How Jean-Laurent Casanova Revolutionized Immunology
The solution to one of medicine's oldest enigmas lies not in the power of pathogens, but in the unique blueprint of our own genes.
For centuries, the prevailing wisdom in medicine held that the severity of an infection depended primarily on the virulence of the microbe and the dose of exposure. This explanation seemed logical—more dangerous germs caused more severe disease. Yet, this paradigm failed to explain a common observation in clinics worldwide: why, when exposed to the same pathogen under similar conditions, does one child develop a life-threatening illness while others experience mild symptoms or no disease at all?
This fundamental question—what pioneering immunologist Jean-Laurent Casanova calls "the infection enigma"—has defined his life's work 2 . His groundbreaking research, honored with the 2016 ASCI/Stanley J. Korsmeyer Award, has fundamentally reshaped our understanding of infectious diseases by revealing a powerful truth: our genes play a crucial role in determining who gets sick and who remains healthy 1 7 .
Genes identified that affect infection susceptibility
Of severe COVID-19 cases linked to autoantibodies
Casanova's journey into the heart of this enigma began not in the laboratory, but during his pediatric training in intensive care units. "As a young paediatrician, I saw children die from infections in intensive care units," he recalls. "That made me realise that infection was the biggest problem in paediatrics. I wanted to understand why some children got severely ill while others did not" 2 .
This clinical experience drove him to pursue dual training in medicine and science, earning both MD and PhD degrees simultaneously—an unusual path in France at the time 1 . This combination of clinical insight and scientific rigor prepared him to tackle the infection problem from a novel angle.
Casanova's work demonstrated that single-gene mutations could create "holes" in the immune system of otherwise healthy children, making them susceptible to specific infectious diseases while maintaining resistance to others 7 8 . This discovery was particularly significant because it challenged the dominant paradigm that single-gene immunodeficiencies were invariably rare and would only appear in patients with numerous infections 8 .
Through his research spanning more than three decades, Casanova and his team have identified over 70 genes that, when mutated, impair the body's ability to fight off specific infections 2 .
One of Casanova's early landmark investigations illustrates this paradigm beautifully. The case involved children who developed severe, life-threatening infections from the BCG vaccine—a live but weakened bacterial strain used to protect against tuberculosis that rarely causes problems in most recipients 1 .
The investigation began with a simple but crucial observation: a child developed a severe, idiopathic (without known cause) infection following BCG vaccination 1 . This was puzzling because the vast majority of children handle the vaccine without issue.
Casanova suspected a genetic origin due to the "lack of an alternative, plausible, and testable hypothesis" 1 . He postulated that a hidden inborn error of immunity might be responsible.
The research expanded to study a kindred (family group) where one child had developed disseminated BCG infection, while a sibling who had not received the BCG vaccine developed clinical tuberculosis .
The team tested cellular response to interferon-gamma (IFN-γ)—a crucial immune signaling molecule. They discovered that cells from the affected siblings showed a blunted response compared to normal cells .
Through molecular investigation, they identified a homozygous missense IFNγR1 mutation—a specific genetic error in the interferon-gamma receptor gene .
The team confirmed the mutation's pathogenic role through molecular complementation, definitively linking the genetic error to the immune dysfunction .
The investigation yielded crucial insights with profound clinical implications:
| Aspect | Complete IFNγR1 Deficiency | Partial IFNγR1 Deficiency |
|---|---|---|
| Cellular Response to IFN-γ | No response even to high concentrations (10,000 IU/ml) | Response only to high concentrations |
| BCG Infection Characteristics | Fatal, lepromatoid granulomas | Curable, tuberculoid granulomas |
| Response to IFN-γ Therapy | No benefit | Beneficial |
| Clinical Outcome | Fatal without intervention | Treatable with antimicrobials |
Table 1: Comparing Complete vs. Partial Interferon-Gamma Receptor Deficiency
This case demonstrated for the first time that partial genetic defects could cause susceptibility to specific infections, opening new avenues for diagnosis and treatment . It exemplified Casanova's core principle: by studying rare patients with unusual susceptibility, we can uncover biological mechanisms with broad implications.
