Viruses and bacteria have a very long history. Because viruses cannot reproduce without a host, they have been invading bacteria for millions of years. some of those bacteria eventually became mitochondriaTo synergistically adapt to life within eukaryotic cells (cells that have a nucleus that contains chromosomes).
Ultimately, mitochondria became the powerhouses within all human cells.
Fast forward to the rise and global spread of novel coronaviruses like SARS-CoV-2 COVID-19, About five percent of people infected with SARS-CoV-2 suffer respiratory failure (low blood oxygen), which requires hospitalization. In Canada, about 1.1 percent of infected patients (about 46,000 people) have died.
This is the story of how a team gathered during EpidemicRecognized the mechanism by which these viruses were causing lung injury and lowering oxygen levels in patients:
It is a return to the primitive war between viruses and bacteria – specifically, between this novel virus and the evolutionary progeny bacteriaour mitochondria.
SARS-CoV-2 is the third novel coronavirus to cause a human outbreak in the 21st century, after SARS-CoV in 2003 and MERS-CoV in 2012. We need to better understand how coronaviruses cause lung injury to prepare for the next pandemic.
How does COVID-19 affect the lungs
serious people COVID-19 pneumonia Often arrive at the hospital with abnormally low oxygen levels. They have two unusual features that set them apart from patients with other types of pneumonia: First, they have extensive injury to their lower airways (the alveoli, where oxygen is carried).
Second, they send blood to unventilated areas of the lungs, called airy– Spraying mismatch. This means that the blood is going to parts of the lungs where it will not get enough oxygen.
Together, these abnormalities reduce blood oxygenation. However, the cause of these abnormalities was unknown. In 2020, our team of 20 researchers from three Canadian universities set out to uncover this mystery. We proposed that SARS-CoV-2 made COVID-19 pneumonia worse by targeting mitochondria in airway epithelial cells (cells that line the airway) and pulmonary artery smooth muscle cells.
People with severe COVID-19 pneumonia often arrive at the hospital with abnormally low oxygen levels (File)
We already knew that mitochondria are not only the powerhouse of the cell, but also its main consumers and sensors. oxygen, Mitochondria control the process of programmed cell death (called apoptosis), and they control the distribution of blood flow to the lungs by a mechanism called hypoxic pulmonary vasoconstriction.
This system has an important function. This directs blood away from areas of pneumonia into the better ventilated lobes of the lungs, which optimizes the absorption of oxygen. By damaging the mitochondria in the smooth muscle cells of the pulmonary artery, the virus allows blood flow to continue to areas of pneumonia, which also reduces oxygen levels.
It appeared plausible that SARS-CoV-2 was damaging the mitochondria. The consequences of this damage – increased apoptosis in airway epithelial cells, and loss of hypoxic pulmonary vasoconstriction – were creating lung injury and hypoxemia (low blood). oxygen) Worse.
Our discovery, published in Redox Biology, explains how SARS-CoV-2, the coronavirus that causes COVID-19 pneumonia, lowers blood oxygen levels.
We show that SARS-CoV-2 kills airway epithelial cells by damaging their mitochondria. This results in accumulation of fluid in the lower airways, which hinders the absorption of oxygen. We also show that SARS-CoV-2 damages mitochondria in pulmonary artery smooth muscle cells, which inhibits hypoxic pulmonary vasoconstriction and reduces oxygen levels.
attack on mitochondria
Coronavirus damages mitochondria in two ways: by regulating gene expression related to mitochondria, and by direct protein-protein Conversation. When SARS-CoV-2 infects a cell, it hijacks the host’s protein synthesis machinery to make copies of the new virus. However, these viral proteins also target host proteins, causing them to degrade. We soon learned that many host cellular proteins targeted by SARS-CoV-2 were in the mitochondria.
Viral proteins fragment mitochondria, depriving cells of energy and interfering with their oxygen-sensing capacity. The viral attack on mitochondria begins within hours of infection, triggering genes that break down mitochondria into fragments (called mitochondrial fission) and cause their membranes to leak (an early stage in apoptosis known as mitochondrial fission). called mitochondrial depolarization).
In our experiments, we did not need to use replicates virus Introducing only a single SARS-CoV-2 protein was sufficient to cause these adverse effects – to damage the mitochondria. This mitochondrial damage also occurred with other coronaviruses that we studied.
We are now developing drugs that may one day combat COVID-19 by blocking mitochondrial fission and apoptosis, or by preserving hypoxic pulmonary vasoconstriction. Our drug discovery efforts have already enabled us to identify a promising mitochondrial fission inhibitor, called Drpitor1a.
Our team’s infectious disease specialist Gerald Evans noted that the finding also has the potential to help us understand long covid, “The key features of that condition—fatigue and neurological dysfunction—may be due to the effects of mitochondrial damage caused by SARS-CoV-2 infection,” he tells WebMD.
the ongoing evolutionary battle
There is also an interesting evolutionary angle to this research. Given that mitochondria were once bacteria, back in the primary soup before being adopted by cells, our findings reveal an alien versus predatory landscape in which viruses are invading “bacteria.” Bacteria are regularly attacked by viruses, called bacteriophages, which require a host to replicate.
The bacteria in turn fight back using an ancient form of the immune system called the CRISPR-Cas system, which cuts off the virus’ genetic material. Humans have recently harnessed this CRISPR-cas system for a Nobel Prize-winning gene editing discovery.
The ongoing competition between bacteria and viruses is very old; And remember that our mitochondria were once bacteria. So perhaps it is not surprising at all that SARS-CoV-2 attacks our mitochondria as part of the COVID-19 syndrome.
Epidemic Pivot
The original team members on this project are heart and lung researchers specializing in mitochondrial biology. In early 2020 we were inspired to apply it to another field – virology – in an effort to make a small contribution to the COVID-19 puzzle.
Our discovery will be translated into new drugs to combat future pandemics (Source: Getty Images/Thinkstock)
The diverse team we put together also brings expertise in mitochondrial biology, cardiopulmonary physiology, SARS-CoV-2, transcriptomics, synthetic chemistry, molecular imaging and infectious diseases.
The credit for our discovery goes to our virology colleagues. Early in the pandemic, University of Toronto virologist Gary Levy offered us a mouse coronavirus (MHV-1) to work with, which we used to create a model of COVID-19 pneumonia. Che Colpits, a virologist at Queen’s University, helped us study mitochondrial injury caused by another human beta coronavirus, HCoV-OC43.
Finally, Arinjay Banerjee and his specialist SARS-CoV-2 virology team at the Vaccines and Infectious Diseases Organization (VIDO) in Saskatoon conducted a major study of human SARS-CoV-2 in airway epithelial cells. VIDO is one of the few Canadian centers equipped to deal with the highly contagious SARS-CoV-2 virus.
Our team’s super-resolution microscopy specialist, Jeff Mewburn, notes the specific challenges the team had to deal with.
“Having followed several more comprehensive COVID-19 protocols, they were still able to remodel our laboratory and demonstrate incredible flexibility, particularly on the study of coronavirus infection and its effects on cellular/mitochondrial functions, So very relevant to our global situation. ” They said.
Our discovery is expected to translate into new drugs to combat future pandemics.
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