The Infection Enigma: Why some get sick and others don’t

Paris, early 1990s. A baby girl is rushed to the ICU. Her lungs are inflamed, her liver and bone marrow are failing, and strange lesions appear across her skin and bones. Doctors are puzzled. She had seemed perfectly healthy-born at term, growing normally. Like nearly every newborn in France, she had received the BCG vaccine, designed to protect against tuberculosis. It’s a routine shot given to millions of infants around the world. Safe. Standard. Harmless – almost always.

But not this time.

“This was a perfectly normal child,” Jean-Laurent Casanova recalls. “And then suddenly, everything collapsed – lungs, liver, lymph nodes, skin. We tried everything, but nothing helped. It was devastating.”

What made the case even stranger was her family. Her two older brothers had received the same vaccine. They were completely healthy. She was dying. Despite weeks of aggressive treatment, the infection couldn’t be stopped. The girl died before her first birthday.

“Her immune profile looked normal,” Casanova remembers. “Normal T cells, B cells, immunoglobulins. All the classic markers said: this child should be able to fight infection. But clearly, she couldn’t.”

At the time, no one knew what had gone wrong. But Casanova couldn’t let go of the question. It wasn’t the vaccine that killed her – that much was clear. It was something hidden. Something deeper. Something inside.

“It felt like a riddle,” he says. “Something hiding in plain sight. Why her? Why only her? That question – it stuck with me.”

He didn’t know it then, but that single case would become the spark for a career-defining scientific journey.

“I saw it as a real enigma,” Casanova says. “And I thought – this is worth a lifetime.”

The germ theory wasn’t wrong – just incomplete

After the devastating BCG case, Jean-Laurent Casanova found himself drawn to a question that medicine seemed to have forgotten: if everyone is exposed to the same microbes, why do only a few people get severely ill?

He had trained as a paediatrician in Paris, earning his medical degree from Université Paris Descartes. But he wasn’t content with diagnosing disease – he wanted to understand its roots. So, alongside his clinical work, he dove into basic science, focusing on immunology and the logic of host defence.

“I wasn’t satisfied just treating patients,” he says. “I wanted to understand the underlying causes. That meant understanding biology – real biology, down to the molecule.”

In those early years, he often bounced between hospital shifts and lab benches – paediatrics by day, immunology by night. But the question that haunted him wasn’t in any textbook.

“Pasteur showed that microorganisms – bacteria and fungi – were the cause of diseases, and it was a revolution,” Casanova explains. “But it was only part of the story. Most people infected with a microbe recover – or never get sick at all. So, why does the same pathogen kill only a few?”

“It’s like peanut allergy,” he says. “No one says the peanut is the cause. The cause is the person’s immune system. The peanut is just the trigger. That’s how I see microbes now.”

He began to wonder if the real cause of disease was hidden inside the host – perhaps encoded in our genes.

“I always tell my students: the cause of disease precedes the infection. The virus or bacterium is just the match. The fuel is already there – in the form of a genetic or immunological weakness.”

It was a shift in perspective that would change his career – and eventually, his field.

The ignored clue from plants and twins

If the true cause of infection wasn’t just the microbe – but something hidden in the host – Casanova reasoned there must be a deeper pattern. And it turned out the idea wasn’t new. Clues had been sitting in the margins of science for over a century.

In 1905, British plant scientists showed that wheat could inherit vulnerability to fungal infection. Infected plants weren’t just unlucky – they were genetically predisposed. Similar findings followed in animals. And by the 1920s and ’30s, twin studies in humans revealed something remarkable: if one identical twin got tuberculosis or diphtheria, the other often did too.

If one identical twin got tuberculosis or diphtheria, the other often did too. This didn’t happen nearly as often in fraternal twins, where the genetic differences are greater.

“Plant geneticists proved in 1905 that infection could be a genetic disease”, Casanova says. “It’s astonishing how early this was shown – and how quickly it was forgotten.”

The message was clear: genetics shaped infection outcomes. But as microbiology advanced in the 20th century—with breakthroughs in pathogens, antibiotics, and vaccines—that early insight faded.

“That’s classical genetics. A clear signal. But microbiologists were fixated on pathogens. Immunologists on antibodies. No one wanted to believe infection could come from within.”

For Casanova, those dusty studies weren’t just history. They were an open invitation.

“For me, those old studies were not history – they were clues,” he says. “I thought: let’s bring the tools of molecular genetics to bear on this forgotten question.”

The lab built on a hunch

Yet no one had pursued the idea using the new genetic tools of modern science. So, Casanova decided to do it himself. There were no MD–PhD programs in France, so he built his own – earning a medical degree from one university while completing a PhD in immunology at another. He wanted to connect the hospital bed to the lab bench.

“I wasn’t trained to think small,” he says. “I wanted to understand disease mechanisms—at the molecular and cellular level. That meant starting with the patient and tracing backward.”

The question that gripped him was simple but radical: could a single child’s deadly infection be caused by a single mutation?

