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A better understanding of how SARS-CoV-2 behaves in human cells is key to developing treatments.
The global COVID-19 pandemic continues to race across the planet with thousands of new infections confirmed every day. However, another race is currently underway worldwide – the race to develop an effective treatment. One of the key steps in developing a treatment is gaining a thorough understanding of the disease process itself. A new study published in the journal Cell examines host-virus interactions that take place through a process called phosphorylation (1). Phosphorylation alters the structure and function of particular intracellular proteins by adding one or more phosphorous-containing molecules (a phosphoryl group). It is hoped that a better understanding of this phosphorylation process in COVID-19 will reveal potential targets for drug therapies.
The approach the research team adopted was to use proteomics. This process measures changes both in the quantities of varies proteins and also in their level of phosphorylation. They carried out a lab-based experiment using a cell type that is particularly susceptible to SARS-CoV-2 infection. Using proteomics, they measured the impact that infection had on cellular proteins.
For most host-cell proteins, infection appeared to change phosphorylation levels rather than altering their abundance. Most of the proteins that showed an increase in abundance during the infection were viral proteins, reflecting the fact that the virus hijacks cellular machinery to replicate itself. Some of the host proteins that were found to be downregulated or switched off by phosphorylation are usually involved in preventing blood coagulation. This presents a possible mechanism for the blood clotting complications experienced by some coronavirus sufferers.
The study also examined changes that happen to the viral proteins within a host cell. Proteomics revealed 49 phosphorylation sites spread across seven viral proteins. However, it remains unclear exactly what roles these individual sites play. There is some evidence to suggest phosphorylation at some of these sites may influence the binding of the coronavirus “spike protein” to receptors on human cells, the key step in the initial infection process.
In healthy human cells, phosphorylation plays a role in cellular signalling. Certain “native” signalling pathways involved in mRNA processing and apoptosis (programmed cell death) were boosted by the presence of viral proteins, while signalling pathways involved in the response to infection are downregulated. This reflects the intentions of the virus within a host cell – to replicate its RNA and avoid an immune response from the host.
The level of viral protein showed an increase approximately eight hours after infection began, giving an indication of the timeframe from viral entry to replication. The widespread changes in host cell protein phosphorylation highlights how the virus operates within its host. In particular the changes to as many as 97 host kinases highlight the particular signalling pathways the virus exploits.
The identification of pathways and proteins involved in the COVID-19 disease process allowed the research team to test existing drugs known to target these specific areas. They tested a total of 68 drugs that are either already approved for use in humans or in late-stage clinical trials. Many of them showed antiviral activity. However, this is in a lab setting only. It remains to be seen whether this activity will be replicated in humans.
Overall this study provides valuable knowledge of how the coronavirus works within human cells. It identifies many of the pathways and proteins that the virus exploits and as a result, generates several targets for drug therapies to interrupt the viral replication. However, more research is needed before we can confidently identify effective treatments.
Written by Michael McCarthy
1. Bouhaddou M, Memon D, Meyer B, White KM, Rezelj VV, Marrero MC, et al. The Global Phosphorylation Landscape of SARS-CoV-2 Infection. Cell. 2020.
Image by Pete Linforth from Pixabay
Trump Announces Partnership With CVS, Walgreens For Nursing Home COVID Vaccination
The Trump administration announced a new partnership with two major national pharmacy chains to facilitate the distribution of a future coronavirus vaccine to nursing homes on Friday.
“Today, I’m thrilled to announce that we have just finalized a partnership with CVS and Walgreens,” President Trump told a group in Fort Myers, Fla., at an event centered on seniors. He said the plan was for the pharmacies to “deliver the vaccine directly to nursing homes at no cost to our seniors.”
The Pharmacy Partnership for Long Term Care Program is part of the Trump administration’s Operation Warp Speed effort. No coronavirus vaccines have yet been authorized by the government, though several vaccine candidates are in the final stages of clinical trials.
“Early in the COVID-19 vaccination program, there may be a limited supply of vaccine and our planning efforts need to focus on those at highest risk for developing severe illness from COVID-19,” Dr. Jay Butler, deputy director for infectious diseases at the Centers for Disease Control and Prevention told reporters on a press call.
That includes people older than 65, who are much more likely to get severely ill and die from the coronavirus than other age groups. The details of which would be the first groups to get a vaccine once one is authorized is still in flux, but seniors would likely be among the first to be eligible.
The pharmacy program “provides end-to-end management of the COVID-19 vaccination process,” Butler explained. That includes scheduling on site clinic dates with each facility, ordering supplies like syringes, and ensuring cold-chain management of the vaccine. Once the vaccine is on site, pharmacy staff will administer it to residents and staff and report it to the required public health department.
The program will be free for facilities, but optional. “This is voluntary. They have to opt-in,” Paul Mango, deputy chief of staff for policy at the Department of Health and Human Services told reporters. “This will be something that will be available to every nursing home and senior living facility in the country.”
