Study offers understanding into metabolic pathways hijacked by SARS-CoV-2 for viral replication

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• Source: Brigham and Women's Hospital


• Date: 16 Mar,2021

When SARS-CoV-2, the virus which causes COVID-19, infects a human cell, it quickly begins to replicate by seizing the cell’s existing metabolic machinery. The infected cells churn out thousands of viral genomes and proteins while halting the creation of their own sources. Researchers from Brigham and Women’s Hospital, Massachusetts General Hospital (MGH), and the Broad Institute, studying cultured cells soon after infecting them with the virus, have more insight into the metabolic pathways co-opted from the virus.

The findings, published in Nature Communications, emphasize the potential therapeutic benefit of drugs such as methotrexate, which inhibit folate and one-carbon metabolic pathways appropriated from the virus.

One of the things we’re lacking in this pandemic is a pill that can be taken orally, as a prophylactic agent, before someone is hospitalized or even before they’re infected. Monoclonal antibodies have a lot of promise but need to be given intravenously. Blocking the metabolism pathways that viruses rely on to replicate could be a new strategy for treating patients at an early timepoint.”

Benjamin Gewurz, MD, PhD, Corresponding Author, Division of Infectious Diseases

To identify which metabolic pathways to target, the researchers obtained samples of the virus and cultivated them in a highly protected facility known as a BSL-3 laboratory, located at the Broad Institute. Then they paired up with the lab of co-senior writer Vamsi Mootha, MD, of MGH, to employ mass spectrometry approaches to identify the resources being consumed and produced by healthy cells and infected cells. They analyzed the infected cells at an”eclipse stage,” eight hours after infection, once the virus has begun manufacturing its RNA and proteins but hasn’t yet exerted a severe impact on host cell growth and survival.

In assessing the amino acids and thousands of chemical metabolites produced by the cells, the researchers observed that infected cells had depleted stores of glucose and folate. They demonstrated that the SARS-CoV-2 virus diverts building blocks out of glucose production to the assembly of purine bases, which are necessary for creating considerable amounts of viral RNA. Furthermore, they discovered that the 1-carbon pathway used to metabolize folate was hyperactive, thus providing the virus with carbon groups for making bases for DNA and RNA.

Drugs that inhibit folate metabolism, like methotrexate, are frequently used to treat autoimmune conditions like arthritis and might be therapeutic candidates for COVID-19. Methotrexate is currently being assessed as a treatment for the inflammation that accompanies more complex COVID-19 infections, but the researchers suggest it could also be beneficial early on. Their research also found that it could provide a synergistic effect when administered with the anti-viral drug remdesivir. Methotrexate’s immune-suppressing properties could make its proper administration as a prophylactic challenging, however. Researchers would need to determine how to maximize the drug’s antiviral effects without significantly compromising a patient’s natural immune response.

However, Gewurz points out that oral antivirals are an essential addition to an arsenal of treatments for COVID-19, serving both as a direct treatment for infection as well as a defense against new versions and other coronaviruses.

“We’re hoping that, ultimately, we can find a means of preventing viruses from using cells’ metabolism pathways to replicate themselves because that could limit the ability of viruses to evolve resistance,” Gewurz said. “We’re beginning to see new viral variants, and we’re hoping that we can stay ahead of that — treating patients before the virus has the chance to make copies of itself that can become resistant to antibodies.”