Posted on by Dr. Francis Collins
More than 3 million people around the world, now tragically including thousands every day in India, have lost their lives to severe COVID-19. Though incredible progress has been made in a little more than a year to develop effective vaccines, diagnostic tests, and treatments, there’s still much we don’t know about what precisely happens in the lungs and other parts of the body that leads to lethal outcomes.
Two recent studies in the journal Nature provide some of the most-detailed analyses yet about the effects on the human body of SARS-CoV-2, the coronavirus that causes COVID-19 [1,2]. The research shows that in people with advanced infections, SARS-CoV-2 often unleashes a devastating series of host events in the lungs prior to death. These events include runaway inflammation and rampant tissue destruction that the lungs cannot repair.
Both studies were supported by NIH. One comes from a team led by Benjamin Izar, Columbia University, New York. The other involves a group led by Aviv Regev, now at Genentech, and formerly at Broad Institute of MIT and Harvard, Cambridge, MA.
Each team analyzed samples of essential tissues gathered from COVID-19 patients shortly after their deaths. Izar’s team set up a rapid autopsy program to collect and freeze samples within hours of death. He and his team performed single-cell RNA sequencing on about 116,000 cells from the lung tissue of 19 men and women. Similarly, Regev’s team developed an autopsy biobank that included 420 total samples from 11 organ systems, which were used to generate multiple single-cell atlases of tissues from the lung, kidney, liver, and heart.
Izar’s team found that the lungs of people who died of COVID-19 were filled with immune cells called macrophages. While macrophages normally help to fight an infectious virus, they seemed in this case to produce a vicious cycle of severe inflammation that further damaged lung tissue. The researchers also discovered that the macrophages produced high levels of IL-1β, a type of small inflammatory protein called a cytokine. This suggests that drugs to reduce effects of IL-1β might have promise to control lung inflammation in the sickest patients.
As a person clears and recovers from a typical respiratory infection, such as the flu, the lung repairs the damage. But in severe COVID-19, both studies suggest this isn’t always possible. Not only does SARS-CoV-2 destroy cells within air sacs, called alveoli, that are essential for the exchange of oxygen and carbon dioxide, but the unchecked inflammation apparently also impairs remaining cells from repairing the damage. In fact, the lungs’ regenerative cells are suspended in a kind of reparative limbo, unable to complete the last steps needed to replace healthy alveolar tissue.
In both studies, the lung tissue also contained an unusually large number of fibroblast cells. Izar’s team went a step further to show increased numbers of a specific type of pathological fibroblast, which likely drives the rapid lung scarring (pulmonary fibrosis) seen in severe COVID-19. The findings point to specific fibroblast proteins that may serve as drug targets to block deleterious effects.
Regev’s team also describes how the virus affects other parts of the body. One surprising discovery was there was scant evidence of direct SARS-CoV-2 infection in the liver, kidney, or heart tissue of the deceased. Yet, a closer look heart tissue revealed widespread damage, documenting that many different coronary cell types had altered their genetic programs. It’s still to be determined if that’s because the virus had already been cleared from the heart prior to death. Alternatively, the heart damage might not be caused directly by SARS-CoV-2, and may arise from secondary immune and/or metabolic disruptions.
Together, these two studies provide clearer pictures of the pathology in the most severe and lethal cases of COVID-19. The data from these cell atlases has been made freely available for other researchers around the world to explore and analyze. The hope is that these vast data sets, together with future analyses and studies of people who’ve tragically lost their lives to this pandemic, will improve our understanding of long-term complications in patients who’ve survived. They also will now serve as an important foundational resource for the development of promising therapies, with the goal of preventing future complications and deaths due to COVID-19.
 A molecular single-cell lung atlas of lethal COVID-19. Melms JC, Biermann J, Huang H, Wang Y, Nair A, Tagore S, Katsyv I, Rendeiro AF, Amin AD, Schapiro D, Frangieh CJ, Luoma AM, Filliol A, Fang Y, Ravichandran H, Clausi MG, Alba GA, Rogava M, Chen SW, Ho P, Montoro DT, Kornberg AE, Han AS, Bakhoum MF, Anandasabapathy N, Suárez-Fariñas M, Bakhoum SF, Bram Y, Borczuk A, Guo XV, Lefkowitch JH, Marboe C, Lagana SM, Del Portillo A, Zorn E, Markowitz GS, Schwabe RF, Schwartz RE, Elemento O, Saqi A, Hibshoosh H, Que J, Izar B. Nature. 2021 Apr 29.
 COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Delorey TM, Ziegler CGK, Heimberg G, Normand R, Shalek AK, Villani AC, Rozenblatt-Rosen O, Regev A. et al. Nature. 2021 Apr 29.
COVID-19 Research (NIH)
Izar Lab (Columbia University, New York)
Aviv Regev (Genentech, South San Francisco, CA)
NIH Support: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Human Genome Research Institute; National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism
Posted on by Dr. Francis Collins
This striking portrait features the spike protein that crowns SARS-CoV-2, the coronavirus that causes COVID-19. This highly flexible protein has settled here into one of its many possible conformations during the process of docking onto a human cell before infecting it.
This portrait, however, isn’t painted on canvas. It was created on a computer screen from sophisticated 3D simulations of the spike protein in action. The aim was to map its many shape-shifting maneuvers accurately at the atomic level in hopes of detecting exploitable structural vulnerabilities to thwart the virus.
For example, notice the many chain-like structures (green) that adorn the protein’s surface (white). They are sugar molecules called glycans that are thought to shield the spike protein by sweeping away antibodies. Also notice areas (purple) that the simulation identified as the most-attractive targets for antibodies, based on their apparent lack of protection by those glycans.
This work, published recently in the journal PLoS Computational Biology , was performed by a German research team that included Mateusz Sikora, Max Planck Institute of Biophysics, Frankfurt. The researchers used a computer application called molecular dynamics (MD) simulation to power up and model the conformational changes in the spike protein on a time scale of a few microseconds. (A microsecond is 0.000001 second.)
The new simulations suggest that glycans act as a dynamic shield on the spike protein. They liken them to windshield wipers on a car. Rather than being fixed in space, those glycans sweep back and forth to protect more of the protein surface than initially meets the eye.
But just as wipers miss spots on a windshield that lie beyond their tips, glycans also miss spots of the protein just beyond their reach. It’s those spots that the researchers suggest might be prime targets on the spike protein that are especially promising for the design of future vaccines and therapeutic antibodies.
This same approach can now be applied to identifying weak spots in the coronavirus’s armor. It also may help researchers understand more fully the implications of newly emerging SARS-CoV-2 variants. The hope is that by capturing this devastating virus and its most critical proteins in action, we can continue to develop and improve upon vaccines and therapeutics.
 Computational epitope map of SARS-CoV-2 spike protein. Sikora M, von Bülow S, Blanc FEC, Gecht M, Covino R, Hummer G. PLoS Comput Biol. 2021 Apr 1;17(4):e1008790.
COVID-19 Research (NIH)
Mateusz Sikora (Max Planck Institute of Biophysics, Frankfurt, Germany)
The surprising properties of the coronavirus envelope (Interview with Mateusz Sikora), Scilog, November 16, 2020.
Posted on by Dr. Francis Collins
Clinical trials have shown the COVID-19 vaccines now being administered around the country are highly effective in protecting fully vaccinated individuals from the coronavirus SARS-CoV-2. But will they continue to offer sufficient protection as the frequency of more transmissible and, in some cases, deadly emerging variants rise?
More study and time is needed to fully answer this question. But new data from Israel offers an early look at how the Pfizer/BioNTech vaccine is holding up in the real world against coronavirus “variants of concern,” including the B.1.1.7 “U.K. variant” and the B.1.351 “South African variant.” And, while there is some evidence of breakthrough infections, the findings overall are encouraging.
Israel was an obvious place to look for answers to breakthrough infections. By last March, more than 80 percent of the country’s vaccine-eligible population had received at least one dose of the Pfizer/BioNTech vaccine. An earlier study in Israel showed that the vaccine offered 94 percent to 96 percent protection against infection across age groups, comparable to the results of clinical trials. But it didn’t dig into any important differences in infection rates with newly emerging variants, post-vaccination.
