It would not just inhibit the growth of one specific coronavirus, but of several viruses and maybe even coronaviruses that haven't emerged yet.” 

Puschnik said he and his colleagues are following up on some of the pathways identified in the study to learn how they function in human cells and interact with coronaviruses. They will also continue research into hepatitis viruses that has been put on hold during the COVID-19 pandemic.

The article, “Genetic screens identify host factors for SARS-CoV-2 and common cold coronaviruses,” was published Dec. 8 in CellThe authors of the study were Ruofan Wang, Jessie Kulsuptrakul, Katherine Travisano and Andreas Puschnik, Chan Zuckerberg Biohub; Camille Simoneau, Mehdi Bouhaddou, Jennifer Hayashi, Parinaz Fozouni, Nevan Krogan, Melanie Ott, Gladstone Institutes and University of California, San Francisco; Jared Carlson-Stevermer, Jennifer Oki, Kevin Holden, Synthego Corporation; James Zengel, Christopher Richards, Jan Carette Stanford University; Lauren Rodriguez, Bastian Joehnk, Keith Walcott, Anita Sil, University of California, San Francisco. The lead authors were Melanie Ott and Andreas Puschnik.

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