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Posts Tagged ‘Longitudinal proteomic analysis of plasma’


Nir Hacohen and Marcia Goldberg, Researchers at MGH and the Broad Institute identify protein “signature” of severe COVID-19

Curator and Reporter: Aviva Lev-Ari, PhD, RN

Longitudinal proteomic analysis of plasma from patients with severe COVID-19 reveal patient survival-associated signatures, tissue-specific cell death, and cell-cell interactions

Open AccessPublished:April 30, 2021DOI:https://doi.org/10.1016/j.xcrm.2021.100287

Highlights

  • 16% of COVID-19 patients display an atypical low-inflammatory plasma proteome
  • Severe COVID-19 is associated with heterogeneous plasma proteomic responses
  • Death of virus-infected lung epithelial cells is a key feature of severe disease
  • Lung monocyte/macrophages drive T cell activation, together promoting epithelial damage

Summary

Mechanisms underlying severe COVID-19 disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNAseq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell type-specific intracellular death signatures, cellular ACE2 expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.

Graphical Abstract

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Image Source: DOI: https://doi.org/10.1016/j.xcrm.2021.100287

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00115-4

The quest to identify mechanisms that might be contributing to death in COVID-19: Why do some patients die from this disease, while others — who appear to be just as ill do not?

Researchers at Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard have identified the protein “signature” of severe COVID-19

Interest was to develop methods for studying human immune responses to infections, which they had applied to the condition known as bacterial sepsis. The three agreed to tackle this new problem with the goal of understanding how the human immune system responds to SARS-CoV-2, the novel pathogen that causes COVID-19.

How scientists launched a study in days to probe COVID-19’s unpredictability

Collecting these specimens required a large team of collaborators from many departments, which worked overtime for five weeks to amass blood samples from 306 patients who tested positive for COVID-19, as well as from 78 patients with similar symptoms who tested negative for the coronavirus.

Alexandra-Chloé Villani

Credit : Alexandra-Chloé VillaniResearch associates at Mass General who worked countless hours to process blood samples for the COVID Acute Cohort Study (from left to right: Anna Gonye, Irena Gushterova, and Tom Lasalle)By Leah Eisenstadt

https://www.broadinstitute.org/news/how-scientists-launched-study-days-probe-covid-19%E2%80%99s-unpredictability

As the COVID-19 surge began in March, Mass General and Broad researchers worked around the clock to begin learning why some patients fare worse with the disease than others

Protein signatures in the blood

https://www.broadinstitute.org/news/researchers-identify-protein-%E2%80%9Csignature%E2%80%9D-severe-covid-19

The study found that most patients with COVID-19 have a consistent protein signature, regardless of disease severity; as would be expected, their bodies mount an immune response by producing proteins that attack the virus. “But we also found a small subset of patients with the disease who did not demonstrate the pro-inflammatory response that is typical of other COVID-19 patients,” Filbin said, yet these patients were just as likely as others to have severe disease. Filbin, who is also an assistant professor of emergency medicine at Harvard Medical School (HMS), noted that patients in this subset tended to be older people with chronic diseases, who likely had weakened immune systems.

Among other revelations, this showed that the most prevalent severity-associated protein, a pro-inflammatory protein called interleukin-6 (IL-6) rose steadily in patients who died, while it rose and then dropped in those with severe disease who survived. Early attempts by other groups to treat COVID-19 patients experiencing acute respiratory distress with drugs that block IL-6 were disappointing, though more recent studies show promise in combining these medications with the steroid dexamethasone.

Hacohen, who is a professor of medicine at HMS and director of the Broad’s Cell Circuits Program:

“You can ask which of the many thousands of proteins that are circulating in your blood are associated with the actual outcome,” he said, “and whether there is a set of proteins that tell us something.”

Goldberg, who is a professor of emergency medicine at HMS:

They are highly likely to be useful in figuring out some of the underlying mechanisms that lead to severe disease and death in COVID-19,” she said, noting her gratitude to the patients involved in the study. Their samples are already being used to study other aspects of COVID-19, such as identifying the qualities of antibodies that patients form against the virus.

SOURCES

Original Research

Filbin MR, Mehta A, et al. Longitudinal proteomic analysis of plasma from patients with severe COVID-19 reveal patient survival-associated signatures, tissue-specific cell death, and cell-cell interactionsCell Reports Medicine. Online April 30, 2021. DOI: 10.1016/j.xcrm.2021.100287.

Adapted from a press release originally issued by Massachusetts General Hospital.

https://www.broadinstitute.org/news/researchers-identify-protein-%E2%80%9Csignature%E2%80%9D-severe-covid-19

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00115-4

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