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Tissue Atlases Provide Peek Into Single-Cell Level Effects of SARS-CoV-2 Infections

NEW YORK – Two new tissue atlases point to how SARS-CoV-2 affects the lungs and can lead to mortality.

SARS-CoV-2 has led to nearly 150 million cases of COVID-19 and more than 3 million deaths worldwide, according to the Johns Hopkins Coronavirus Resource. About 15 percent of people infected with SARS-CoV-2 develop severe disease marked by acute respiratory distress syndrome, which may also lead to death.

In two new papers appearing in Nature, researchers have generated tissue atlases to examine how single cells, especially in the lungs, are affected by SARS-CoV-2 infection. Severe COVID-19, they reported, can lead to increased inflammation, failed lung cell regeneration, and higher levels of lung fibrosis.

"It's a devastating disease, but the picture we're getting of the COVID-19 lung is the first step towards identifying potential targets and therapies that disrupt some of the disease's vicious circuits," Benjamin Izar, an assistant professor of medicine at Columbia University Irving Medical Center and senior author of one of the papers, said in a statement.

Both Izar's Columbia-led team and the other Harvard University-led team generated their tissue atlases using samples from people who died of COVID-19. The Columbia cohort included 19 patients, and the Harvard one included 17 patients. The Columbia study further encompassed patients with other respiratory illnesses like influenza or pneumonia for comparison, while the Harvard study had tissue samples from other organs, such as heart, kidney, and liver. For both studies, the tissue samples underwent single-cell or single-nuclei sequencing and were annotated into cell types.

The atlases both uncovered differences between cells in COVID-19 affected lungs and normal lungs.

In their paper, Izar and his colleagues noted that lung samples from patients with COVID-19 harbored high numbers of myeloid cells, particularly alveolar macrophages and monocyte-derived macrophages, but had impaired T-cell responses. These macrophages from COVID-19 patients further produced higher levels of IL-1β than patients with other respiratory illnesses or controls.

At the same time, Harvard's Aviv Regev, who is now at Genentech, and her colleagues noted in their study a loss of both alveolar type I, or AT1, and type II, or AT2, cells, which are involved in gas exchange, among COVID-19 patients. As the AT1 cells died, they found that the AT2 cells attempted to transform themselves into the missing AT1 cells, but that process failed, leaving the cells in an intermediary state. A similar effort to transform intrapulmonary basal-like progenitor cells into AT1 cells also fell short. This inability to regenerate cells lost to damage, the researchers noted, likely contributed to lung failure among patients.

Bolstering that finding, Izar and his team similarly reported an incomplete transition of AT2 cells to AT1 cells in COVID-19 patients and noted a role for IL-1β in preventing that transition from happening. There are, according to Izar, already drugs that target IL-1β.

They also noted an increase of fibroblast cells, particularly CTHRC1+ cells, within samples from COVID-19 patients, which then contribute to pulmonary fibrosis and lung scarring. Izar and his colleagues additionally found that therapies targeting STAT signaling could help ameliorate some of the effects of these fibroblasts.

Additionally, Harvard's Regev and her team found other alterations among cells from other tissues, and particularly identified damage affecting heart tissue.

When they further combined their analysis with results from a previous genome-wide association study of COVID-19 that linked 27 genes to severe COVID-19, they found that a number of these genes — like FOXP4, CCR1, and CCRL2 — were highly expressed in key tissues and cells, including lung and AT1 and AT2 cells.

The researchers hope that these atlases can power further studies into COVID-19. "We created a foundational resource for other researchers to use in the future to ask specific questions," Orit Rozenblatt-Rosen, a co-senior author on the Harvard study and institute scientist at the Broad, who is also now at Genentech, said in a statement. "Hopefully, our findings will allow people to find better therapeutics for COVID-19."

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