How Our Genes Predispose Us to Infection with Jean-Laurent Casanova, MD, PhD

Jean-Laurent Casanova, MD, PhD: The fact is that people are born with a mutation that predisposes them to a specific range of infections, not necessarily a single infection it may be a couple of infections, and they're completely fine until the age of 5 years or 50 years when they unfortunately encounter that specific microbe. For example, they can fend off influenza, but they cannot control COVID. Or they can control COVID and influenza, but they're gonna die of tuberculosis. 

Erin Spain, MS: Why does one person become critically ill from a virus while the person next to them exposed to the same microbe remains completely healthy? This is the Infection Enigma, and our guest today, Dr. Jean-Laurent Casanova, has spent his career trying to solve this mystery. A French pediatrician and immunologist, now at the University of Texas Southwestern Medical Center, Dr. Casanova has shifted our understanding of infectious disease from the germ to the genetics of the person who gets sick. Dr. Casanova is the winner of the 2026 Mechthild Esser Nemmers Prize in Medical Science here at Northwestern University, which carries a $350,000 stipend and is awarded to a physician-scientist whose body of research exhibits outstanding achievement in their discipline as demonstrated by works of lasting significance. We are thrilled to have Dr. Casanova on the show today to talk about his paradigm-shifting discoveries that have changed the way we think about immunity and genetic predisposition to infectious diseases. Welcome to the show. 

Jean-Laurent Casanova, MD, PhD: Thank you. Thank you for having me. 

[00:01:54] Erin Spain, MS: Well, let's take us back to the beginning, to the early days as a pediatrician in France in the 1990s. Now, there were some specific cases of children becoming ill after a tuberculosis vaccination that made you suspect a genetic explanation. Tell me about this time and how it really started your life's work into this infection Enigma. 

Jean-Laurent Casanova, MD, PhD: Well. There were in France and in the many countries that were giving BCG vaccination to newborns, uh, there were kids who developed, disseminated disease, due to the vaccine, which is innocuous in other people. And we tried to find an explanation to this, uh, condition, and we discovered mutations in genes that control gamma interferon immunity. Gamma interferon is a bit of a misnomer because it is more a macrophage activating factor than an antiviral interferon. 

Erin Spain, MS: So this was the early '90s, this started this line of research for you, and since then you've uncovered genetic causes of more than 20 severe infections: influenza, COVID-19, herpes encephalitis. So this central idea to emerge from your work is that when someone becomes seriously ill, we shouldn't just look at the germ, we should look at the genetics of the person. How radical was this idea when you first proposed it, and how has it changed how we understand infectious disease today? 

Jean-Laurent Casanova, MD, PhD: When we started, I was alone with a master's student, so we focused on, you know, a few kids with, uh, severe microbe disease and progressively the lab grew and as the team was growing, we tackled other infections one after another. And the bottom line is that for every infection that we've studied, we've discovered that affected patients—not only kids by the way, but also adults—are sick often because they carry mutations at birth that are silent until they're exposed to and infected with the microbe to which they were unfortunately predisposed to suffer from. 

Erin Spain, MS: When, when you first discovered this and it was starting to be published in journals, what was the reaction from your peers in the community? 

Jean-Laurent Casanova, MD, PhD: Well, there was skepticism because from the end of the 19th century onward, the theory that has dominated, um, medical knowledge is the germ theory, and more specifically the germ theory that's Pasteur's, and that's 1867. But in 1881, Koch came with a radical version of the germ theory. Koch proposed that microbes are necessary and sufficient for the development of disease. Pasteur had never claimed that. But what has imprinted the medical community is that the microbes are the culprits, even though it has been shown from 1900 onward that for the vast majority of microbes only a small and often a very small proportion of infected individuals develop life-threatening disease. From 1900 until 1950, uh, not the microbiologists or the immunologists, but geneticists have shown by means of classical genetics that infectious diseases are strongly driven by the germline genetic background. And our work from the early nineties onward, aimed at, identifying the molecules and the cells that are responsible for someone being admitted to an intensive care unit when, you know, a, a, a classmate or a teammate or a relative infected with the same microbe, uh, is doing fine. 

Erin Spain, MS: You've described these genetic vulnerabilities as specific holes in our immune defenses, so explain that a little more. How can someone have a hole for one specific infection, but remain completely robust against everything else? 

Jean-Laurent Casanova, MD, PhD: Yeah, that has been one of the surprises, and that also explains the skepticism. It is hard to explain why this contradicts the history of immunology, but let me try to describe the facts. The fact is that people are born with a mutation that predisposes them. A specific range of infections, not necessarily a single infection. It may be a couple of infections, and they're completely fine until the age of 5 years or 50 years when they unfortunately encounter that specific microbe. That's why, you know, it's a hole, because these patients are otherwise normally resistant to other microbes. For example, they can fend off influenza, but they cannot control COVID. Or they can control COVID and influenza, but they're gonna die of tuberculosis and so on and so forth. 

