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The Prime Cellular Targets for the Novel Coronavirus

Posted on by Dr. Francis Collins

Credit: NIH

There’s still a lot to learn about SARS-CoV-2, the novel coronavirus that causes COVID-19. But it has been remarkable and gratifying to watch researchers from around the world pull together and share their time, expertise, and hard-earned data in the urgent quest to control this devastating virus.

That collaborative spirit was on full display in a recent study that characterized the specific human cells that SARS-CoV-2 likely singles out for infection [1]. This information can now be used to study precisely how each cell type interacts with the virus. It might ultimately help to explain why some people are more susceptible to SARS-CoV-2 than others, and how exactly to target the virus with drugs, immunotherapies, and vaccines to prevent or treat infections.

This work was driven by the mostly shuttered labs of Alex K. Shalek, Massachusetts Institute of Technology, Ragon Institute of MGH, MIT, and Harvard, and Broad Institute of MIT and Harvard, Cambridge; and Jose Ordovas-Montanes at Boston Children’s Hospital. In the end, it brought together (if only remotely) dozens of their colleagues in the Human Cell Atlas Lung Biological Network and others across the U.S., Europe, and South Africa.

The project began when Shalek, Ordovas-Montanes, and others read that before infecting human cells, SARS-CoV-2 docks on a protein receptor called angiotensin-converting enzyme 2 (ACE2). This enzyme plays a role in helping the body maintain blood pressure and fluid balance.

The group was intrigued, especially when they also learned about a second enzyme that the virus uses to enter cells. This enzyme goes by the long acronym TMPRSS2, and it gets “tricked” into priming the spike proteins that cover SARS-CoV-2 to attack the cell. It’s the combination of these two proteins that provide a welcome mat for the virus.

Shalek, Ordovas-Montanes, and an international team including graduate students, post-docs, staff scientists, and principal investigators decided to dig a little deeper to find out precisely where in the body one finds cells that express this gene combination. Their curiosity took them to the wealth of data they and others had generated from model organisms and humans, the latter as part of the Human Cell Atlas. This collaborative international project is producing a comprehensive reference map of all human cells. For its first draft, the Human Cell Atlas aims to gather information on at least 10 billion cells.

To gather this information, the project relies, in part, on relatively new capabilities in sequencing the RNA of individual cells. Keep in mind that every cell in the body has essentially the same DNA genome. But different cells use different programs to decide which genes to turn on—expressing those as RNA molecules that can be translated into protein. The single-cell analysis of RNA allows them to characterize the gene expression and activities within each and every unique cell type. Based on what was known about the virus and the symptoms of COVID-19, the team focused their attention on the hundreds of cell types they identified in the lungs, nasal passages, and intestines.

As reported in Cell, by filtering through the data to identify cells that express ACE2 and TMPRSS2, the researchers narrowed the list of cell types in the nasal passages down to the mucus-producing goblet secretory cells. In the lung, evidence for activity of these two genes turned up in cells called type II pneumocytes, which line small air sacs known as alveoli and help to keep them open. In the intestine, it was the absorptive enterocytes, which play an important role in the body’s ability to take in nutrients.

The data also turned up another unexpected and potentially important connection. In these cells of interest, all of which are found in epithelial tissues that cover or line body surfaces, the ACE2 gene appeared to ramp up its activity in concert with other genes known to respond to interferon, a protein that the body makes in response to viral infections.

To dig further in the lab, the researchers treated cultured cells that line airways in the lungs with interferon. And indeed, the treatment increased ACE2 expression.

Earlier studies have suggested that ACE2 helps the lungs to tolerate damage. Completely missed was its connection to the interferon response. The researchers now suspect that’s because it hadn’t been studied in these specific human epithelial cells before.

The discovery suggests that SARS-CoV-2 and potentially other coronaviruses that rely on ACE2 may take advantage of the immune system’s natural defenses. When the body responds to the infection by producing more interferon, that in turn results in production of more ACE2, enhancing the ability of the virus to attach more readily to lung cells. While much more work is needed, the finding indicates that any potential use of interferon as a treatment to fight COVID-19 will require careful monitoring to determine if and when it might help patients.

It’s clear that these new findings, from data that weren’t originally generated with COVID-19 in mind, contained several potentially important new leads. This is another demonstration of the value of basic science. We can also rest assured that, with the outpouring of effort from members of the scientific community around the globe to meet this new challenge, progress along these and many other fronts will continue at a remarkable pace.


[1] SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Ziegler, CGK et al. Cell. April 20, 2020.


Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)

Human Cell Atlas (Broad Institute, Cambridge, MA)

Shalek Lab (Harvard Medical School and Massachusetts Institute of Technology, Cambridge)

Ordovas-Montanes Lab (Boston Children’s Hospital, MA)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; National Heart, Lung, and Blood Institute


  • Barbara Lewis says:

    Wow! Congratulations and profound thanks to all the folks in all the labs providing this leading edge information.

  • minakshi prasad says:

    Amazing information. Good to share with undergraduate and post graduate students.

  • Vernon McAlister says:

    Amazing what you guys are learning, very dramatic mystery being broken step by step, keep the good news flowing.

  • MARK RUSSELL says:


  • Joel Huberman says:

    Thanks for this interesting story, and three cheers for basic research!

  • Vic Shorrocks says:

    Is anyone looking into the effects of supplementing the diet with selenium in order to minimise the virulence of Covid-19?

  • GUEYE says:

    Hello. Good. Hypomagnesaemia in long-term users of proton-pump inhibitors and Covid-19 : is there a link ?

  • jackie r. says:

    Could any of this research and findings be used for Fibrosis of the Lungs and Scleroderma?
    Thank you for all you do.

  • dani bowman says:

    Knowledge is power–thank you for all you are doing for research. Do ACE and ARB medications increase the expression of ACE2? Is this a risk factor for more severe Covid-19 infection?

  • Sylvia Reddom says:

    Thank you for your dedicated and professionalism in this important undertaking for us all. Keep up the great work and stay well yourselves!

  • Eric Nelson says:

    Cancer researchers in Cuba have used interferon for treating lung cancer for years. I recommend NIH collaborate with Cuba’s labs to speed the treatment process.

  • DR. SAUMYA PANDEY, PH.D. says:

    An enlightening and scientifically appealing snapshot from the American expert Dr. Collins to further propel my continued clinical research endeavors in the complex biomedical/life sciences and physiology-pathophysiology fields!
    The molecular regulatory networks at the transmembrane-signaling domains, primarily ACE-2 receptor-SARS-Covid-2 interactomes warrants future high-quality studies with eventual cost-effective, public health impact.
    I wish to further add that gender and ethnicity-specific health disparities-epidemiology-immunopharmacology-genetics association studies with relatively large sample-size for drawing definitive conclusions in the complex immunobiology and clinical sequelae of Covid-2 pathogenesis and cellular/molecular/genetic interactions at the membrane interfaces/host-pathogen interfaces.

  • Jan M Peterson says:

    your studies are very interesting to me, especially the involvement of alveoli and goblet producing cells. Is there any connection with the presence of COPD.

  • D.J. says:

    knowledgeable blog for everyone. thanks sir

  • Linda says:

    I am really bothered by the meat packing plants and the high rates of infections. There have been enough animal to people infectious disease in the past, is it impossible for there to be a chance of transmission of SARS CoV -2 from these dead animals to the people who are working with meat on them all day long

  • Kumudini says:

    Excellent Post. Which type of interferons? Alpha, beta or gamma?

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