Tag: SARS-CoV-1

Categories : COVIDTags :

How COVID Damages Lungs: The virus attacks mitochondria, continuing an ancient battle that began in the primordial soup

On By ModernMedia
Red mitochondria in airway cells become coated with green SARS-COV-2 proteins after viral infection: Researchers discovered that the virus that causes COVID-19 damages lungs by attacking mitochondria. Credit: Stephen Archer

By Stephen L Archer, The Conversation

Viruses and bacteria have a very long history. Because viruses can’t reproduce without a host, they’ve been attacking bacteria for millions of years. Some of those bacteria eventually became mitochondria, synergistically adapting to life within eukaryotic cells (cells that have a nucleus containing chromosomes).

Ultimately, mitochondria became the powerhouses within all human cells.

Fast-forward to the rise of novel coronaviruses like SARS-CoV-2, and the global spread of COVID-19. Approximately five per cent of people infected with SARS-CoV-2 suffer respiratory failure (low blood oxygen) requiring hospitalisation. In Canada about 1.1 per cent of infected patients (almost 46,000 people) have died.

This is the story of how a team, assembled during the pandemic, recognized the mechanism by which these viruses were causing lung injury and lowering oxygen levels in patients: It is a throwback to the primitive war between viruses and bacteria – more specifically, between this novel virus and the evolutionary offspring of bacteria, our mitochondria.

SARS-CoV-2 is the third novel coronavirus to cause human outbreaks in the 21st century, following 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 COVID-19 affects lungs

People with severe COVID-19 pneumonia often arrive at the hospital with unusually low oxygen levels. They have two unusual features distinct from patients with other types of pneumonia:

  • First, they suffer widespread injury to their lower airway (the alveoli, which is where oxygen is taken up).
  • Second, they shunt blood to unventilated areas of the lung, which is called ventilation-perfusion mismatch. This means blood is going to parts of the lung where it won’t get sufficiently oxygenated.

Together, these abnormalities lower blood oxygen. However, the cause of these abnormalities was unknown. In 2020, our team of 20 researchers at three Canadian universities set about to unravel this mystery. We proposed that SARS-CoV-2 worsened COVID-19 pneumonia by targeting mitochondria in airway epithelial cells (the cells that line the airways) and pulmonary artery smooth muscle cells.

We already knew that mitochondria are not just the powerhouse of the cell, but also its main consumers and sensors of oxygen. Mitochondria control the process of programmed cell death (called apoptosis), and they regulate the distribution of blood flow in the lung by a mechanism called hypoxic pulmonary vasoconstriction.

This mechanism has an important function. It directs blood away from areas of pneumonia to better ventilated lobes of the lung, which optimizes oxygen-uptake. By damaging the mitochondria in the smooth muscle cells of the pulmonary artery, the virus allows blood flow to continue into areas of pneumonia, which also lowers oxygen levels.

It appeared plausible that SARS-CoV-2 was damaging mitochondria. The results of this damage – an increase in apoptosis in airway epithelial cells, and loss of hypoxic pulmonary vasoconstriction – were making lung injury and hypoxaemia (low blood oxygen) worse.

Our discovery, published in Redox Biology, explains how SARS-CoV-2, the coronavirus that causes COVID-19 pneumonia, reduces blood oxygen levels.

We show that SARS-CoV-2 kills airway epithelial cells by damaging their mitochondria. This results in fluid accumulation in the lower airways, interfering with oxygen uptake. We also show that SARS-CoV-2 damages mitochondria in the pulmonary artery smooth muscle cells, which inhibits hypoxic pulmonary vasoconstriction and lowers oxygen levels.

Attacking mitochondria

Coronaviruses damage mitochondria in two ways: by regulating mitochondria-related gene expression, and by direct protein-protein interactions. When SARS-CoV-2 infects a cell, it hijacks the host’s protein synthesis machinery to make new virus copies. However, these viral proteins also target host proteins, causing them to malfunction. We soon learned that many of the host cellular proteins targeted by SARS-CoV-2 were in the mitochondria.

How SARS-CoV-2 targets mitochondria to kill lung cells and prevent oxygen sensing. Credit: Brooke Ring, provided by Stephen Archer

Viral proteins fragment the mitochondria, depriving cells of energy and interfering with their oxygen-sensing capability. The viral attack on mitochondria starts within hours of infection, turning on genes that break the mitochondria into pieces (called mitochondrial fission) and make their membranes leaky (an early step in apoptosis called mitochondrial depolarization).

In our experiments, we didn’t need to use a replicating virus to damage the mitochondria – simply introducing single SARS-CoV-2 proteins was enough to cause these adverse effects. This mitochondrial damage also occurred with other coronaviruses that we studied.

We are now developing drugs that may one day counteract 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 diseases expert, Gerald Evans, notes that this discovery also has the potential to help us understand Long COVID. “The predominant features of that condition – fatigue and neurologic dysfunction – could be due to the lingering effects of mitochondrial damage caused by SARS-CoV-2 infection,” he explains.

