Does SARS-CoV-2 kill its host cell or not?

Does SARS-CoV-2 kill its host cell or not?

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Wikipedia says that

Initial spike protein priming by transmembrane protease, serine 2 (TMPRSS2) is essential for entry of SARS-CoV-2.After a SARS-CoV-2 virion attaches to a target cell, the cell's protease TMPRSS2 cuts open the spike protein of the virus, exposing a fusion peptide in the S2 subunit, and the host receptor ACE2. After fusion, an endosome forms around the virion, separating it from the rest of the host cell. The virion escapes when the pH of the endosome drops or when cathepsin, a host cysteine protease, cleaves it. The virion then releases RNA into the cell and forces the cell to produce and disseminate copies of the virus, which infect more cells

What happens next? Can this cell stop to produce the virus and start to divide ?

For example this article (SARS-CoV-2 RNA reverse - transcribed and integrated into the human genome) suggests that virus also inserts its portion into DNA so the person can have PCR-positive tests even if "no replication - competent virus was isolated or spread from these PCR-positive patients".

The answer is yes, as there is no indication that SARS-COV-2 is an exception to the rule.

Cp., for instance: SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation, Shufen Li, Yulan Zhang, Zhenqiong Guan, Huiling Li, Meidi Ye, Xi Ch

On exceptions to the rule cp., for instance V. Kaminskyy, B. Zhivotovsky, To kill or be killed: how viruses interact with the cell death machinery

In my opinion, only in the context you cited your question seems a still open one:

"… Baltimore says. “It is also not clear if, in people, the cells that harbor the reverse transcripts stay around for a long time or they die.”

However, this statement does not contradict the general rule that cells infected by viruses finally die.

There is always, as cited, some "staying around" - otherwise the immunogenic mechanism of presenting antigen would not exist.

As for retro viruses, host cells might divide, thereby multiplying the integrated genome of the virus, so one might speak of "no dying" as in such case the cell is still able to divide. However, that should be seen as only "staying around" for a very much longer time, as every infected cell will sooner or later become the retro viruses' friendly host - if that cell hasn't died before because of other reasons:-) Still, if CoV-2 were a retro virus the answer to question had to be "no" - but it is not, CoV is no retro virus.

Refering to integration by LINE elements: this is different from retro viruses and it might be an open question, see the text passage cited, if the integration as a coincidental and irregular one (that should be current common belief) does interfere with viral replication of CoV-19. In the study cited it is suggested that the RNA of the virus that has been retrotranscribed and integrated into the host's DNA is being read and transcribed to viral RNA. Interestingly, at that point the study speaks of viral "chimeric RNA" being detected, not viral proteins that maybe have not been searched for. The study also speaks of antigen that has been transcribed and translated from retro-integrated RNA may still be presented (on MHC) to immune cells. The latter possibility might be ruled out if viral proteins or peptides have not been found - in that case it is much more probable that the expression of viral genes has stopped the host from producing virions which is in line with a known strategy of "restriction" (e.g. by small or large interfering RNA).

In other words: to me it is highly probable that the reading of integrated viral RNA is a mechanism of "restriction" in a wider sense in that by activating the transposon after integration the cell activities that would help the invading virus to replicate are being halted which different from o known defence mechanisms in bacteria/procaryotes leads to cell death probably by apoptosis, but maybe by necrosis.

This indeed seems coherent to "cytokine storm" as a reaction to SARS-Covid not of the adaptive but the innate immune systems that tries to clear up dead cells.

Another argument pro cell death is the fact that - maybe contrary to common belief - it does not seem a seldom and random event that viral RNS becomes integrated as the study's outcome apparently is a "first hit - success". To my mind, the - disputable - fact that there are no viruses that infect cells of the germ-line with the exception of certain retro(!)-viruses, cp.,, can be reconciled with and thus corroborates my opinion that integration of viral genes as transposons a. is no rare event and b. leads to cell death in eucaryotes because, otherwise, the integration of transposons the activation of which leads to apoptotic processes in stem cells might put the indivual if not the host species at risk.

