by Peter Wang and Elise Wachspress
How does COVID-19 pervert the very mechanism designed to destroy it?
Our bodies contain magnificent networks of cells, signals, and interactions that serve as sentries against harmful bacteria and viruses. But in the case of the coronavirus, it seems the most lethal blow sometimes comes from the immune system itself.
When a virus or bacterium—or sometimes even an unrecognized substance—enters the cells of the body, our immune systems send out small proteins to signal “get the war on these aliens started.” These small proteins, called cytokines, then attach to the outside of the cells and rev up inflammation, heating up the environment in an attempt to rid the body of the offenders.
In the case of this novel coronavirus, the response to the interlopers can quickly escalate, with more and more cytokines produced—a “cytokine storm.” It’s kind of like sending thousands of soldiers and tanks trampling across a landscape when the actual enemy is a guerilla cadre hiding safely underground: the potential result is a lot of damage done without ever defanging the real enemy.
For decades, Thomas Gajewski, MD, PhD, has led investigations of how to help the body fine-tune immune responses to cancer. In the coronavirus emergency that has commandeered all our lives, Gajewski is now working to understand the mechanisms of the immune response against SARS-CoV-2 in an effort to tamp down what may be the most dangerous element of this disease.
Within the first few weeks of the coronavirus pandemic in Chicago, Gajewski had put together a team of 40 investigators—from cancer clinicians to microbiome specialists to molecular engineers—to focus on detailing the mechanisms when the immune response to COVID-19 goes haywire. They organized a clinical study of 600 people—500 confirmed to have the disease and 100 healthy controls—and started measuring lots of parameters on each: the patients’ DNA sequences, blood cell composition, cytokines in the serum, antibodies and T cells against the virus, airway microbiota. They were looking for any relevant factor that shaped the immune response and potentially led to severe disease—the kind requiring intensive care unit support—versus mild disease that resolved spontaneously.
The goal: to understand which of these parameters was important in causing favorable or unfavorable outcome, and how clinicians could use these biological markers to decide the best treatment for each patient.
Already, Gajewski and his team had noticed that the lungs of some patients seemed to be full of macrophages, large white blood cells that protect places where our tissues meet the outside environment. And these macrophages seem to put out high levels of a specific cytokine known as interleukin-6 (IL-6), often implicated in severe cytokine storm.
Gajewski was well-positioned to launch this effort for multiple reasons. As a cancer immunologist, he has been studying how to increase or tamp down immune responses to disease for decades; he published his first papers on the interleukins nearly thirty years ago. To advance insights in cancer during decades of medical practice, he has relentlessly collected and carefully assessed as many patient samples as possible; these include samples less commonly studied, like stool—where he and his lab can identify the presence of the gut microbes that affect the immune response. And serendipitously, Jonathan Trujillo, MD, PhD, a fellow in Gajewski’s lab supported by Ruth and Elliot Sigal, had studied cytokines in coronaviruses earlier in his training, providing a direct expert on the team.
Gajewski and his team have already developed assays that reliably distinguish immune responses to SARS-CoV-2 and other coronaviruses. They are testing patients over a period of several days to follow disease progress and considering lots of questions. Does the degree of the immune response correlate with the severity of the disease? What other biomarkers correlate? Are there early warning signs that indicate which patients are most at risk for bad outcomes? Why does the drug Remdesivir seem to reduce the course of the disease? Does it also reduce the immune response?
With all the data the team is collecting, from microbial sequencing to patients’ personal genomes, they hope to develop much more knowledge about COVID-19 and why certain patients seem to get much sicker, in a very short period of time. The multiplex tests they are developing—assessing many types of cytokines and other markers at once—will also be extremely useful in addressing other diseases.
Cytokine storms are a complication not only of COVID-19 but of respiratory diseases caused by other coronaviruses, such as SARS and MERS. In fact, an out-of-control cytokine response was linked to the high fatality rate for the 2005 outbreak of the H5N1 “bird flu” virus. They are also associated with non-infectious diseases, such as multiple sclerosis and pancreatitis, and are a common side effect of the cancer immunotherapy approach utilizing CAR-T cells. So what we learn about these mechanisms can help advance medical science on several fronts.
Peter Wang is a second-year undergraduate student in The College.
Elise Wachspress is a senior communications strategist for the University of Chicago Medicine & Biological Sciences Development office.
