The origins and evolutionary path of SARS-CoV-2 and the lingering effects of long COVID-19 are two mysteries that have puzzled scientists since the onset of the pandemic. In an effort to shed light on COVID-19 and its complications, the Howard Hughes Medical Institute (HHMI) has provided $10 million to HHMI Investigators at Yale, an HHMI host institution. The funding supports collaborative research projects through the labs of some of the leading experts at the forefront of COVID-19 research.
“HHMI’s support is a reflection of the fact that there’s a real, urgent societal need for this kind of research,” says Richard Flavell, PhD, Sterling Professor of Immunobiology.
The funding from HHMI supports two projects involving Yale HHMI investigators tackling different areas of COVID-19 research. One project includes Flavell alongside Akiko Iwasaki, PhD, Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellular, and Developmental Biology and professor of epidemiology (microbial diseases); Pietro De Camilli, MD, John Klingenstein Professor of Neuroscience and professor of cell biology; and Anna Marie Pyle, PhD, Sterling Professor of Molecular, Cellular, and Developmental Biology and professor of chemistry. The researchers have combined their labs and each is studying a different aspect of the pathogenesis of COVID-19. A second project by Iwasaki and Ruslan Medzhitov, PhD, Sterling Professor of Immunobiology, focuses on long COVID-19 and the potential underlying causes of the disease.
Why COVID-19 Takes Lives
While illness due to COVID-19 is mild for many, in others, the disease can lead to hospitalization or even be fatal. To better understand why COVID-19 can turn deadly, Yale researchers wanted to create an animal model that accurately reflected what happens in humans. Over the past two decades, Flavell’s lab has been developing humanized mouse models, with human-like characteristics, and the mice in this research are bred to have a human-like immune system. Through infecting the humanized mice with the virus, researchers can study how the human immune system probably would respond to COVID-19 infection.
“What happens in the lungs of the mice is extremely similar to what is happening in humans,” says Flavell. “The model does a good job mimicking severe human COVID-19, allowing us to figure out how the pathogenesis works.”
In general, with viral infections, it is not the virus that makes individuals ill, but rather the immune response that’s designed to fight the virus. Interestingly, when the human immune system is not transferred to the mice, the animals don’t get sick—rather, it is the human immune system that causes them to fall ill. Flavell and his colleagues are using his humanized mice to identify problematic factors of the human immune system in an effort to figure out how to reduce the severity of the disease through drugs and other therapies.
Using the humanized mice models, Iwasaki’s lab is interested in transferring auto-antibodies that develop in severe COVID-19 patients to the animals in an attempt to recapitulate some of the symptoms in the models. Pyle, meanwhile, looks at the kinds of RNA structures present in the mice to better understand the persistent presence of viral RNA that is found far beyond the infectious virus period. And De Camilli will study how different intracellular transport mechanisms in lipids are contributing to the production of membranes that envelope the virus. “Understanding precisely the biogenesis of this virus will advance our knowledge for providing potential targets for therapy,” says De Camilli.
Why Long COVID Can Occur
Iwasaki is also involved in a second HHMI-funded project with Medzhitov on possible drivers of long COVID-19. The researchers have several hypotheses on why the illness persists in some individuals who contract it. It may be a persistent viral infection, an autoimmune response, or latent viruses becoming reactivated. By monitoring many different parameters—from cytokines to T-cells and B-cells to antibodies—in patients with long COVID-19, they hope to form hypotheses about what might be going on. They are also developing a parallel mouse model that mimics aspects of long COVID-19.
“Right now, long COVID is a big issue that is happening in 10 to 30 percent of survivors of even mild infections, but we don’t know what’s driving the disease,” says Iwasaki. “We need to understand the different drivers of this disease so we can be better informed on therapies for patients.”
COVID-19 is not the first pandemic, and epidemiologists agree that pandemics following COVID-19 will unfortunately become more frequent. In preparation for future outbreaks, HHMI is investing $250 million toward its new Emerging Pathogens Initiative. Through March 1, it will be accepting proposals from HHMI investigators for research on confronting future pandemics and emerging pathogens.
“Most people would agree that this is a very big problem that is not going to go away. We were saved by a scientific miracle this time because of new technology in vaccine development,” says Flavell. “Through recruiting a range of creative people, we can come up with fresh ideas that will lead to new approaches.