While most COVID-19 Cases are asymptomatic or mild. Serious complications associated with acute respiratory distress have resulted in more than a million deaths worldwide in just a few months.
Researchers from the Morgridge Institute for Research, the University of Wisconsin-Madison, and Albany Medical College sought to better understand the molecular factors that determine the severity of COVID-19 and provide insight into treatment options for people with advanced disease.
The collaborative study published online in Cell systems identified more than 200 molecular features that strongly correlate with the severity of COVID-19.
“To the best of my knowledge, this is the largest outcome study,” says Dr. Ariel Jaitovich, pulmonologist and intensive care doctor at Albany Medical Center. “I know there are some big studies out there looking at diagnostics (infected versus not infected). We have a large group of just COVID patients but with a very detailed difference in severity … I didn’t see that. ”
The team analyzed 102 blood samples from patients diagnosed with COVID-19 and 26 samples from patients with acute respiratory distress syndrome (ARDS) – but negative for COVID-19 – as controls.
“I felt that we had a unique opportunity with Ariel’s cohort that he had recruited. It was very early in the COVID epidemic here in the US so he was really at the forefront of getting these types of samples out of the clinic, ”says Josh Coon, Morgridge metabolic researcher and professor of biomolecular chemistry at UW-Madison School for medicine and public health.
Using methods of mass spectrometry, RNA Sequencing and machine learning, researchers examined a database of more than 17,000 different proteins, metabolites, lipids, and RNA transcripts that are associated with clinical outcomes.
They identified 219 molecules and genes that affect blood clotting, vascular damage, inflammation and other biological processes that are reported to play a role in serious illness.
“We had to figure out how we could actually compare it to the data we had,” says Ron Stewart, Morgridge investigator and assistant director of bioinformatics, whose team was tasked with analyzing the transcriptome data. “For the most part, what we found is that we rounded up previous work on what is good.”
One particularly unique aspect of the study that contributed to the robust dataset was its use by the team plasma Rehearse.
“In most proteomics studies, the blood samples use the serum fraction that has no clotting factors,” says Jaitovich. “This is very important as patients with COVID-19 have accelerated clotting activity.”
A metabolite called citrate is used as a therapeutic anticoagulant to reduce the likelihood of clotting development. However, the study found that the presence of metabolic citrate decreased when patients emerged with more severe disease.
“The fact that citrate is reduced in these patients may suggest that the reduction facilitates the hypercoagulation phenotype that we found in these patients,” says Jaitovich.
Another molecule that may contribute to hypercoagulation in severe COVID-19 is a protein called gelsolin, which is normally released in response to inflammation from cell injury or infection. Gelsolin was also reduced in the plasma samples of people with severe illness.
In addition to biomarkers associated with hypercoagulation, the team also identified a group of proteins involved in blood vessel damage that are more common in severe COVID-19 samples.
“There are all of these pre-process factors that are actually changed, and you only need to look at the clotting process to manage this phenotype,” says Evgenia Shishkova, a research fellow at the Coon Lab.
The analysis also revealed elevated levels of proteins and upregulated genes involved in neutrophil degranulation, which has been linked to inflammation, thrombosis, and the development of ARDS.
“So there seems to be a really strong interplay between the inflammatory response and likely those thrombotic events that also occur in COVID patients,” says Katie Overmyer, associate director of the Laboratory for Biomolecular Mass Spectrometry at UW-Madison.
Finally, the multi-omic analysis found that a network of high density lipoproteins – the proteins APOA1 and APOA2, as well as a group of lipids known as plasmalogens that act as antioxidants – all lower in severe COVID-19 cases were.
“These aspects weren’t on our radar,” says Jaitovich. “The ability to bring these dimensions together into a single unified narrative enabled us to understand things that were completely hidden from us.”
Identifying these different molecules opens the potential for the development of targeted therapeutics that can help alleviate disease.
“We can offer hard data to people who specialize in all of these different areas to educate themselves on the prospect of what they think might affect COVID,” Coon says.
Researchers made the data publicly available through an interactive web tool, covid-omics.app, where the scientific community compared and analyzed the data along with their own workflows.
Coon adds, “I think we’ve tried our best to highlight vignettes that we think are important, but the bigger impact will likely come from the community who can look into it.”
Reference: “Large-Scale Multi-omic Analysis of COVID-19 Severity” by Katherine A. Overmyer, Evgenia Shishkova, Ian Miller, Joseph Balnis, Matthew N. Bernstein, Trenton M. Peters-Clarke, Jesse G. Meyer, Qiuwen Quan, Laura K. Mühlbauer, Edna A. Trujillo, Yuchen He, Amit Chopra, Hau Chieng, Anupama Tiwari, Marc A. Judson, Brett Paulson, Dain R. Brademan, Yunyun Zhu, Lia R. Serrano, Vanessa Linke, Lisa A. Drake Alejandro P. Adam, Bradford S. Schwartz, Harold A. Singer, Scott Swanson, Deane F. Mosher, Ron Stewart, Joshua J. Coon and Ariel Jaitovich, accepted October 5, 2020, Cell systems.
DOI: 10.1016 / j.cels.2020.10.003