New Discovery Helps Explain How COVID-19 Overpowers the Immune System

The discovery of unique virus signatures offers possible explanations for why older adults and those with diabetes or heart disease may react more severely to COVID-19 than others, USC researchers say.

To understand why COVID-19 can suppress the body’s immune response, new research from the USC Leonard Davis School of Gerontology suggests mitochondria are one of the first lines of defense against COVID-19 and identifies key differences in how SARS-CoV-2 , the virus that causes COVID-19, affects mitochondrial genes compared to other viruses. These differences offer possible explanations for why older adults and people with metabolic disorders respond more severely to COVID-19 than other individuals, and they also provide a starting point for more targeted approaches that can help identify therapies, said senior author Pinchas Cohen, professor of gerontology. , medicine and biological sciences and dean of the USC Leonard Davis School.

“If you already have mitochondrial and metabolic dysfunction, you may have a poor first line of defense against COVID-19 as a result. Future work should consider mitochondrial biology as a primary intervention target for SARS-CoV-2 and other coronaviruses,” he said.

The study, published in the Nature journal Scientific Reports, builds on recent findings that COVID-19 dampens the body’s innate inflammatory response and reports that it does so by distracting mitochondrial genes from their normal function.

Portrait of Pinchas Cohen, MD, Dean of the USC Leonard Davis School of Gerontology. Credit: USC/Stephanie Kleinman

“We already knew that our immune response was not a successful defense against COVID-19, but we didn’t know why,” said lead author Brendan Miller, a senior doctoral student at USC Leonard Davis School. “What we did differently was look at how the virus specifically targets mitochondria, a cellular organelle that is a critical part of the innate immune system and the body’s energy production.”

Using the massive amounts of public data uploaded in the early days of the virus outbreak, the research team conducted RNA sequencing analyzes that compared mitochondrial-COVID interactions with those of other viruses: respiratory syncytial virus, seasonal influenza A virus, and human parainfluenza virus. 3. These re-analyses identified three ways in which COVID-19, but not the other viruses, dampens the body’s cellular protective response.

Chief among their findings is that SARS-CoV-2 uniquely lowers levels of a group of mitochondrial proteins known as Complex One, which are encoded by nuclear DNA. It’s possible that this effect “rests” the cell’s metabolic output and the formation of reactive oxygen species, which, when functioning correctly, produce an inflammatory response that can kill a virus, they say.

Portrait of senior PhD student Brendan Miller. Credit: USC/Fiona Pestana

“COVID-19 reprograms the cell not to make these Complex One-related proteins. That could be one way the virus continues to spread,” said Miller, noting that this, along with the study’s other observations, has yet to be validated in future experiments.

The study also revealed that SARS-CoV-2 does not alter levels of the messenger protein, MAVS mRNA, which usually tells the cell that a viral attack has occurred. Normally, this protein functions as an alarm system, warning the cell to destroy itself so the virus can’t replicate, Miller says.

In addition, the researchers found that genes encoded by the mitochondria were not turned on or off by SARS-CoV-2 — a process believed to produce energy that can help the cell evade a virus — at rates to be expected. when confronted with a virus.

“This study adds to a growing body of research on mitochondrial-COVID interactions and presents tissue- and cell-specific effects that should be carefully considered in future experiments,” Cohen said.

Reference: “Host mitochondrial transcriptome response to SARS-CoV-2 in multiple cell models and clinical samples” by Brendan Miller, Ana Silverstein, Melanie Flores, Kevin Cao, Hiroshi Kumagai, Hemal H. Mehta, Kelvin Yen, Su-Jeong Kim and Pinchas Cohen, January 8, 2021, Scientific Reports.
DOI: 10.1038/s41598-020-79552-z

Funding sources for the study include the National Institutes of Health, including grants R01AG061834 (Cohen) and P01AG034906 (Cohen), and the National Institute on Aging (AG000037, Miller).

dr. Cohen is a co-founder, shareholder and board member of Cohbar Inc.