In my opinion it is a possibility that the LINE insertion is part of a yet rather unknown "restriction process" of certain infected cells that interferes with viral replication. The study found viral RNA transcribed from DNA that had been successfully integrated into cell's genome. The RNA found in samples might be some "interfering RNA" of some mechanism of "restriction". If this is correct, it seems a possibility that cells stays alive with viral genes integrated and - refering to maybe the gist of your question - divide and multiply, in an attempt to replace other cells who were not successful with this restriction strategy. Moreover, those successful restrictive cells might (seems like a paradox) NOT present antigen to cytotoxic T-cells, and not get killed by those. However, I think this is highly unlikely. Much more coherent with findings of chimeric RNA is some induction of cell death by expression of integrated viral genes. It is known that active transposons can interact with genes they transpose to, leading to heritable disease (in eukaryotes). That should be - next to adaptive immune system defence - another way infected cells die altruistically, in order to stop the progression of viral invasion.

In any case, the answer is: yes, cells infected by SARS-CoV-2 die.

Still, it is a possibility that "successful restriction" (integrated RNA becomes interfering RNA) leads to destruction of the virus, as this seems to be a known defence outcome in the bacterial world. However, the findings - RNA detected outside cells - suggest that apoptosis or necrosis is the way to die for human cells infected by CoV-19.

Hint: In any case, the fact that killer cells of the immune system lead to apoptosis of infected cells does not imply that a cell would survive an infection (if it were not for the killing by killer cells).

Coronavirus Entering and Replicating in a Host Cell

We still don't know everything about the coronavirus (SARS-CoV-2) causing the current COVID-19 outbreak, but research is progressing rapidly. We know, for example, that SARS-CoV-2 shares a strong homology with its better-studied cousin SARS-CoV, responsible for an outbreak of SARS (Severe Acute Respiratory Syndrome) between 2002 and 2003. MERS-CoV, another member of this genus, has caused the Middle East respiratory syndrome (MERS) first reported in 2012.

Most coronaviruses are known to infect only non-human species.

Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer

Long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding was observed from the upper respiratory tract of a female immunocompromised individual with chronic lymphocytic leukemia and acquired hypogammaglobulinemia. Shedding of infectious SARS-CoV-2 was observed up to 70 days, and of genomic and subgenomic RNA up to 105 days, after initial diagnosis. The infection was not cleared after the first treatment with convalescent plasma, suggesting a limited effect on SARS-CoV-2 in the upper respiratory tract of this individual. Several weeks after a second convalescent plasma transfusion, SARS-CoV-2 RNA was no longer detected. We observed marked within-host genomic evolution of SARS-CoV-2 with continuous turnover of dominant viral variants. However, replication kinetics in Vero E6 cells and primary human alveolar epithelial tissues were not affected. Our data indicate that certain immunocompromised individuals may shed infectious virus longer than previously recognized. Detection of subgenomic RNA is recommended in persistently SARS-CoV-2-positive individuals as a proxy for shedding of infectious virus.

Keywords: COVID-19 SARS-CoV-2 asymptometic chronic lymphocytic leukemia convalescent plasma immunocompromised infectious virus long-term shedding within host evolution.

SARS-CoV-2 invades host cells via a novel route: CD147-spike protein

Currently, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been widely spread around the world nevertheless, so far there exist no specific antiviral drugs for treatment of the disease, which poses great challenge to control and contain the virus. Here, we reported a research finding that SARS-CoV-2 invaded host cells via a novel route of CD147-spike protein (SP). SP bound to CD147, a receptor on the host cells, thereby mediating the viral invasion. Our further research confirmed this finding. First, in vitro antiviral tests indicated Meplazumab, an anti-CD147 humanized antibody, significantly inhibited the viruses from invading host cells, with an EC50 of 24.86 μg/mL and IC50 of 15.16 μg/mL. Second, we validated the interaction between CD147 and SP, with an affinity constant of 1.85×10 −7 M. Co-Immunoprecipitation and ELISA also confirmed the binding of the two proteins. Finally, the localization of CD147 and SP was observed in SARS-CoV-2 infected Vero E6 cells by immuno-electron microscope. Therefore, the discovery of the new route CD147-SP for SARS-CoV-2 invading host cells provides a critical target for development of specific antiviral drugs.

