Rapid Results: COVID-19 Funding Spurs Publication, R01 Supplement
NUCATS members continue to seek answers to the severe effects of the deadly pandemic
Severe COVID-19, which requires prolonged mechanical ventilation, differs in a number of ways from other pneumonias with similar severity, according to early findings from a group of Northwestern researchers published in bioRxiv.
“Our previous understanding of what drives these differences in the clinical course has been imperfect, particularly because most researchers limited their analysis of patients with COVID-19 to peripheral blood,” says Alexander “Sasha” Misharin, MD, PhD, assistant professor of Medicine: Pulmonary and Critical Care and one of the lead authors of the preprint article. “Unfortunately, the analysis of peripheral blood rarely explains what’s happening in the affected organ – the lung.”
To gain insight about differences between severe COVID-19 and other pneumonias the Northwestern Medicine research team systematically sampled the inflammatory cells in the lung using bronchoalveolar lavage, a procedure that involves passing a bronchoscope through the mouth or nose into the lungs. A measured amount of fluid is then introduced and collected for examination.
The work was funded, in part, by a COVID-19 Rapid Response grant from the Northwestern University Clinical and Translational Sciences (NUCATS) Institute. The research team has been able to continue to expand the scope of Northwestern’s NIH-funded Successful Clinical Response In Pneumonia Therapy (SCRIPT) Systems Biology Center, which is led by Richard Wunderink, MD, professor of Medicine: Pulmonary and Critical Care, and one of the world’s leading experts in severe pneumonia. Both Misharin and Wunderink are NUCATS members.
Doctors routinely use bronchoalveolar lavage to guide the diagnosis and treatment of patients with severe pneumonia, and the SCRIPT study has been collecting and analyzing these samples for two years. The previous data and their new NUCATS funding allowed the team to correctly interpret samples from patients with COVID-19.
“We found that immune response in COVID-19 was substantially different from other viral or bacterial pneumonias. Unlike the robust but short immune response typical for other types of pneumonia, lung inflammation in COVID-19 is characterized by prolonged and sustained activation of specific immune cells – alveolar macrophages and T cells — which formed stable circuits that maintain long-lasting inflammation,” says Misharin.
The findings suggest that macrophages, a type of cell found at the site of infections, could be a new target for therapeutic interventions and that breaking pathological circuits between alveolar macrophages and T cells could prevent progression from mild to severe COVID-19.
“In fact, several already available drugs could be repurposed to target these cells,” says Misharin. “This research has been highly collaborative and it would not be possible without the coordinated effort of more than 100 researchers, physicians, nurses, respiratory therapists, clinical coordinators, and data scientists from different departments at Northwestern.”
Preprint data analysis was led by Rogan Grant, a graduate student in the Northwestern University Interdepartmental Neuroscience program, Luisa Morales-Nebreda, a Pulmonary and Critical Care fellow in the Physician-Scientist Training Program, and Nikolay Markov, a computational postdoctoral fellow. Grant, Morales-Nebreda and Markov work within laboratories in the Division of Pulmonary and Critical Care Medicine and all three are equally contributing first authors.
COVID-19 BioBank Continues to Grow
A novel COVID-19 BioBank, created with the help of a Rapid Response grant from NUCATS, has enrolled more than five dozen patients since launching this spring. The research study collects blood, urine and viral samples from patients who are sick with SARS-CoV-2 infection.
“Ongoing analyses have allowed us to begin to understand the evolution of the virus in patients given a range of treatments, as well as a better correlation of the clinical course of patients with the virology and their immune responses to the virus,” says Michael Ison, MD, MS, professor of Medicine: Infectious Diseases, Surgery: Organ Transplantation and director of the NUCATS Center for Clinical Research. “The research could only happen with the help of our Comprehensive Transplant Center research coordinators who consented the patients and collected samples from the subjects. The samples were then taken to the lab of Judd Hultquist, PhD, where they were processed, analyzed and stored by research technician Lacy Simons. We’ve been collaborating with Judd, Lacy, Egon Ozer, MD, PhD, and Ramon Lorenzo Redondo, PhD, to perform detailed analyses of the virus and samples collected.”
The project has also relied on clinical data from the COVID-19 Datamart, led by Chad Achenbach, MD, MPH, associate professor of Medicine: Infectious Diseases and Preventive Medicine. The research team continues develop new lines of exploration, sharing samples with the labs of Douglas Vaughan, MD; Anat Roitberg-Tambur, DMD, PhD and Alexis Demonbreun, PhD.
The samples were also the basis of a National Institutes of Health R01 supplement to Daniel Kim, PhD, and Daniel C Lee, MD, who will explore cardiac complications of COVID-19.
A second major component of the BioBank funded by the NUCATS grant and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University involves collecting blood from patients who have recovered from the virus.
“We have enrolled nearly 50 patients and have shown that antibody titers — a measurement of how much antibody has been produced — and B cell clones — cells responsible for immune response — are higher in patients with more severe disease than those with milder disease,” says Ison.
These samples are being fed into efforts led by Huiping Liu, MD, PhD, and Deyu Fang, PhD,
to better understand the role of B cell and humoral immunity as well as the role of extracellular vesicles known as exosomes in recovered patients.
NUCATS and the COVID-19 Rapid-Response Grants are supported, in part, by the National Institutes of Health's National Center for Advancing Translational Sciences, Grant Number UL1TR001422.
Written by Roger Anderson
