John Wherry, PhD
Conversations in the news, at home, and in the workplace are frequently turning to reopening and co-existing with SARS-CoV-2. How do we do it, and how can we stay safe? E. John Wherry, PhD, chair of Systems Pharmacology and Translational Therapeutics and director of the Institute for Immunology, and Michael Betts, PhD, a professor of Microbiology, are investigating immune response in patients critically ill with COVID-19, rapidly taking their insights from the lab about how the immune system responds to infection, back to clinicians on the front lines. Next, they are looking toward future research and what immunity might be conferred on those previously infected.
Benchmarks sat down with Wherry and Betts to discuss their work and how the collaborative environment at Penn is pushing research ahead during the coronavirus pandemic.
What’s on the horizon in COVID-19 research?
MB: There’s a notion going around that people do not develop long-term protective immunity [after COVID-19 infection]; this is in the headlines all over the place. I have my family calling me saying, “Is this true?” I think the answer is, right now, we don’t know. But I think John agrees with this, it’s exceptionally unusual to think that’s the case. There’s no evidence that protective immunity is not generated. If it turns out that is the case, then I think we would be in a very good position to try to understand why.
JW: I think this is actually one of the biggest next questions we have to address. Our focus right now is getting information back to the clinic, like today literally. But the next really important question is what happens after you recover and how does knowledge about that inform how we go back to a normal society. Mike and I are investing a lot of time and energy to build an infrastructure that allows us to turn our attention to that when the time is appropriate. We are really applying the concept of defining Immune Health to understand COVID-19 disease and then recovery and — we hope — immunity to reinfection.
Tell us about your project.
Michael Betts, PhD
John Wherry: In the absence of a good antiviral drug, or a vaccine, we need to understand where we are on the spectrum of immune responses from doing a really good job controlling the virus to maybe overdoing it and causing damage. A simple way of thinking about the immune response is just low, intermediate, or high. Another dimension is what flavor of immune response do we have — you can make an immune response that will protect you from a virus, but if you get a parasitic infection, that immune response won’t help. Sometimes it can actually make things worse. So the whole goal of what Mike and I have set up is: one, make sure we can get samples from patients so we can understand what’s happening immunologically; two, set up an immune profiling platform to answer those questions of how much — low, medium, high — and what flavor [of immune system activity]; and three, something that Penn is probably in a better position than many other institutions to do, take our insights right back to the clinic in real time. We’re talking about our results with clinicians almost daily trying to get information in their hands so they can interpret it in the context of what they’re seeing clinically, adjust their treatments and think about what other options might be available.
Mike Betts: There’s a huge amount of heterogeneity among people’s response to this virus, and we are identifying some relatively unifying characteristics as well, mechanisms that everybody uses initially to fight off infections that are somewhat non-specific to viruses. In people with severe infections, those pathways and mechanisms are potentially overactive, and in fact, we’re still trying to figure out if the virus-specific responses are delayed in those individuals. In people who seem to be less symptomatic, we don’t find those same broad effects in the early phase of the immune response.
How does this work build on your previous work?
JW: Mike and I have worked on these things for many years both separately and together. We’ve learned a lot from animal models of respiratory infections. So, we have a general map of what a respiratory viral infection looks like in terms of immune response. We’re using that as a guidepost. Nevertheless, we are in uncharted territory in every respect of the word — scientifically, clinically, and societally. This infection is challenging us to use that previous foundation to understand new manifestations of disease. For example, one thing we’re struggling with is the idea that there’s a very clear cardiovascular and thrombotic component that seems to be linked to immune response. It’s an event that you don’t see very often in other respiratory viral infections. So, again, the beautiful thing about Penn is how quickly people with that kind of expertise stepped in, contributed knowledge, really actually put their feet to the ground and started doing experiments and helping to set up experiments, so we are now being pushed in a good way, out of our comfort zone. It is so important that the community has been acting as a real team bringing everything to bear on this, being selfless and being present when something comes up that the person finds and doesn’t understand.
MB: We’ve been able to generate so much data so quickly and it’s been disseminated amongst the Penn community. You have experts coming out in areas new to us that are proving to be helpful to guide how things are moving forward. Even at this point, John’s lab and my lab, we’re already taking that information and starting to prepare the next phase of analysis to get more detailed understanding of what’s potentially driving the cardiovascular changes, the thrombotic problems, and so on. It’s forcing us to think completely differently about the immune effects here.