“I asked: could one mutation—in a single gene—make a child vulnerable to one infection? A gene they were born with? Harmless until the right—or wrong—microbe appears?”

He had no major funding, no large team. Just a few collaborators and a handful of mysterious cases at Necker Hospital for Sick Children in Paris. The work began late at night, between shifts, driven by instinct and frustration.

“We started very small – two or three of us, working nights, weekends. But we had a clear hypothesis, and we had patients. That’s all we needed to begin.”

“That’s how I describe our work: patient-based basic research. It’s not abstract. It’s always anchored in the real suffering of a person.”

What began as a side project would soon upend the basic assumptions of immunology – and change how medicine understands infection.

Jean-Laurent Casanova and Laurent Abel co-founded their laboratory in 1999 to uncover the genetic roots of infectious diseases—combining Casanova’s clinical insights with Abel’s expertise in epidemiology and human genetics.

The first crack in the immune armor

Casanova had set out on a hunch: that a deadly infection in a single child might be caused by a single genetic defect. But hypotheses need proof. Then it came.

He encountered two children who developed severe, disseminated infections after receiving the BCG vaccine, routinely used to protect against tuberculosis. For most children, it’s harmless. But in these cases, the infection spread throughout the body – lungs, liver, skin, bone.

Both children had appeared healthy. No known immunodeficiency. No history of chronic illness. But something had clearly failed.

“These were not immune-compromised children,” Casanova recalls. “They were healthy—until the BCG vaccine nearly killed them. That contradiction forced us to look deeper.”

His lab sequenced their DNA and found a mutation in the interferon-gamma receptor (IFN-γR1)—a key part of the immune response to mycobacterial infection.

“We found mutations in the IFN-γ receptor pathway,” he explains. “This pathway activates macrophages—immune cells that engulf and destroy bacteria like mycobacteria. Without that signal, the defense collapses.”

It was the first time a single-gene mutation had been shown to cause a specific infection in an otherwise healthy child.

“This wasn’t just a rare case – it was proof-of-concept. We showed you could go from patient to gene to pathway. And from there, to therapy.”

The discovery didn’t just confirm a theory – it launched a new way of thinking about infection, vulnerability, and the genome.

Mapping the hidden genome of infection

The discovery of the interferon-gamma receptor mutation was only the beginning. If one gene could explain one infection, Casanova reasoned, there had to be others – hidden defects, silently waiting for the right microbe to reveal them.

So, his lab expanded the search. Patient by patient, they uncovered a new category of disease: inborn errors of immunity that don’t destroy the entire immune system, but instead create highly specific vulnerabilities.

“Most people think of inborn errors of immunity as rare disorders – kids who get sick all the time,” Casanova says. “But we found something different: healthy children who get very sick from one infection.”

Over the years, Casanova and his collaborators discovered more than 60 such genetic diseases, many involving single-gene mutations that disrupt distinct immune pathways. Each one revealed a new crack in the body’s defence.

“Many of them are caused by single-gene mutations,” he explains. “We don’t just look for missing immune cells – we look for subtle holes in specific pathways.”

Some of these disorders follow clear inheritance patterns—what Casanova calls Mendelian infections. Others appear sporadically, caused by newly acquired mutations or genetic quirks that stay silent until the wrong pathogen strikes. Sometimes, these mutations don’t cause disease in everyone who carries them—whether they show up can depend on other genes, environmental triggers, or chance.

“Even in sporadic cases, you often find a mutation with incomplete penetrance,” he says. “It’s there, just waiting.”

This work challenged medical orthodoxy. Infections once seen as bad luck – like tuberculosis or herpes encephalitis – could now be traced to specific genetic flaws.

“This overturned the old paradigm,” Casanova says. “Inborn errors don’t just cause opportunistic infections – they can cause common infections in a rare subset of people.”

COVID and the autoantibody surprise

By the late 2010s, Casanova’s lab had shown that many severe infections were rooted in silent genetic vulnerabilities—some inherited, some arising spontaneously. Then came COVID-19, caused by the SARS-CoV-2 virus.

As the virus swept the globe, one of the most puzzling patterns emerged: its radical selectivity. While many people had mild or no symptoms, others – often previously healthy – spiralled into respiratory failure. Casanova recognised a familiar signal.

“From the very beginning, I was asking: why do some people die while others don’t even know they’re infected?” he says.

In March 2020, he launched the COVID Human Genetic Effort, a global initiative to sequence the genomes of patients with life-threatening COVID. The first discovery confirmed his hypothesis.

“In April 2020, we identified mutations in type I interferon pathways in patients with severe COVID pneumonia,” he explains. “These interferons are the body’s fire alarm against viruses. Without them, the virus spreads unchecked.”

But what came next was even more unexpected: many severely ill patients had no mutations. Instead, their immune systems had mistakenly turned on themselves.

“The real shock came when we found autoantibodies – produced by the body itself – that block type I interferon,” Casanova says. “They were present in at least 15% of critical COVID cases, and in 20% of deaths.”

“It was astonishing. These people looked healthy. But they carried a silent, self-inflicted weakness – until COVID revealed it.”