Erin Spain, MS: Is this something that is passed down inherited from parents, grandparents that changes the genome? 

Jean-Laurent Casanova, MD, PhD: So it can be inherited, the mutation, or what we call the genotype—that is, because we have two copies of most chromosomes—can be inherited, or it can be de novo—that is, it can appear in the germline of the parents who are not, uh, themselves genetically affected. 

Erin Spain, MS: Well, you mentioned COVID, so this was a great example. During the COVID-19 pandemic, we saw vast differences in clinical outcomes, and you were part of this from the beginning. Looking at the infection enigma to provide a scientific explanation for why some people were in the ICU and others barely noticed the virus. Tell me about this timeframe with the pandemic and how you were able to contribute. 

Jean-Laurent Casanova, MD, PhD: So in 2019. Just prior to the pandemic, we had, for 25 years studied the infection enigma. So when COVID-19 struck the planet, we were not surprised that 10% of people developed life-threatening pneumonia. And the remaining 90% were fine because, you know, this is. Typical. So, we decided to form an international consortium. We teamed up with colleagues in, I don't know, 30, 40, 50 countries. And in a few months we discovered mutations in the type I interferon immunity loop and autoantibodies neutralizing type I interferons as being causal, collectively, of about 15, 20% of cases of life-threatening COVID. 

Erin Spain, MS: You mentioned this international consortium. I mean, you're originally from France, but you've had your laboratory in both the US and in France for many, many years. How important are these international relationships for pushing your work forward? 

Jean-Laurent Casanova, MD, PhD: Well, international collaborations are very important for many reasons, uh, depending on the field. In our field, in the field of human genetics, molecular medicine. It is important because, hypothetically that there is in Chicago, a child with a mutation in a gene, and there's another child in Tokyo. If you only study the patients in Chicago, it's gonna be hard to even see this mutation as a candidate mutation to study further. Whereas if you're aware that in Tokyo there's another child with a mutation in the same gene, then it's like a eureka moment. You know that it might be true and you ask a student or a post-doc to devote a few weeks or a few months to try to clarify this matter. 

Erin Spain, MS: You work with human subjects all the time. Talk to me about that. Why is human genetics so important versus a laboratory model? 

Jean-Laurent Casanova, MD, PhD: Well, first of all, because, uh, humans matter more. Second, which is not a, a medical, but a scientific reason is because humans are being studied. Regularly by physicians, by practitioners, and we have a wealth of clinical information, which when understood at the molecular level, provides a depth of mechanistic understanding of diseases that cannot be achieved or is more difficult to achieve with animals bred in facilities in an institution. 

Erin Spain, MS: Your work points towards what you've called the unified genetic theory of human infectious diseases. What does that mean for how we think about infectious diseases? 

Jean-Laurent Casanova, MD, PhD: Well, what it means is that the infectious agents, the microbe, the pathogen is in our view, merely just a trigger. It is not the root cause of life-threatening disease. The root cause of disease, by definition, across conditions must be chronologically first and must mechanistically explain life or death. Right? So. If you carry a mutation at birth, and you encounter this virus or these bacteria at age 25, and you die, well then I claim that the cause of death is the mutation you had at birth. The microbe has been the trigger, like peanut is the trigger of peanut allergy. Nobody would say that the peanut causes death, right? People would say, well, is the allergy to peanuts that killed that child or that adult? Well, we see the same paradigm for infectious diseases, which we think are misnamed. 

Erin Spain, MS: Do you think we're approaching a future where a person's genome could tell us which infections pose the greatest threat to them before they ever encountered those infections? 

Jean-Laurent Casanova, MD, PhD: Yeah. That is the long term plan. Absolutely. 

Erin Spain, MS: Would it be when a baby is born you could sequence their genome? 

Jean-Laurent Casanova, MD, PhD: Yes. The genome of babies will be sequenced. I don't have a crystal ball. I don't know when that will be implemented, but in a not-too-distant future, for example, I'm certain that my children will see a world when everyone is sequenced at birth. It will happen. I can say with confidence that this is gonna happen in the next 50 years. That's inevitable. So once babies are sequenced at birth, then not only their, the threats, the infectious threats, but also other threats will be analyzed by medical teams and they will try to prevent these conditions from occurring. 

Erin Spain, MS: How are these discoveries changing patient care today? And can understanding someone's specific genetic or immunological vulnerability change the way that you diagnose or treat them? 

Jean-Laurent Casanova, MD, PhD: Yes, it does. Over the last 35 years, there's a growing number of genetic conditions affecting host defense. We refer to these conditions as inborn errors of immunity, the identification of which has had a major clinical impact to prevent infections or treat infections. Unfortunately, for some conditions, this has not led to a medical therapeutic breakthrough. You know, medical progress takes time. 

