A coup for comparative medicine

When the COVID-19 pandemic took hold of the United States in the spring of 2020, Yale’s Department of Comparative Medicine was uniquely positioned to adapt its research and pivot to studying SARS-CoV-2, the virus that causes the disease. Scientists in the department were already focusing on many of the chronic conditions and risk factors that predispose people to develop complications from COVID-19. When the labs were forced to shut down in March 2020, the department held a faculty meeting to discuss how to go forward.

“In the last 15 years the individual researchers who were recruited and excelled in their works represent aspects of COVID-19 that turned out to be the major vulnerabilities—aging research, research on obesity, research on diabetes,” said Tamas Horvath, DVM, PhD, the Jean and David W. Wallace Professor of Comparative Medicine and chair of the department, and director of the Yale Program on Integrative Cell Signaling and Neurobiology of Metabolism. “It turned out that we have a full package. The researchers didn't have to adjust their approach or conceptual framework, but they could ask questions about COVID.”

To hit the ground running, the department’s members had to have access to an appropriate animal model that would have translational value, and shed light not only on how the virus causes symptoms but also on why some patients fare worse than others. The answer was to use MHV-A59, a strain of mouse hepatitis coronavirus that naturally infects rodents and behaves similarly in mice as SARS-CoV-2 does in humans. (SARS-CoV-2 itself does not infect rodents.) Reserves of the murine virus were immediately available in the lab’s freezer.

Several MHV strains were discovered in comparative medicine several decades ago—a period in which there was robust research related to coronaviruses, lab protocols, and contagion—but, according to Carlos Fernandez-Hernando, PhD, professor of comparative medicine and of pathology, these rodent coronaviruses didn’t get a lot of attention at the time. “People thought it's only going to be relevant for … mice and rats because they get sick from it and it spreads rapidly among laboratory rodent colonies—but these infection models that were available turned out to be what is needed today,” he said.

Fernandez-Hernando is studying how SARS-CoV-2 causes cardiovascular complications and the potentially chronic effects of COVID-19 as seen in so-called “long haulers”— those patients who recover from the acute phase of the infection but go on to have such lingering or permanent health problems as lung damage. The mouse model using a specific MHV virus strain (MHV-A59), he said, is ideal for studying these chronic issues, and fundamental for developing new therapeutic targets.

“Sometimes the way science works is very unexpected,” he said. “Nobody, at least most people, predicted that there would be a coronavirus that would cause such major havoc in the world. Suddenly, this expertise is deployed now to study that virus, and has become extremely relevant as a model for COVID-19—in fact, superior to current animal models, the transgenic or genetically manipulated models that exist today.”

Vishwa Deep Dixit, DVM, PhD, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology, is currently investigating the reasons that elderly people make up a disproportionate number of COVID-19 patients. “One of the biggest problems, as we all know now, is the risk of severe infections in the elderly,” he said. “Mortality is highest in the elderly. What we really do not understand is what are the mechanisms that are responsible for causing an increase in susceptibility to COVID infection in the elderly. For that, what we need are models that can be immediately deployed to study the underlying deficits in the immune system of aged individuals.”

Dixit’s lab maintains a colony of aging mice at Yale. Teaming with Andrew Wang, MD, PhD, assistant professor of internal medicine and immunobiology, the researchers infected the young and old mice with the MHV-A59 mouse coronavirus.

“We compare them to the young animals, study their responses, and how they are different in terms of their immune system. What are the underlying deficits in the metabolic systems? The idea behind this is that if we understand what are the basic problems and defects in the immune system of the aged, we can intervene at those particular steps to develop various interventions that could be deployed to do the preclinical research that could eventually go into clinical trials.”

“And that's how this MHV-A59, I think, is something that is now serendipitously important for studies of COVID-19,” Dixit said, echoing Fernandez-Hernando’s appreciation of the relevance of a strain discovered years ago.

Others in the department, including James Macy Jr., DVM, a professor of comparative medicine and director of Yale’s Animal Resources Center, are using a grant funded by the National Science Foundation (NSF) to investigate the host and viral factors that influence MHV disease. Another professor of comparative medicine, Caroline Zeiss, BVSc, PhD, is modeling a rat coronavirus infection to better understand the dynamics of infection in populations, including the emergence of herd immunity; she is also funded by the NSF. In addition, Zeiss is developing a COVID-19 hamster model through an NIH grant, using SARS CoV-2 because hamsters can be naturally infected with the human virus.

“People thought that, oh, the mouse is getting sick off of coronavirus. But how that mouse dies of that coronavirus, now it's telling us how people die of COVID. Isn't that fascinating?”