Gundappa Saha is a postdoctoral researcher at University of Pennsylvania studying how the innate immune system's memory drives interconnected chronic inflammatory diseases. In this Postdoc Portrait interview, he shares how multiple chronic diseases arising in the same person could be caused by a trigger that has long since gone.
Uncovering Innate Immune Memory and Bone Marrow Reprogramming
Q | What drew you to immune memory?
My journey into this field began with a fascination for how microbes interact with the immune system. Early in my research training, I was focused on understanding how pathogens evade immune responses, a kind of microscopic arms race between host and invader. But over time, I became more intrigued by what happens when the immune system itself becomes dysregulated. In many chronic diseases, there isn’t a clear external threat, yet the immune system remains persistently active. That curiosity led me to delve into the concept of trained immunity. What drew me in was how this idea challenged traditional thinking. The notion that innate immune cells could remember past exposures and influence future responses opened an entirely new way of understanding disease. It also provided a unifying framework to explain why seemingly unrelated conditions often occur together. For me, this shift from studying isolated immune responses to exploring system-wide immune memory, made the field both intellectually exciting and highly relevant to real-world health challenges.
Q | What scientific problem are you trying to solve?
With my background in immunology, particularly in host-pathogen interactions, I felt fortunate to join a postdoctoral lab where I was introduced to a new and evolving concept in the field—one that shifted my perspective entirely. Instead of focusing on a single disease, I found myself asking a broader question: How do multiple chronic diseases arise together in the same individual? Clinical reports have long shown that people with conditions like diabetes are more likely to develop other inflammatory diseases such as cardiovascular disease or atherosclerosis. Similarly, individuals with chronic gum disease are often at higher risk of systemic conditions like arthritis. While these connections are well recognized, the biological explanation behind them has remained unclear. My research explores whether this link is driven by a process called trained immunity, where the body’s first line of defense develops a lasting memory of past inflammation. I study how this memory can reprogram immune cells at their source—the bone marrow—creating a long-term bias that drives disease across multiple organs.
Reversing Trained Immunity for Chronic Disease Prevention
Q | What’s one thing you learned from studying system-wide immune memory that you didn’t expect?
One of the most unexpected insights from my work has been realizing how central the bone marrow is to shaping long-term inflammation. I initially thought of diseases as local events, something goes wrong in one tissue and that’s where the problem stays primarily. But what I’ve learned is that inflammatory signals from one part of the body, whether from the gums, liver, heart, adipose tissue, or elsewhere, can travel to the bone marrow and reprogram the cells that will later circulate throughout the body to cause susceptibility to other comorbid conditions. It’s almost like changing the blueprint at the source. What’s even more surprising is how persistent this effect can be. Even after the original trigger is gone, the immune system can remain in this altered state, responding more aggressively than it should with the same or different stimuli. This has changed how I think about disease—not as isolated incidents, but as part of a longer, interconnected story shaped by past immune experiences.
Q | If your research succeeds, what could it change for science or society?
This research could reshape how we approach chronic inflammatory diseases. Instead of treating conditions like cardiovascular disease, arthritis, or metabolic disorders separately, we could target the underlying immune programming that connects them. By focusing on trained immunity, we may be able to develop therapies that reset harmful immune memory and restore balance across the system. This could lead to more effective treatments that address multiple conditions at once. For society, this approach has the potential to reduce the overall burden of chronic diseases, which are among the leading causes of illness worldwide. It also shifts the focus toward prevention, identifying and correcting harmful immune changes before they lead to long-term complications.
Q | What question are you most excited to answer next?
I want to know whether trained immunity can be reversed. If the immune system can develop a harmful memory that drives disease, can we “retrain” it to return to a healthier state? I’m also interested in how long these immune changes last and whether they can influence future generations. If environmental factors like diet or chronic inflammation can shape immune responses over time, they may have implications that extend beyond a single individual. Answering these questions could open up entirely new strategies for treating and preventing disease.
Responses have been edited for length and clarity.
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