Erin Spain, MS: You've recently joined UT Southwestern and one new avenue you plan to explore is applying the same genetic lens to cancer. Do you think the enigma of why some people are more resistant to cancer is similar to infectious disease or is there a difference? 

Jean-Laurent Casanova, MD, PhD: A part of the team is pivoting to study, uh, the human genetic and immunological basis of cancer, but primarily the virus-induced cancers. That is one reason for this transition. The other is that over the last 22 years, our team and others have found that there are what we call autoimmune phenocopies of inborn errors of immunity. That is, autoantibodies, antibodies that recognize self, that mimic inborn errors of the corresponding gene product. That is, autoantibodies can underlie severe infections, and the same severe infections as patients carrying mutations in the product that is neutralized by these autoantibodies. So, that works for infections. A British team recently found that autoantibodies against another molecule can underlie an inflammatory condition, a gastrointestinal, uh, disorder. So we thought that maybe there are autoantibodies that can underlie cancer, that can aggravate cancer or prevent cancer in patients at risk. This is a hypothesis. 

Erin Spain, MS: Tell me how your lab is structured. This is an international lab. How does it work to have space both in Paris and now in Texas? 

Jean-Laurent Casanova, MD, PhD: So historically we started the lab in 1995. We were a small team in a bigger lab in Paris at the Necker Hospital for Sick Children. We became an independent lab. And in 2008 we opened a second branch of the lab at Rockefeller University in New York. And in 2026, this summer, we moved the New York lab to UT Southwestern. While we did that, I also stepped down from my role as head of lab in Paris and Vivien Béziat, a young, brilliant scientist—Vivien is the lead of, uh, the Paris branch of the Laboratory of Human Genetics of Infectious Diseases at Necker. So this whole thing, how has it been organized from the start? Well, there are scientists in charge of specific themes of research. For example, uh, scientists are in charge of viral encephalitis, another one of viral pneumonia, a third of tuberculosis, and so on and so forth. 

Erin Spain, MS: It sounds like you are really creating a pipeline of these young investigators who are coming up. How important is it to you to bring in these folks who are maybe at the beginning or middle of their careers and help you kind of take these next steps? 

Jean-Laurent Casanova, MD, PhD: Important. You know, we have trained many young scientists; many of them run their own labs all over the world. Others run clinical departments or clinical services all over the world. And locally, in the lab itself, or our former lab in Paris, in our current lab in Dallas, there are young or mid-career investigators who thrive. That brings us back to the collaboration theme that you raised at the beginning of our conversation. The best way to be collaborative outside the lab is to be educated to collaborate inside the lab, you know? It's a good culture. Once you are ingrained with the idea that you should be collaborative and inclusive in your own lab, things become much easier when it comes to collaborating with people in Tokyo or Anchorage or Buenos Aires. 

Erin Spain, MS: As you look ahead to the next decade, what do you think we're on the verge of understanding about human immunity that we don't understand today? 

Jean-Laurent Casanova, MD, PhD: I think a new frontier is understanding immunity in different tissues, different organs. For example, by studying viral encephalitis we've discovered cells and molecules that control viruses, some viruses in the human brain. Uh, but there's a lot to be discovered, in many, many organs, not as noble as the brain. You know, for example, my voice is coarse. I know that my larynx has a problem, and you know, I don't think anybody has ever studied immunity of the larynx, even though the human voice, you know, deserves it. So, you know, my call would be, you know, if there's a young ENT investigator, physician-scientist, well, you know, study immunity of the larynx. I think over the last 50 years, the number of labs led by physician-scientists has been stable, when the number of labs, research labs led by non-physicians, has grown massively. I think a problem we face is that there are not enough physician-scientists running research labs, and as a result, I'm afraid that most human conditions are not studied seriously. And I think this is a major, major problem in the global scientific endeavor. In biomedical research, I could name many, many important conditions that are simply not studied, and they're not studied because there are not enough physicians running research labs. 

Erin Spain, MS: Well, we're thrilled that you have been named the 2026 Nemmers Prize winner here at Northwestern. What does it mean to you to receive this award at this stage of your career? 

Jean-Laurent Casanova, MD, PhD: It's fantastic for at least two reasons. One is that it is a prize for physician-scientists, and I like to think that I'm a quintessential physician-scientist. And the second reason is that the previous laureates are all eminent physician-scientists whom I have always admired. So I feel privileged to be in their company. I wanna stress how grateful I am to Northwestern University and the jury of the Nemmers Prize. I'm both honored and delighted to receive this award. It's a big moment, the biggest moment in the history of my lab. 

Erin Spain, MS: Thanks for listening. Please click the bell to receive notifications about our latest episodes and follow us on social media @NUFeinbergMed to stay up to date with our latest research findings. 

Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Jean-Laurent Casanova, MD, PhD, has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.