To dig a little deeper into this possibility, a team led by Adi Stern, Tel Aviv University, and Shay Ben-Shachar, Clalit Research Institute, Tel Aviv, looked for evidence of breakthrough infections in several hundred people who’d had at least one dose of the Pfizer/BioNTech vaccine . The idea was, if this vaccine were less effective in protecting against new variants of concern, the proportion of infections caused by them should be higher in vaccinated compared to unvaccinated individuals.
During the study, reported as a pre-print in MedRxiv, it became clear that B.1.1.7 was the predominant SARS-CoV-2 variant in Israel, with its frequency increasing over time. By comparison, the B.1.351 “South African” variant was rare, accounting for less than 1 percent of cases sampled in the study. No other variants of concern, as defined by the World Health Organization, were detected.
In total, the researchers sequenced SARS-CoV-2 from more than 800 samples, including vaccinated individuals and matched unvaccinated individuals with similar characteristics including age, sex, and geographic location. They identified nearly 250 instances in which an individual became infected with SARS-CoV-2 after receiving their first vaccine dose, meaning that they were only partially protected. Almost 150 got infected sometime after receiving the second dose.
Interestingly, the evidence showed that these breakthrough infections with the B.1.1.7 variant occurred slightly more often in people after the first vaccine dose compared to unvaccinated people. No evidence was found for increased breakthrough rates of B.1.1.7 a week or more after the second dose. In contrast, after the second vaccine dose, infection with the B.1.351 became slightly more frequent. The findings show that people remain susceptible to B.1.1.7 following a single dose of vaccine. They also suggest that the two-dose vaccine may be slightly less effective against B.1.351 compared to the original or B.1.1.7 variants.
It’s important to note, however, that the researchers only observed 11 infections with the B.1.351 variant—eight of them in individuals vaccinated with two doses. Interestingly, all eight tested positive seven to 13 days after receiving their second dose. No one in the study tested positive for this variant two weeks or more after the second dose.
Many questions remain, including whether the vaccines reduced the duration and/or severity of infections. Nevertheless, the findings are a reminder that—while these vaccines offer remarkable protection—they are not foolproof. Breakthrough infections can and do occur.
In fact, in a recent report in the New England Journal of Medicine, NIH-supported researchers detailed the experiences of two fully vaccinated individuals in New York who tested positive for COVID-19 . Though both recovered quickly at home, genomic data in those cases revealed multiple mutations in both viral samples, including a variant first identified in South Africa and Brazil, and another, which has been spreading in New York since November.
These findings in Israel and the United States also highlight the importance of tracking coronavirus variants and making sure that all eligible individuals get fully vaccinated as soon as they have the opportunity. They show that COVID-19 testing will continue to play an important role, even in those who’ve already been vaccinated. This is even more important now as new variants continue to rise in frequency.
Just over 100 million Americans aged 18 and older—about 40 percent of adults—are now fully vaccinated . However, we need to get that number much higher. If you or a loved one haven’t yet been vaccinated, please consider doing so. It will help to save lives and bring this pandemic to an end.
 Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2 mRNA vaccinated individuals. Kustin T et al. medRxiv. April 16, 2021.
 Vaccine breakthrough infections with SARS-CoV-2 variants. Hacisuleyman E, Hale C, Saito Y, Blachere NE, Bergh M, Conlon EG, Schaefer-Babajew DJ, DaSilva J, Muecksch F, Gaebler C, Lifton R, Nussenzweig MC, Hatziioannou T, Bieniasz PD, Darnell RB. N Engl J Med. 2021 Apr 21.
 COVID-19 vaccinations in the United States. Centers for Disease Control and Prevention.
COVID-19 Research (NIH)
Stern Lab (Tel Aviv University, Israel)
Ben-Shachar Lab (Clalit Research Institute, Tel Aviv, Israel)
NIH Support: National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
COVID-19 is primarily considered a respiratory illness that affects the lungs, upper airways, and nasal cavity. But COVID-19 can also affect other parts of the body, including the digestive system, blood vessels, and kidneys. Now, a new study has added something else: the mouth.
