Since almost the beginning of the covid-19 pandemic caused by the SARS-CoV-2 virus, the scientific community has tried to determine why this virus causes such negative long-term effects compared to those created by most others. coronavirus.

The investigation begins to give some answers. Among them, the one that appears published in Science Translational Medicine and that suggests new approaches to treat covid-19, according to the research team formed by a multicenter consortium led from the Children's Hospital of Philadelphia, United States (CHOP) and the Covid-19. 19 International Research Team (VOC-IRT).

This scientific platform has discovered that genes in mitochondria, the energy producers of our cells, can be negatively affected by the virus, leading to dysfunction in multiple organs beyond the lungs.

Mitochondria are found in every cell in our body.. The genes responsible for generating mitochondria are scattered both in the nuclear DNA located in the nucleus of our cells and in the mitochondrial DNA (mtDNA) located within each mitochondria.

Previous studies have shown that SARS-CoV-2 proteins can bind to mitochondrial proteins in host cells, potentially leading to mitochondrial dysfunction.

To understand how SARS-CoV-2 affects mitochondria, researchers at CHOP's Center for Mitochondrial and Epigenomic Medicine (CMEM), together with colleagues at COV-IRT, analyzed mitochondrial gene expression to detect differences caused by the mitochondria. virus. To do this, they analyzed a combination of nasopharyngeal and autopsy tissues from affected patients and animal models.

Recovered in the lungs, not in other organs

Joseph Guarnieri, MCEH postdoctoral researcher at CHOP notes that tissue samples from human patients allowed us to see how mitochondrial gene expression was affected “at the beginning and end of disease progression, whereas animal models allowed us to complete the blank spaces and look at the progression of differences in gene expression over time.

The study found that, in autopsy tissue, mitochondrial gene expression had recovered in the lungs, but mitochondrial function remained suppressed in the heart, as well as in the kidneys and liver.

By studying animal models and measuring the time when the viral load peaked in the lungs, mitochondrial gene expression was suppressed in the cerebellum, although SARS-CoV-2 was not observed in the brain.. Additional animal models revealed that during the middle phase of SARS-CoV-2 infection, mitochondrial function in the lungs began to recover.

Taken together, these results reveal that host cells respond to initial infection in a way that involves the lungs, but over time, mitochondrial function in the lungs is restored, while in other organs, particularly the heart, mitochondrial function is restored. mitochondrial function remains impaired.

For Douglas C.. Wallace, Director of CMEM at CHOP, this study provides strong evidence that COVID-19 needs to move away from viewing it strictly as an upper respiratory disease and start viewing it as a systemic disorder affecting multiple organs.”

Potential therapeutic target

“The ongoing dysfunction that we are seeing in organs other than the lungs suggests that mitochondrial dysfunction could be causing long-term damage to the internal organs of these patients.”

While future studies using these data will explore how systemic immune and inflammatory responses may be responsible for more severe disease in some patients, the research team found a potential therapeutic target in microRNA 2392 (miR-2392), which they demonstrated regulate mitochondrial function in the human tissue samples used in this study.

“This microRNA was upregulated in the blood of patients infected with SARS-CoV-2, which is not something we would normally expect to see,” says co-lead author Afshin Beheshti, a biostatistician and visiting researcher at The Broad Institute in Cambridge. , and founder and president of COV-IRT.

In his opinion, “neutralizing this microRNA could prevent the replication of the virus, providing an additional therapeutic option for patients who are at risk of suffering more serious complications related to the disease.”

Earlier this year, the Gates Foundation provided funding to Douglas C. Wallace and MEMC to investigate how mtDNA variation between global populations could affect mitochondrial function and therefore individual susceptibility to SARS-CoV-2.

According to Wallace, the demonstration that SARS-CoV-2 markedly affects mitochondrial function “supports the hypothesis that individual differences in mitochondrial function could be a factor in the individual severity of covid-19.”