The ongoing evolutionary battle

This research also has an interesting evolutionary angle. Considering that mitochondria were once bacteria, before being adopted by cells back in the primordial soup, our findings reveal an Alien versus Predator scenario in which viruses are attacking “bacteria.”

Bacteria are regularly attacked by viruses, called bacteriophages, that need a host to replicate in. The bacteria in turn fight back, using an ancient form of immune system called the CRISPR-cas system, that chops up the viruses’ genetic material. Humans have recently exploited this CRISPR-cas system for a Nobel Prize-winning gene editing discovery.

The ongoing competition between bacteria and viruses is a very old one; and recall that our mitochondria were once bacteria. So perhaps it’s not surprising at all that SARS-CoV-2 attacks our mitochondria as part of the COVID-19 syndrome.

Pandemic pivot

The original team members on this project are heart and lung researchers with expertise in mitochondrial biology. In early 2020 we pivoted to apply that in another field – virology – in an effort to make a small contribution to the COVID-19 puzzle.

The diverse team we put together also brought expertise in mitochondrial biology, cardiopulmonary physiology, SARS-CoV-2, transcriptomics, synthetic chemistry, molecular imaging and infectious diseases.

Our discovery owes a lot to our virology collaborators. Early in the pandemic, University of Toronto virologist Gary Levy offered us a mouse coronavirus (MHV-1) to work with, which we used to make a model of COVID-19 pneumonia. Che Colpitts, a virologist at Queen’s University, helped us study the mitochondrial injury caused by another human beta coronavirus, HCoV-OC43.

Finally, Arinjay Banerjee and his expert SARS-CoV-2 virology team at Vaccine and Infectious Disease Organization (VIDO) in Saskatoon performed key studies of human SARS-CoV-2 in airway epithelial cells. VIDO is one of the few Canadian centres equipped to handle the highly infectious SARS-CoV-2 virus.

Our team’s super-resolution microscopy expert, Jeff Mewburn, notes the specific challenges the team had to contend with.

“Having to follow numerous and extensive COVID-19 protocols, they were still able to exhibit incredible flexibility to retool and refocus our laboratory specifically on the study of coronavirus infection and its effects on cellular/mitochondrial functions, so very relevant to our global situation,” he said.

Our discovery will hopefully be translated into new medicines to counter future pandemics.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Categories : COVIDTags :

Key Differences of SARS-CoV-2 Spike Protein over SARS Ancestor

On By ModernMedia
Source: Fusion Medical Animation on Unsplash

New computational simulations of the behaviour of the SARS-CoV-1 and SARS-CoV-2 spike proteins before they fuse with human cell receptors show that SARS-CoV-2, is in fact more stable and slower changing than SARS-CoV-1 that caused the SARS epidemic in 2003.

Though severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) have striking similarities, why the latter is more transmissible remains unclear.

The spike proteins of each, which bind to host cell angiotensin converting enzyme 2 (ACE-2), otherwise known as the human cell receptor, have been proposed as the reason for their difference in transmissibility. A more detailed understanding of the spike proteins prior to binding could lead to the development of better vaccines and medications.

The new finding, which appears in the Journal of Biological Chemistry, does not necessarily mean that SARS-CoV-2 is more likely to bind to cell receptors, but it does mean that its spike protein has a better chance of effective binding.

“Once it finds the cell receptor and binds to it, the SARS-CoV-2 spike is more likely to stay bound until the rest of the necessary steps are completed for full attachment to the cell and initiation of cell entry,” explained Associate Professor Mahmoud Moradi, of the Fulbright College of Arts and Sciences.

To determine differences in conformational behaviour between the two versions of the virus, the researchers performed equilibrium and nonequilibrium simulations of the molecular dynamics of SARS-CoV-1 and SARS-CoV-2 spike proteins, leading up to binding with cell angiotensin converting enzyme 2.

Equilibrium simulations allow the models to evolve spontaneously on their own time, while nonequilibrium simulations change according to external input. The former is less biased, but the latter is faster and allows for many more simulations to run. Both methodological approaches provided a consistent picture, independently demonstrating the same conclusion that the SARS-CoV-2 spike proteins were more stable.

The models revealed other important findings, namely that the energy barrier associated with activation of SARS-CoV-2 was higher, meaning the binding process happened slowly. Slow activation allows the spike protein to evade human immune response more efficiently, because remaining in an inactive state longer means the virus cannot be attacked by antibodies that target the receptor binding domain.

Researchers understand the importance of the receptor-binding domain (RBD), which viruses use to gain entry to human cells. The team’s modelling confirms the importance of the RBD but also suggest that other domains, such as the N-terminal domain, could play a crucial role in the different binding behaviour of SARS-CoV-1 and -2 spike proteins.