Calculating the total number of cells infected with SARS-CoV-2

We use our estimate of the total number of infectious units in the body of an infected individual to estimate the number of cells that are infected by the virus during peak infection. In order to estimate the total number of infected cells, we estimate how many infectious units are found in each infected cell as shown in Figure 2 .

Estimate of the number of infected cells and their fraction out of the potential relevant host cells.

We rely on two lines of evidence in order to estimate the number of infectious units within an infected cell at a given time. The first is data regarding the total number of infectious units produced by an infected cell throughout its lifetime also known as the yield. As we are not aware of studies directly reporting values of the yield of cells infected with SARS-CoV-2, we used values reported for other betacoronaviruses in combination with values we derived from a study ( 20 ) of replication kinetics of SARS-CoV-2. Using a plaque formation assay to count the number of infectious units, two previous studies measured the viral yield as either 10� or 600� infectious units ( 21 , 22 ). Using reported values for replication kinetics of SARS-CoV-2 ( 20 ) we estimated a yield of

10 infectious units per cell at 36� hours from infection, in agreement with the lower end of these estimates. To convert the total number of infectious units produced overall by a cell into the number of units residing in the cell at a given moment, we estimate the ratio between these two quantities to be 3� using two independent methods detailed in the SI. Combining this ratio with our estimate for the total number of units produced by a cell, we thus estimate that, at any given moment, there are somewhere between a few to a few hundreds of infectious units residing in each infected cell.

The second line of evidence concerns the density of virions within a single cell. Several studies have used transmission electron microscopy (TEM) to characterize the intracellular replication of SARS-CoV-2 virions within cells ( 23 – 26 ). Using seven TEM scans taken from those studies we estimated that the density of virions within infected cells is 10 5 virions per 1 pL (see Dataset S1). As the human cells targeted by SARS-CoV-2 have a volume of 𢒁 pL (resulting in a cellular mass of 𢒁 ng) ( 27 , 28 ), TEM data indicate there are � 5 viral particles within a single infected cell at any point in time. As done above, we assume a ratio of 1 infectious unit resulting per 10 4 virions. Thus, TEM scans imply that there are � infectious units that will result from the virions residing inside a cell at any given moment after the initial stages of infection.

Following those lines of evidence we conclude that at a given moment there are

10 5 virions residing inside an infected cell which translates into

10 infectious units. Using the ratio of total production to the value at a given time inside the cell, we further conclude that the overall yield from an infected cell is

10� infectious units, coinciding with the middle range of measurements from other betacoronaviruses. This estimate also agrees well with recent results from dynamical models of SARS-CoV-2 host infection ( 29 , 30 ).

We can perform a sanity check using mass considerations to see that our estimate of the number of virions is not beyond the maximal feasible amount. Each virion has a mass of 𢒁 fg ( 5 ). Hence, 10 5 virions have a mass of 𢒀.1 ng, about 10% of the total mass of a 1 ng host cell and about a third of its dry weight. While a relatively high fraction, this is still within the range observed for other viral infections ( 31 , 32 ).

Combining the estimates for the overall number of infectious units in a person near peak infection and the number of infectious units in a single cell (Cinfectious units per cell), we can calculate the number of infected cells around peak infection:

How does this estimate compare to the number of potential host cells for the virus? The best-characterized route of infection for SARS-CoV-2 is through cells of the respiratory system, specifically the pneumocytes (

10 11 cells ), alveolar macrophages (

10 10 cells) and the mucus cells in the nasal cavity (

10 9 cells) ( 27 , 28 ). Other cell types, like enterocytes (gut epithelial cells) can also be infected ( 33 ) but they represent a similar number of cells ( 34 ) and therefore don’t change the order of magnitude of the potential host cells. As such, our best estimate for the size of the pool of cell types that SARS-CoV-2 likely infects is thus

10 11 cells, and the number of cells infected during peak infection therefore represents a small fraction of this potential pool (1 in 10 5 � 7 ).

