File photo of the team from the tenOever Laboratory, from left to right: Kohei Oishi, PhD, Tristan Jordan, PhD, Daniel Blanco-Melo, PhD, Skyler Uhl, PhD candidate, Ben tenOever, PhD, Rasmus Moeller, PhD candidate, Maryline Panis, Lab Manager, Ben Nilsson-Payan, PhD, and Daisy Hoagland, PhD candidate
Early laboratory tests show the SARS-CoV2 virus, which leads to COVID-19, behaves very differently from the flu or common respiratory syncytial virus (RSV) in that it travels under the radar and enters human and animal cells quietly, eliciting a low-powered immune response that tends to fester, according to preliminary research led by Benjamin tenOever, PhD, the Fishberg Professor of Medicine, and Director of the Virus Engineering Center for Therapeutics and Research, at the Icahn School of Medicine at Mount Sinai. The observations, which provide a snapshot of how cells and organisms respond to the SARS-CoV2 virus, were based on studying RNA from live animal models and human cell lines. RSV often occurs in young children with symptoms that mimic the common cold.
“The take-home message of what we found so far is that the immune response to the virus is actually very muted,” says Dr. tenOever. In a typical reaction to the flu or RSV, the body secretes a whole family of proteins or interferons that assemble to take on a variety of functions to prepare for an imminent attack. Some of the interferons directly inhibit the virus. But with the SARS-CoV2 virus, Dr. tenOever says, “We see little to no evidence that the virus-infected cells are secreting these proteins. So a program that should be induced is not launching.” At most, the defense appears to be only 40 percent to 50 percent as strong as it would be for the flu or RSV.
The new virus behaves differently in another way, as well. Whereas the flu is particularly wily in dismantling the innate immune response in several places, SARS-CoV2 does not appear to do so, according to postdoctoral fellow Daniel Blanco Melo, PhD, who was a lead author of the study in Dr. tenOever’s lab. “We may find that the immune response is being blocked by this new virus too, but it won’t be in the same way as the flu,” he says.
According to the scientists, the preliminary findings show that the very stealth nature of SARS-CoV2 may actually account for its lethalness, a hypothesis that complements the virus’s long clinical progression, with many severely ill patients being hospitalized for more than 10 days. The hypothesis also supports the clinical evidence that patients need a strong immune system to fight COVID-19, the disease produced by the SARS-CoV2 virus. Under the leadership of Miriam Merad, MD, PhD, the Mount Sinai Professor in Cancer Immunology and Director of the Precision Immunology Institute, Mount Sinai is working to improve outcomes in critically ill patients who experience an excessive inflammatory response.
“It would almost appear that if you are a healthy individual under the age of 50 and you get this virus your immune system would have no problem tackling it, inhibiting it, and getting rid of it,” says Dr. tenOever. “But in older individuals and those who have comorbidities—those whose immune system is waning—our early data would suggest that their reduced immune system means they’re not aggressively neutralizing this virus, which leaves it to fester in the lungs and keep replicating.” This low-grade inflammation in the body allows the virus to remain under the radar for days as the patient’s lungs become increasingly damaged.
“Maybe what we’re seeing is a slow burn in some people that eventually takes its toll over 10 to 20 days,” says Dr. tenOever. “In the end, the immune system is reacting both to the virus and to the accumulating damage being done to the lungs. So the body goes into this mode of overly trying to repair itself from lungs that are leaking fluid and becoming hypoxic. By the time these patients come to the hospital it is more about controlling the inflammation to the damage induced by the virus than inhibiting the virus itself.”