“This is really significant,” Claire Hannan, Executive Director of the Association of Immunization Managers wrote to NPR. “We’ve never really had coordinated partnership between pharmacies and public health across all states.”
Friday was the deadline for states to deliver a vaccine distribution plan to CDC, which will be evaluating the plans and providing feedback over the next two weeks, according to federal health officials.
One of the leading vaccine candidates, made by Pfizer, requires ultra-cold storage, which “could pose a major challenge to getting nursing home and long term care residents vaccinated,” explains Hannan, “so the value of this partnership can’t be understated.”
That aspect of the program stood out to Stacie Dusetzina, professor of health policy at Vanderbilt as well.
“Cold storage and the cold chain management has been a huge sticking point — how do you get [vaccine] to everyone who needs it and maintain these super cold temperatures?” she says. If CVS and Walgreens are going to be managing that challenge, she says, “that seems like a really big, positive thing.”
A federal government partnership early in the pandemic with retail pharmacies to provide COVID-19 testing ended up yielding much less testing than promised.
$3.1 Trillion: Pandemic Spending Drives The Federal Budget Deficit To A Record
Updated at 3:16 p.m. ET
The U.S. budget deficit soared to a record $3.1 trillion, following a massive surge in government spending aimed at containing the economic damage from the coronavirus pandemic.
The deficit for the fiscal year that ended Sept. 30 was more than triple that of fiscal 2019 and easily eclipsed the previous record of $1.4 trillion recorded in 2009.
The Treasury Department said the surge was partly due to a drop in corporate and personal tax revenue, which fell by 1%.
But the overwhelming factor driving the deficit higher was a huge increase in federal spending to prop up businesses and keep people employed after the economy nearly ground to a halt in March.
“The increase in the deficit from FY 2019 reflects the effect of COVID-19 on the economy and legislation that created or enhanced programs to protect public health and support hard-hit industries, small businesses, and American individuals and families,” the Treasury statement said.
The higher deficit comes just as Congress and the White House are negotiating a new coronavirus relief package.
While lawmakers and the administration agree on the need for a bill, they remain far apart on the size. While Democrats have pushed for more than $2 trillion in aid, Senate Majority Leader Mitch McConnell has called that “outlandish.”
The federal debt — the total owed by the government — has grown to more than $21 trillion, larger than the size of the U.S. economy.
“This astronomical level of debt is only going to get bigger,” says Maya MacGuineas, president of the Committee for a Responsible Federal Budget.
“Borrowing to combat the pandemic and economic crisis makes sense. But that’s no excuse for the massive tax cuts and spending increases enacted before the pandemic, nor the failure to control the rising costs of our health and retirement programs once normalcy returns,” she added.
Israel To Relax Its 2nd Nationwide Coronavirus Lockdown On Sunday
Israel, which imposed the world’s strictest second nationwide lockdown, will be loosening some restrictions this weekend.
After a four-week lockdown, including a ban on movement beyond one-third of a mile from home, the country has dramatically brought down its number of infections.
On Sept. 30, Israel’s health ministry reported there were 9,013 new cases, among the world’s highest per capita daily infection rates. On Thursday, there were 1,608 new cases.
Israel’s cabinet voted Friday to partially relax the country’s lockdown beginning Sunday. Earlier this week, the country lifted a ban on travel abroad and a ban on Israelis protesting in groups larger than 20. Critics accused Prime Minister Benjamin Netanyahu of seeking to quash months of protests outside his residence. Demonstrators were calling for his resignation due to a corruption indictment.
The ban limiting public protests achieved the opposite result, spurring thousands to protest against Netanyahu and the protest ban, as demonstrations spread across the country.
Jerusalem’s three main holy sites — the Al-Aqsa Mosque compound, the Western Wall and the Church of the Holy Sepulcher — will reopen to the general public with distancing measures, the prime minster’s office said in a statement.
People will be allowed to move without restriction and visit each other’s homes, capping gatherings at 10 people indoors and 20 outdoors. Israel will also reopen beaches and national parks.
Shops can operate without in-store customers. Restaurants will not be able to offer dining inside, but can sell takeout meals. Public transportation will operate at 50% capacity.
Most schools will remain closed, but preschools and kindergartens will reopen for children up to age 6. A group of Hebrew University scientists concluded that children up to age 10 are less likely to spread the virus.
But Israel’s teachers union opposes the reopening, saying authorities have not offered assurances it will be done safely or provided support for preschool and kindergarten teachers who are at home with their own elementary school-age children.
“We believe it is a mistake and that lessons were not learned from the hasty exit of the first lockdown,” when infections spiked among schoolchildren, the union said in a statement.
In a public Facebook post, Israel’s ultra-Orthodox interior minister Aryeh Deri protested Friday against restrictions on large weddings, an important element of ultra-Orthodox Jewish life.
Several cities with mostly ultra-Orthodox populations will remain under restrictions as they continue to suffer high infection rates. Some Orthodox communities flouted the lockdown and held large Jewish holiday gatherings, driving up Israel’s virus rate.
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