Striking the heart

In Brescia, Italy, a 53-year-old woman walked into the emergency room of her local hospital with all the classic symptoms of a heart attack, including telltale signs in her electrocardiogram and high levels of a blood marker suggesting damaged cardiac muscles. Further tests showed cardiac swelling and scarring, and a left ventricle—normally the powerhouse chamber of the heart—so weak that it could only pump one-third its normal amount of blood. But when doctors injected dye in the coronary arteries, looking for the blockage that signifies a heart attack, they found none. Another test revealed why: The woman had COVID-19.

How the virus attacks the heart and blood vessels is a mystery, but dozens of preprints and papers attest that such damage is common. A 25 March paper in JAMA Cardiology documented heart damage in nearly 20% of patients out of 416 hospitalized for COVID-19 in Wuhan, China. In another Wuhan study, 44% of 36 patients admitted to the ICU had arrhythmias.

The disruption seems to extend to the blood itself. Among 184 COVID-19 patients in a Dutch ICU, 38% had blood that clotted abnormally, and almost one-third already had clots, according to a 10 April paper in Thrombosis Research. Blood clots can break apart and land in the lungs, blocking vital arteries—a condition known as pulmonary embolism, which has reportedly killed COVID-19 patients. Clots from arteries can also lodge in the brain, causing stroke. Many patients have “dramatically” high levels of D-dimer, a byproduct of blood clots, says Behnood Bikdeli, a cardiovascular medicine fellow at Columbia University Medical Center.

“The more we look, the more likely it becomes that blood clots are a major player in the disease severity and mortality from COVID-19,” Bikdeli says.

Infection may also lead to blood vessel constriction. Reports are emerging of ischemia in the fingers and toes—a reduction in blood flow that can lead to swollen, painful digits and tissue death.

The more we look, the more likely it becomes that blood clots are a major player in the disease severity and mortality from COVID-19.

Behnood Bikdeli, Columbia University Irving Medical Center

In the lungs, blood vessel constriction might help explain anecdotal reports of a perplexing phenomenon seen in pneumonia caused by COVID-19: Some patients have extremely low blood-oxygen levels and yet are not gasping for breath. It’s possible that at some stages of disease, the virus alters the delicate balance of hormones that help regulate blood pressure and constricts blood vessels going to the lungs. So oxygen uptake is impeded by constricted blood vessels, rather than by clogged alveoli. “One theory is that the virus affects the vascular biology and that’s why we see these really low oxygen levels,” Levitt says.

If COVID-19 targets blood vessels, that could also help explain why patients with pre-existing damage to those vessels, for example from diabetes and high blood pressure, face higher risk of serious disease. Recent Centers for Disease Control and Prevention (CDC) data on hospitalized patients in 14 U.S. states found that about one-third had chronic lung disease—but nearly as many had diabetes, and fully half had pre-existing high blood pressure.

Mangalmurti says she has been “shocked by the fact that we don’t have a huge number of asthmatics” or patients with other respiratory diseases in HUP’s ICU. “It’s very striking to us that risk factors seem to be vascular: diabetes, obesity, age, hypertension.”

Scientists are struggling to understand exactly what causes the cardiovascular damage. The virus may directly attack the lining of the heart and blood vessels, which, like the nose and alveoli, are rich in ACE2 receptors. Or perhaps lack of oxygen, due to the chaos in the lungs, damages blood vessels. Or a cytokine storm could ravage the heart as it does other organs.

“We’re still at the beginning,” Krumholz says. “We really don’t understand who is vulnerable, why some people are affected so severely, why it comes on so rapidly … and why it is so hard [for some] to recover.”

New antivirals kill SARS-CoV-2

A study has found that newly engineered antiviral compounds can neutralize SARS-CoV-2, the virus that causes COVID-19, in human airway cells. The compounds also improved survival rates in mice infected with MERS.

