Study Shows How COVID-19 May Be Able to Overpower the Immune System

For patients with coronavirus disease 2019 (COVID-19), mitochondria are one of the first lines of defense in fighting the virus, according to researchers at the University of Southern California (USC) Leonard Davis School of Gerontology.

The research investigated some of the critical differences between how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses affect mitochondrial genes, as the differences between them may help to provide answers as to why some older adults and people with metabolic disfunction have more severe responses to COVID-19 than others. Additionally, such investigations can help to provide a starting point to identify potential therapeutics.

"If you already have mitochondrial and metabolic dysfunction, then you may, as a result, have a poor first line of defense against COVID-19. Future work should consider mitochondrial biology as a primary intervention target for SARS-CoV-2 and other coronaviruses," said senior author Pinchas Cohen, MD, professor of gerontology, medicine and biological sciences and dean of the USC Leonard Davis School, in a press release.

The results of the research also helped to demonstrate how COVID-19 diverts mitochondrial genes from their normal function in order to mute the body's natural inflammatory response.

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

When conducting the research, the team performed ribonucleic acid (RNA) sequencing analyses that compared mitochondrial-COVID-19 interactions to 3 other viruses, which included respiratory syncytial virus, seasonal influenza A virus, and human parainfluenza virus 3.

The results of the analysis demonstrated that there are 3 ways that COVID-19 mutes the body’s cellular immune response in a way that differs from other viruses. Specifically, they observed that SARS-CoV-2 reduces the levels of complex I, which are a group of mitochondrial proteins that are encoded by nuclear DNA.

The researchers observed that by reducing the levels of complex I, the cell’s metabolic output and reactive oxygen species generation may be quieted, which would in turn limit the inflammatory response to the virus.

"COVID-19 is reprogramming the cell to not make these complex I-related proteins. That could be one way the virus continues to propagate," Miller said in the press release, noting, however, that these findings still need to be validated in future research.

Additionally, the research demonstrated that SARS-CoV-2 does not affect the levels of the messenger protein, mitochondrial antiviral-signaling protein messenger RNA, which is the protein responsible for communicating to the cell that a viral attack has occurred. Normally, upon activation of this protein, it functions as an alarm system that warns the cell to self-destruct in order to stop the replication of the virus.

Also, the researchers noted that genes encoded by mitochondria were not getting switched on or off by SARS-CoV-2. This process of getting turned on and off is currently understood to generate energy that helps the cell evade the attack of a virus.

"This study adds to a growing body of research on mitochondrial-COVID-19 interactions and presents tissue and cell-specific effects that should be carefully considered in future experiments," Cohen said in the press release.

REFERENCE

New findings help explain how COVID-19 overpowers the immune system. Los Angeles, CA: University of Southern California; January 8, 2021. eurekalert.org/pub_releases/2021-01/uosc-nfh010821.php. Accessed January 11, 2021.