Casanova's groundbreaking work relies on a sophisticated array of research tools and methodologies that bridge clinical observation with laboratory science.
| Research Tool | Function and Application |
|---|---|
| Genetic Sequencing | Identifying rare mutations in patients with unusual infection susceptibility |
| Cellular Immune Assays | Testing functional response to immune signals like interferons |
| Molecular Complementation | Validating that specific genetic errors cause immune dysfunction |
| Population Studies | Determining if discovered genetic variants affect broader populations |
| Autoantibody Detection | Identifying harmful antibodies that block critical immune functions |
Table 2: Essential Research Tools in Human Genetics of Infectious Diseases
This multidisciplinary approach has allowed Casanova's team to move seamlessly from bedside observations to laboratory discoveries and back to patient treatments, creating a virtuous cycle of scientific discovery and clinical application.
The true test of Casanova's genetic theory came during the COVID-19 pandemic. His team led the COVID Human Genetic Effort, building on their previous discoveries about influenza susceptibility 8 . What they found would reshape our understanding of severe viral disease.
The research revealed that approximately 15% of severe COVID-19 cases and 20% of COVID-19 deaths could be attributed to "bad" antibodies—autoantibodies that attack the body's own immune system by blocking type I interferons 2 9 .
These autoantibodies effectively disarmed a crucial first-line defense against the virus, leaving patients vulnerable to severe disease.
| Condition | Genetic Cause | Autoimmune Cause | Key Pathogens |
|---|---|---|---|
| Severe Mycobacterial Disease | Mutations in IFN-γ receptor or related pathway genes | Not applicable | BCG vaccine, environmental mycobacteria |
| Critical Influenza | Inborn errors of type I interferon production | Autoantibodies against type I interferons | Influenza virus |
| Critical COVID-19 | Inborn errors of type I interferon immunity | Autoantibodies against type I interferons (15% of severe cases) | SARS-CoV-2 |
| Severe West Nile Virus | Not specified in results | Autoantibodies against type I interferons (up to 40% of severe cases) | West Nile virus |
Table 3: Genetic and Autoimmune Causes of Severe Infection Susceptibility
This discovery had immediate clinical relevance: patients could be screened for these autoantibodies, and those who tested positive might benefit from interferon therapy or plasma exchange to remove the harmful antibodies 2 . The finding also extended beyond COVID-19, with similar autoantibodies explaining nearly 40% of severe cases of influenza and West Nile virus infection 9 .
The American Society for Clinical Investigation honored Casanova with the 2016 Stanley J. Korsmeyer Award for his transformative contributions to medicine 7 . This recognition highlighted not only his scientific discoveries but also his role as a mentor to young physician-scientists—a dual commitment to advancing both knowledge and the next generation of researchers 7 .
His work has continued to garner recognition, including most recently the 2025 Novo Nordisk Prize, further cementing his legacy as a pioneer who reshaped our understanding of infectious disease 2 .
Jean-Laurent Casanova's work has fundamentally rewritten the textbook on infectious diseases, demonstrating that severe infection often results from an interaction between pathogen and individual genetic makeup. His research provides a powerful framework for what he calls "infection enigma"—the puzzling variation in how different people respond to the same microbes 2 .
The clinical implications are profound: genetic testing can now identify vulnerable individuals before they become seriously ill, enabling personalized prevention strategies. For those already affected, understanding the genetic basis of their susceptibility allows for targeted treatments, such as interferon therapy for those with specific deficiencies 2 8 .
Perhaps most importantly, Casanova's work reminds us that scientific revolutions often begin with careful observation of individual cases rather than large-scale population studies. As he notes, "physiology and pathology operate at the level of single individuals" 1 . By focusing on the unique biological stories of rare patients, he has uncovered truths that illuminate why we all get sick—and how we might stay well.