Share on Pinterest Research to find an effective COVID-19 treatment is ongoing.

Coronaviruses are a large group of viruses responsible for respiratory tract infections, ranging from the common cold to severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19.

Although coronaviruses are a familiar threat, currently no vaccines or antiviral drugs can prevent or treat the infections in people.

The ongoing COVID-19 pandemic emphasizes the need for effective treatments and drug development. Scientists are hard at work, trying to find an antiviral agent effective against SARS-CoV-2.

Much hope has been placed in remdesivir, an antiviral drug that was originally developed as a treatment for Ebola.

However, recent clinical practice guidelines developed by an international panel give only a “weak” recommendation for the drug in patients with severe COVID-19, and one recent study suggested that seaweed extract could be more effective.

Amid the continued search for a COVID-19 treatment, new research has homed in on a group of antiviral compounds that target an essential enzyme in coronaviruses.

The study’s authors report that the compounds drastically improved survival rates in a mouse model of MERS and neutralized SARS-CoV-2 in cells from people with COVID-19.

The research, led by scientists from Wichita State University, in Kansas, is based on the inhibition of a critical viral enzyme called 3C-like protease.

This enzyme is essential for the virus to replicate, and therefore survive, and given its crucial role, the enzyme is sometimes known simply as the “main protease.”

The researchers behind the present study specialize in making inhibitors of this enzyme and had previously developed an inhibitor, called GC376, that targets coronavirus infections in animals.

They showed that the compound could reverse the progression of severe feline infectious peritonitis, a coronavirus disease in cats that is fatal in every case. All the cats who received the drug for more than 2 weeks made a full recovery.

In light of the COVID-19 pandemic, the team redirected its focus to the novel coronavirus in humans, SARS-CoV-2.

They synthesized a number of antiviral compounds with activity against a range of coronaviruses. In the first line of tests, the compounds were screened for antiviral activity against MERS-CoV, SARS-CoV, and SARS-CoV-2.

They looked at the ability of the compounds to inhibit the 3C-like protease of these viruses, first in an isolated fashion, then inside cells. Since the protease has not been found in humans, it is a perfect target for an antiviral agent.

The researchers found that two of the 22 compounds that they started with were of interest.

In particular, compound 6e was the most potent against SARS-CoV-2. This means that less of the compound was needed to inhibit the viral protease, compared with the other compounds tested.

Compound 6j was active against SARS-CoV-2 but particularly effective against MERS-CoV, at very low concentrations.

The researchers went on to confirm their findings in cells from the airways of people who had developed SARS-CoV-2 infections. The team found that cells treated with the antiviral compounds had lower viral loads, indicating that the virus’s ability to replicate had been suppressed.

In cells from two of the patients, the compounds reduced viral replication by 10 times. In the third patient, one of the compounds, 6j, was able to inhibit viral replication by 100 times.

At the time, a relevant mouse model of SARS-CoV-2 infection was still under development. There was, however, a mouse model for infection with MERS-CoV.

As well as finding a treatment candidate for SARS-CoV-2, the researchers describe a possible treatment for MERS, which continues to cause outbreaks and has a fatality rate of about 35% .

The researchers found that the same compound that they used in human airway cells, 6j, was able to inhibit the so-called main protease of MERS-CoV.

They went on to test the compound in a mouse model of MERS, administering it to some of the mice 1 day after they had been infected. The researchers found that every mouse that had received the antiviral survived, while those who did not died.

The treated mice fared better internally, with lower viral loads and significantly less lung damage than the mice that did not receive treatment. While the untreated mice had inflammation and congestion in their lungs, and in some cases collapsed lungs, the treated mice experienced limited damage.

Although this preclinical research does not demonstrate efficacy in humans — and though there are very marked clinical differences between MERS-CoV and SARS-CoV-2 infections in humans — it has established an exciting proof-of-concept for the team.

They plan to continue their research to see whether one of their compounds could treat both MERS and COVID-19 in people.

