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Imaging Mass Cytometry Study Reveals Immune Processes Involved in Severe COVID-19

NEW YORK – Researchers at Weill Cornell Medicine have used imaging mass cytometry to profile the cellular makeup and spatial composition of lung injury due to COVID-19.

The study, detailed this week in a paper published in Nature, provides insight into the sites within patient lungs most prominently affected by the virus and the immune response to infection at these sites. It also points towards potential treatments for the disease, said Robert Schwartz, an associate professor of medicine at Weill Cornell Medicine and senior author on the study.

The Weill Cornell Medicine team used Fluidigm's Hyperion Imaging System to measure the expression level of 36 proteins at single-cell resolution, allowing them to characterize the pathophysiology and immune response in the lungs of 10 patients who died from COVID-19. The panel included "phenotypic markers of endothelial, epithelial, mesenchymal, and immune cells, functional markers (activation, inflammation and cell death), and an antibody specific to the spike protein of SARS-CoV-2," they wrote. They used immunohistochemistry and targeted spatial transcriptomic measurements to validate their imaging mass cytometry findings.

In addition to the COVID-19 samples, Schwartz and his colleagues looked at samples from patients who died with acute respiratory distress syndrome from influenza (two patients), bacterial infection (four patients), and bacterial pneumonia (three patients), along with post-mortem lung tissue from four otherwise healthy individuals.

The researchers noted several commonalities across all the infections, including, they wrote, "a significant reduction in alveolar lacunar space, increased immune infiltration, and cell death by apoptosis compared with healthy lungs. They also observed several patterns unique to COVID-19, including "a high degree of inflammation, infiltration of interstitial macrophages, complement activation, and fibrosis," in late-stage disease.

"In contrast to other lung injury or disease processed, there is widespread tissue damage in late COVID-19 marked by the high amounts of pro-apoptotic cleaved caspase 3 and the off-target deposition of activated complement C5b-C9 attack complex in epithelial cells," Schwartz said.

He added that another potentially significant observation was that while SARS-CoV-2 infection increased the recruitment of immune cells to the lungs, immune cells did not have increased interactions with SARS-CoV-2 infected cells (as measured by the presence of the virus's spike protein).

This finding ran against the researchers' expectations and "stands in contrast to other viral and bacterial pulmonary infections," Schwartz said.

He suggested that this finding combined with the observation of increased complement activity could explain the widespread "off-target" lung tissue damage seen in severe COVID-19 cases, adding that this suggests that acting early in the disease process to prevent complement pathway activity could offer a potential treatment.

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