N-terminal domain of a protein is a domain located at the N-terminus or simply the start of the polypeptide chain, as opposed to the C-terminus, which is the end of the chain. Though it is near the receptor-binding domain and is known to be targeted by some antibodies, the function of the N-terminal domain in SARS-CoV-1 and -2 spike proteins is not fully understood. Moradi’s team is the first to find evidence for potential interaction of the N-terminal domain and the receptor binding domain.

“Our study sheds light on the conformational dynamics of the SARS-CoV-1 and SARS-CoV-2 spike proteins,” Moradi said. “Differences in the dynamic behaviour of these spike proteins almost certainly contribute to differences in transmissibility and infectivity.”

Source: University of Arkansas

Categories : COVID Immune SystemTags :

Almost ‘Superhuman’ Immune Response Found in Certain People

On By ModernMedia
Photo by Klaus Nielsen from Pexels

A series of studies in recent months has found that, thanks to the mRNA vaccine and previous infection, some people mount an extraordinarily powerful immune response against SARS-CoV-2 which some scientists have referred to as ‘superhuman’.

Called ‘hybrid immunity’, their bodies produce very high levels of antibodies, with great flexibility: likely capable of fighting off the SARS-CoV-2 variants currently circulating but also likely effective against future variants.

“Overall, hybrid immunity to SARS-CoV-2 appears to be impressively potent,” Crotty wrote in commentary in Science published in June.

“One could reasonably predict that these people will be quite well protected against most  and perhaps all of — the SARS-CoV-2 variants that we are likely to see in the foreseeable future,” says Paul Bieniasz, a virologist at Rockefeller University who helped lead several of the studies.

Bieniasz and his colleagues found antibodies in these individuals capable of strongly neutralising the six variants of concern tested, including Delta and Beta, as well as several other viruses related to SARS-CoV-2, including SARS-CoV-1.

“This is being a bit more speculative, but I would also suspect that they would have some degree of protection against the SARS-like viruses that have yet to infect humans,” Bieniasz said.

People who have had a ‘hybrid’ exposure to the virus, were infected with it in 2020 and then immunised with mRNA vaccines this year. “Those people have amazing responses to the vaccine,” said virologist Theodora Hatziioannou at Rockefeller University, who also helped lead several of the studies. “I think they are in the best position to fight the virus. The antibodies in these people’s blood can even neutralize SARS-CoV-1, the first coronavirus, which emerged 20 years ago. That virus is very, very different from SARS-CoV-2.”

These antibodies were so effective they were even able to deactivate a virus purposefully engineered to be highly resistant to neutralisation, containing 20 mutations that are known to prevent SARS-CoV-2 antibodies from binding to it. Antibodies from those who were only vaccinated or who only had prior coronavirus infections were ineffecgtive against this engineered virus..

This shows how powerful the mRNA vaccine can be in those infected with SARS-CoV-2, she said. “There’s a lot of research now focused on finding a pan-coronavirus vaccine that would protect against all future variants. Our findings tell you that we already have it.

The catch is getting COVID. “After natural infections, the antibodies seem to evolve and become not only more potent but also broader. They become more resistant to mutations within the [virus].”

Hatziioannou and colleagues don’t know if this applies to all those mRNA-vaccinated and previously COVID-infected. “We’ve only studied the phenomena with a few patients because it’s extremely laborious and difficult research to do,” she said.
“With every single one of the patients we studied, we saw the same thing.” The study reports data on 14 patients.

Several other studies lend credence to her hypothesis and reinforce the idea that exposure to both a coronavirus and an mRNA vaccine triggers an exceptionally powerful immune response. In one study in NEJM, scientists analysed antibodies generated by people who had been infected with SARS-CoV-1 back in 2002 or 2003 and who then received an mRNA vaccine this year.

Remarkably, these people also produced high levels of antibodies that could neutralise a whole range of variants and SARS-like viruses. Many questions remain, such as the effect of a third booster shot, or being infected again.

“I’m pretty certain that a third shot will help a person’s antibodies evolve even further, and perhaps they will acquire some breadth [or flexibility], but whether they will ever manage to get the breadth that you see following natural infection, that’s unclear.”

Immunologist John Wherry, at the University of Pennsylvania, is a bit more hopeful. “In our research, we already see some of this antibody evolution happening in people who are just vaccinated,” he said, “although it probably happens faster in people who have been infected.”

In a recent study, Wherry and colleagues showed that, over time, uninfected people with only two doses of the vaccine begin to produce more flexible antibodies, so a third dose would give even more of an evolutionary boost to the antibodies, Wherry said. So a person will be better equipped to fight off whatever variant the virus puts out there next.

“Based on all these findings, it looks like the immune system is eventually going to have the edge over this virus,” said Bieniasz, of Rockefeller University. “And if we’re lucky, SARS-CoV-2 will eventually fall into that category of viruses that gives us only a mild cold.”

Source: NPR