New research on SARS-CoV-2 virus 'survivability'

How long does SARS-CoV-2 last on different surfaces? Credit: CSIRO

Researchers at CSIRO, Australia's national science agency, have found that SARS-CoV-2, the virus responsible for COVID-19, can survive for up to 28 days on common surfaces including banknotes, glass—such as that found on mobile phone screens—and stainless steel.

The research, undertaken at the Australian Centre for Disease Preparedness (ACDP) in Geelong, found that SARS-CoV-2:

  • survived longer at lower temperatures
  • tended to survive longer on non-porous or smooth surfaces such as glass, stainless steel and vinyl, compared to porous complex surfaces such as cotton
  • survived longer on paper banknotes than plastic banknotes.

Results from the study The effect of temperature on persistence of SARS-CoV-2 on common surfaces was published in Virology Journal.

CSIRO Chief Executive Dr. Larry Marshall said surface survivability research builds on the national science agency's other COVID-19 work, including vaccine testing, wastewater testing, Personal Protective Equipment (PPE) manufacture and accreditation, and big data dashboards supporting each state.

"Establishing how long the virus really remains viable on surfaces enables us to more accurately predict and mitigate its spread, and do a better job of protecting our people," Dr. Marshall said.

Droplets of SARS-CoV-2 virus in artificial mucous were applied to test surfaces at CSIRO's Australian Centre for Disease Preparedness (ACDP) at Geelong. Pictured is a droplet on an Australian five dollar note. Credit: CSIRO

"Together, we hope this suite of solutions from science will break down the barriers between us, and shift focus to dealing with specific virus hotspots so we can get the economy back on track.

"We can only defeat this virus as Team Australia with the best Australian science, working alongside industry, government, research and the Australian community."

Dr. Debbie Eagles is Deputy Director of ACDP, which has been working on both understanding the virus and testing a potential vaccine.

"Our results show that SARS-CoV-2 can remain infectious on surfaces for long periods of time, reinforcing the need for good practices such as regular handwashing and cleaning surfaces," Dr. Eagles said.

"At 20 degrees Celsius, which is about room temperature, we found that the virus was extremely robust, surviving for 28 days on smooth surfaces such as glass found on mobile phone screens and plastic banknotes.

"For context, similar experiments for Influenza A have found that it survived on surfaces for 17 days, which highlights just how resilient SARS-CoV-2 is."

The research involved drying virus in an artificial mucus on different surfaces, at concentrations similar to those reported in samples from infected patients and then re-isolating the virus over a month.

Further experiments were carried out at 30 and 40 degrees Celsius, with survival times decreasing as the temperature increased.

The study was also carried out in the dark, to remove the effect of UV light as research has demonstrated direct sunlight can rapidly inactivate the virus.

"While the precise role of surface transmission, the degree of surface contact and the amount of virus required for infection is yet to be determined, establishing how long this virus remains viable on surfaces is critical for developing risk mitigation strategies in high contact areas," Dr. Eagles said.

Director of ACDP Professor Trevor Drew said many viruses remained viable on surfaces outside their host.

"How long they can survive and remain infectious depends on the type of virus, quantity, the surface, environmental conditions and how it's deposited—for example touch vs droplets emitted by coughing," Professor Drew said.

"Proteins and fats in body fluids can also significantly increase virus survival times.

"The research may also help to explain the apparent persistence and spread of SARS-CoV-2 in cool environments with high lipid or protein contamination, such as meat processing facilities and how we might better address that risk."

Viruses & Vaccination: Decrease in Vaccination against Measles as a Threat for the Individual & for Public Health

“Measles is a highly contagious, serious disease . . . . Before the introduction of measles vaccine in 1963 and widespread vaccination, . . . measles caused an estimated 2.6 million deaths each year.”

“Measles . . . is normally passed through direct contact and through the air. The virus infects the respiratory tract, then spreads throughout the body.”

“During 2000–2017, measles vaccination prevented an estimated 21.1 million deaths. Global measles deaths have decreased by 80% from an estimated 545 000 in 2000 to 110 000 in 2017.”