The study, published in the journal Nature Medicine, shows that SARS-CoV-2, which is the coronavirus that causes COVID-19, can actively infect cells that line the mouth and salivary glands. The new findings may help explain why COVID-19 can be detected by saliva tests, and why about half of COVID-19 cases include oral symptoms, such as loss of taste, dry mouth, and oral ulcers. These results also suggest that the mouth and its saliva may play an important—and underappreciated—role in spreading SARS-CoV-2 throughout the body and, perhaps, transmitting it from person to person.
The latest work comes from Blake Warner of NIH’s National Institute of Dental and Craniofacial Research; Kevin Byrd, Adams School of Dentistry at the University of North Carolina, Chapel Hill; and their international colleagues. The researchers were curious about whether the mouth played a role in transmitting SARS-CoV-2. They were already aware that transmission is more likely when people speak, cough, and even sing. They also knew from diagnostic testing that the saliva of people with COVID-19 can contain high levels of SARS-CoV-2. But did that virus in the mouth and saliva come from elsewhere? Or, was SARS-CoV-2 infecting and replicating in cells within the mouth as well?
To find out, the research team surveyed oral tissue from healthy people in search of cells that express the ACE2 receptor protein and the TMPRSS2 enzyme protein, both of which SARS-CoV-2 depends upon to enter and infect human cells. They found the proteins may be expressed individually in the primary cells of all types of salivary glands and in tissues lining the oral cavity. Indeed, a small portion of salivary gland and gingival (gum) cells around our teeth, simultaneously expressed the genes encoding ACE2 and TMPRSS2.
Next, the team detected signs of SARS-CoV-2 in just over half of the salivary gland tissue samples that it examined from people with COVID-19. The samples included salivary gland tissue from one person who had died from COVID-19 and another with acute illness.
The researchers also found evidence that the coronavirus was actively replicating to make more copies of itself. In people with mild or asymptomatic COVID-19, oral cells that shed into the saliva bathing the mouth were found to contain RNA for SARS-CoV-2, as well its proteins that it uses to enter human cells.
The researchers then collected saliva from another group of 35 volunteers, including 27 with mild COVID-19 symptoms and another eight who were asymptomatic. Of the 27 people with symptoms, those with virus in their saliva were more likely to report loss of taste and smell, suggesting that oral infection might contribute to those symptoms of COVID-19, though the primary cause may be infection of the olfactory tissues in the nose.
Another important question is whether SARS-CoV-2, while suspended in saliva, can infect other healthy cells. To get the answer, the researchers exposed saliva from eight people with asymptomatic COVID-19 to healthy cells grown in a lab dish. Saliva from two of the infected volunteers led to infection of the healthy cells. These findings raise the unfortunate possibility that even people with asymptomatic COVID-19 might unknowingly transmit SARS-CoV-2 to other people through their saliva.
Overall, the findings suggest that the mouth plays a greater role in COVID-19 infection and transmission than previously thought. The researchers suggest that virus-laden saliva, when swallowed or inhaled, may spread virus into the throat, lungs, or digestive system. Knowing this raises the hope that a better understanding of how SARS-CoV-2 infects the mouth could help in pointing to new ways to prevent the spread of this devastating virus.
 SARS-CoV-2 infection of the oral cavity and saliva. Huang N, Pérez P, Kato T, Mikami Y, Chiorini JA, Kleiner DE, Pittaluga S, Hewitt SM, Burbelo PD, Chertow D; NIH COVID-19 Autopsy Consortium; HCA Oral and Craniofacial Biological Network, Frank K, Lee J, Boucher RC, Teichmann SA, Warner BM, Byrd KM, et. al Nat Med. 2021 Mar 25.
COVID-19 Research (NIH)
Saliva & Salivary Gland Disorders (National Institute of Dental and Craniofacial Research/NIH)
Blake Warner (National Institute of Dental and Craniofacial Research/NIH)
Kevin Byrd (Adams School of Dentistry at University of North Carolina, Chapel Hill)
NIH Support: National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Center for Advancing Translational Sciences