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Mapping Severe COVID-19 in the Lungs at Single-Cell Resolution

Posted on by Dr. Francis Collins

lung microscopy with red macrophages and green fibrosis cells
Caption: Image shows macrophages (red), fibroblast cells (green), and other cells (blue). In late COVID-19, macrophages migrate near fibroblasts, which may play a role in fibrosis. Credit: Images courtesy of André Rendeiro

A crucial question for COVID-19 researchers is what causes progression of the initial infection, leading to life-threatening respiratory illness. A good place to look for clues is in the lungs of those COVID-19 patients who’ve tragically lost their lives to acute respiratory distress syndrome (ARDS), in which fluid and cellular infiltrates build up in the lung’s air sacs, called alveoli, keeping them from exchanging oxygen with the bloodstream.

As shown above, a team of NIH-funded researchers has done just that, capturing changes in the lungs over the course of a COVID-19 infection at unprecedented, single-cell resolution. These imaging data add evidence that SARS-CoV-2, the coronavirus that causes COVID-19, primarily infects cells at the surface of the air sacs. Their findings also offer valuable clues for treating the most severe consequences of COVID-19, suggesting that a certain type of scavenging immune cell might be driving the widespread lung inflammation that leads to ARDS.

The findings, published in Nature [1], come from Olivier Elemento and Robert E. Schwartz, Weill Cornell Medicine, New York. They already knew from earlier COVID-19 studies about the body’s own immune response causing the lung inflammation that leads to ARDS. What was missing was an understanding of the precise interplay between immune cells and lung tissue infected with SARS-CoV-2. It also wasn’t clear how the ARDS seen with COVID-19 compared to the ARDS seen in other serious respiratory diseases, including influenza and bacterial pneumonia.

Traditional tissue analysis uses chemical stains or tagged antibodies to label certain proteins and visualize important features in autopsied human tissues. But using these older techniques, it isn’t possible to capture more than a few such proteins at once. To get a more finely detailed view, the researchers used a more advanced technology called imaging mass cytometry [2].

This approach uses a collection of lanthanide metal-tagged antibodies to label simultaneously dozens of molecular markers on cells within tissues. Next, a special laser scans the labeled tissue sections, which vaporizes the heavy metal tags. As the metals are vaporized, their distinct signatures are detected in a mass spectrometer along with their spatial position relative to the laser. The technique makes it possible to map precisely where a diversity of distinct cell types is located in a tissue sample with respect to one another.

In the new study, the researchers applied the method to 19 lung tissue samples from patients who had died of severe COVID-19, acute bacterial pneumonia, or bacterial or influenza-related ARDS. They included 36 markers to differentiate various types of lung and immune cells as well as the SARS-CoV-2 spike protein and molecular signs of immune activation, inflammation, and cell death. For comparison, they also mapped four lung tissue samples from people who had died without lung disease.

Altogether, they captured more than 200 lung tissue maps, representing more than 660,000 cells across all the tissues sampled. Those images showed in all cases that respiratory infection led to a thickening of the walls surrounding alveoli as immune cells entered. They also showed an increase in cell death in infected compared to healthy lungs.

Their maps suggest that what happens in the lungs of COVID-19 patients who die with ARDS isn’t entirely unique. It’s similar to what happens in the lungs of those with other life-threatening respiratory infections who also die with ARDS.

They did, however, reveal a potentially prominent role in COVID-19 for white blood cells called macrophages. The results showed that macrophages are much more abundant in the lungs of severe COVID-19 patients compared to other lung infections.

In late COVID-19, macrophages also increase in the walls of alveoli, where they interact with lung cells known as fibroblasts. This suggests these interactions may play a role in the buildup of damaging fibrous tissue, or scarring, in the alveoli that tends to be seen in severe COVID-19 respiratory infections.

While the virus initiates this life-threatening damage, its progression may not depend on the persistence of the virus, but on an overreaction of the immune system. This may explain why immunomodulatory treatments like dexamethasone can provide benefit to the sickest patients with COVID-19. To learn even more, the researchers are making their data and maps available as a resource for scientists around the world who are busily working to understand this devastating illness and help put an end to the terrible toll caused by this pandemic.


[1] The spatial landscape of lung pathology during COVID-19 progression. Rendeiro AF, Ravichandran H, Bram Y, Chandar V, Kim J, Meydan C, Park J, Foox J, Hether T, Warren S, Kim Y, Reeves J, Salvatore S, Mason CE, Swanson EC, Borczuk AC, Elemento O, Schwartz RE. Nature. 2021 Mar 29.

[2] Mass cytometry imaging for the study of human diseases-applications and data analysis strategies. Baharlou H, Canete NP, Cunningham AL, Harman AN, Patrick E. Front Immunol. 2019 Nov 14;10:2657.


COVID-19 Research (NIH)

Elemento Lab (Weill Cornell Medicine, New York)

Schwartz Lab (Weill Cornell Medicine)

NIH Support: National Center for Advancing Translational Sciences; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute


  • John Plaschke says:

    While the similarity is low there are other articles about how low binding energies may be more important as far as how the proteins interact

    similar human proteins to those produced by sars-cov-2
    using Blast

    I only ran the first viral protein NSP1 (cellular saboteur) and it has 20% similarity to
    Mouse Platelet endothelial aggregation receptor 1 protein and 20% to the human protein

    COVID-19 does cause coagulopathy

  • Cynthia Smith says:

    Would dexamethasone help people with advanced Pulmonary Fibrosis?

  • Karina P. says:

    My mother suffers from severe leg pain inflammation along with dislocated disc which doctors can’t figure out how to fix. she now has taken the j & j vaccine. isn’t breathing right. how do I take her to see she doesn’t get more blood cloths that will cause her to die from a bleeding hemorrhage in her brain?

  • Andy Miller says:

    If you ask someone that has fought the lung problem sense 2006, I will give you an Idea! The drug Amiodaron will do the same thing, causing pneumonitis of the lungs! I contend the overload of iron in the lungs from the virus invading the red cell to replicate will cause pneumonitis!

    Mitochondria are so integral to cell function that the stress caused by excessive iron buildup can lead to inflammation and damage to the lung’s air sacs, as well as to cells that line the airways — all of which is common in COPD patients.

  • Cynthia Rivanis says:

    Wouldn’t it make sense to give people antibiotics if they develop a bad cough before it even gets to this point. That’s what I did for myself so I would’t get pneumonia

  • Christopher Hostland says:

    One of the important macrophages mentioned in this article is GM-CSF. It’s been shown to play a key role in the progression to cytokine storm in COVID-19

    There is a drug that just passed positive phase 3 results that neutralizes GM-CSF, and it’s currently being tested by the NIH in their ACTIV 5 / BET-B trial.

    Really hoping this can get approval and sent to hospitals ASAP.

    • jayne says:

      Eua hopefully will come sooner then later!

    • Mike says:

      I’ve been following anti GM-CSF drugs as well. The ACTIV-5 trial for Lenzilumab just increased their trial sites while other trials have been closed . . . Watching closely and helping this could prevent a lot of deaths.

  • Adam Smith says:

    Thanks to your wonderful content . . .

  • Horacio Gonzalez says:

    This study seems to reafirm the benficial effect of Ibuprophen as profilactic treatment, preventing blood clots and inlammation

  • J M Strines says:

    If indeed the virus causes the immune system to go haywire, causing potentially fatal damage, might not targeted immune-suppressing therapies apply?

  • Estadística says:

    Thank you for this content! Hope the pandemic ends soon…

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