In our study, only two-thirds of university students and less than half of the schoolchildren were able to name viral diseases for which vaccination exists. Furthermore, even among freshman biology students, only 29% agreed with the statement that vaccination against some viral diseases is possible. This level dropped to 12% for non-biology students. Finally, only 21 participants named measles (Simon et al., 2017). Apparently, the awareness among students that vaccination is essential to decrease the chance of contracting and spreading viral diseases like measles is very low. Clearly, this must be addressed at school much more prominently, which is particularly important for countries without close surveillance of a child’s vaccination status. Furthermore, there seems to exist a gap in understanding the role of vaccination on the personal and the societal levels (Rafolt et al., 2019). It will be interesting to see how the current COVID-19 pandemic influences the vaccination debate. In Germany and Austria, there are already people publicly demonstrating against a possibly mandatory COVID-19 vaccination, once this should be available.

Unfortunately, there is no vaccination available yet for many other viral diseases. Thus, it is even more important to discuss and playfully demonstrate at school easy and yet highly effective prevention measures such as sneezing in one’s armpit or tissue, hand washing, and social distancing, including mask wearing if required.

Scientists uncover new details of SARS-CoV-2 interactions with human cells

In order to infect cells, SARS-CoV-2, the virus that causes COVID-19, needs to insert itself into the membrane of human cells new molecular models show what parts of SARS-CoV-2 are critical for that interaction, revealing new potential drug targets

IMAGE: The SARS-CoV-2 virus inserts itself into the membrane of a host human cell using a small part of its spike protein (yellow), called a fusion peptide. Computer simulations revealed the. view more

Credit: Image courtesy of Defne Gorgun.

ROCKVILLE, MD - If the coronavirus were a cargo ship, it would need to deliver its contents to a dock in order to infect the host island. The first step of infection would be anchoring by the dock, and step two would be tethering to the dock to bring the ship close enough that it could set up a gangplank and unload. Most treatments and vaccines have focused on blocking the ability of the ship to anchor, but the next step is another potential target. New research by Defne Gorgun, a graduate student, and colleagues in the lab of Emad Tajkhorshid at the University of Illinois addresses the molecular details of this second step, which could inform the design of drugs that block it. Gorgun will present her research on Thursday, February 25 at the 65th Annual Meeting of the Biophysical Society to be held virtually.

In order to infect our cells, the virus that causes COVID-19, SARS-CoV-2, first attaches a molecule on our cell surface, but then it has to fuse with human cells. Before the pandemic, Gorgun was studying the interactions of molecules that stick to and insert into cell membranes, and when COVID-19 began to spread, Gorgun quickly pivoted her studies to understand how SARS-CoV-2 fused with cells.

A small region of the SARS-CoV-2 outer spike protein called the "fusion peptide," inserts itself into the human cell membrane to begin the fusion process. Scientists knew the location and approximate shape of the fusion peptide however, they did not know exactly how it interacted with and penetrated into the human cell membrane and whether there would be changes in its shape when it stuck to the membrane. Without knowing the three-dimensional interactions between the SARS-CoV-2 fusion peptide and the cell membrane, it is not possible to design drugs that specifically disrupt that interaction.

Using computer simulations, the team merged what is known about the SARS-CoV-2 fusion peptide with the established three-dimensional structures and behaviors of other coronavirus fusion peptides and simulated its interaction with a model human cell membrane. Their simulations reveal how the SARS-CoV-2 fusion peptide interacts with, and penetrates, the cell membrane. "Our study shows which parts of the fusion peptide are important and how it sticks to and sits in the membrane," Gorgun says.

Because their model is theoretical, the next step is to repeat their computer experiments in the lab with pieces of SARS-CoV-2 and cell membranes. But having already revealed parts of the fusion peptide that are likely to be critical to its function, those experiments will likely be completed faster and more efficiently. After that, Gorgun says, it will be possible to start testing drugs that disrupt the interaction and could help block SARS-CoV-2 from docking at our cells.

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