These autoantibodies were especially common in older men – explaining much of the pandemic’s age bias.

“Five percent of people over 70 carry them,” Casanova says. “That’s more than 100 million people worldwide.”

“That discovery, in my view, is one of the most important in the history of infectious disease.”

From diagnosis to treatment

When COVID exposed hidden weaknesses in the immune system, Casanova’s discoveries quickly moved from lab benches to hospital wards. The same logic that explained why some people became critically ill also opened the door to new ways of treating them – or even preventing disease altogether.

For patients with genetic mutations – like those missing a functional interferon-gamma receptor – the treatment could be as specific as the defect itself.

“We’re not just discovering genes – we’re changing medicine,” Casanova says. “If you know a child has a mutation in the interferon-gamma pathway, you can treat them with gamma interferon. That can prevent or even cure the disease.”

During the pandemic, the team’s discovery of autoantibodies against interferon led to immediate clinical strategies. If the immune system was blocking its own defences, the answer was to replace them – with plasma from recovered patients or monoclonal antibodies.

“In COVID, once we found the autoantibodies, we could recommend passive immunization – using plasma from people who recovered,” he says. “Or we could say: vaccinate the elderly first, because they’re the ones at risk.”

The larger implication was just as important. Casanova’s work had made it possible to predict and stratify risk – something that was once unimaginable in infectious disease. With genetic sequencing and antibody screening, doctors could finally see the invisible cracks before they shattered.

“Diagnostics are now more precise. We can screen for gene mutations or autoantibodies and offer personalised risk assessment. That wasn’t possible before.”

“That’s the whole point,” Casanova says. “Not just understanding disease – but preventing it. Or treating it before it becomes catastrophic.”

A paradigm shift still in progress

Casanova’s discoveries have changed diagnosis and treatment. But changing minds? That’s been harder.

In medicine and microbiology, the microbe still reigns as the central cause of infectious disease. The idea that disease might instead begin with a host’s hidden vulnerability – that it’s the person, not just the pathogen – remains a minority view, even after decades of mounting evidence.

“Most microbiologists still say: the microbe causes the disease. And I understand that,” Casanova says. “It’s how we’ve been taught. But the data say otherwise.”

Convincing the field requires more than publishing papers. It means asking clinicians and researchers to reframe their basic assumptions – something science is famously slow to do.

“We’ve shown over and over that for many infectious diseases – common or rare – the microbe is necessary but not sufficient,” he explains. “The real cause is in the host.”

At conferences and in journals, Casanova still hears the same scepticism: These are rare cases. Exceptions. Anecdotes. But his answer is always the same.

“People still think: oh, these are exceptions. But after 30 years of so-called exceptions, at some point it becomes clear – it’s a general rule.”

The resistance isn’t scientific, he believes. It’s historical. Pasteur’s germ theory was so transformative that it became the endpoint, rather than a stepping stone. And that’s the challenge Casanova now faces – not disproving the past, but expanding it.

“We’re still riding the wave of Pasteur’s tsunami,” he says. “He was right, but the world stopped there. The next step is understanding why some people die from infection and others don’t. And that answer is in the genome.”

From one patient to the world

While many researchers build their studies around microbes or model organisms, Casanova starts somewhere else entirely – with a single patient whose illness can’t be explained. Often, it’s a previously healthy child suddenly struck by a severe infection. No warning. No known risk factors. But for Casanova, that’s not a dead end – it’s a signal.

“Everything begins with the patient. Always,” he says. “We don’t chase microbes in isolation. We start with a person – with their infection, their story – and ask: what failed inside them?”

This approach, now central to his lab, is known as patient-based basic research. Instead of starting in a petri dish or animal model, Casanova works backward from human biology – using the patient as a window into the immune system.

“From the patient, we find the gene. From the gene, the pathway. From the pathway, the mechanism. And sometimes, from the mechanism, a therapy.”

It’s a loop of discovery: a rare case reveals a mutation, the mutation points to a previously unknown vulnerability, and that insight leads to targeted diagnostics and treatments.

“We don’t invent models in mice or petri dishes,” he says. “The model is the human being.”

The method has caught on. Over the years, Casanova has built a global network of clinicians who send him puzzling cases – patients who don’t fit the textbook. Together, they’ve traced new immunological pathways and redefined how infection risk is understood.

“We’ve collaborated with physicians in nearly 100 countries,” he says. “It’s one of the most rewarding aspects of this work – building a network of clinicians and scientists all chasing the same question.”

A global lab built on rare cases

Today, Casanova’s laboratory spans two continents – with one laboratory at Necker Hospital in Paris and another at Rockefeller University in New York, where Casanova was recruited in 2008. Together, they form a unified team of more than 60 researchers and a wide network of global collaborators. But the core approach remains unchanged.

“It started with a few of us in Paris, working nights and weekends,” Casanova says. “Now we’re 30 in Paris and 30 in New York. But the method is still the same.”

Each case begins with a patient and a mystery. The condition might be rare, but the insights often are not. One thread can lead to a previously unknown gene, a new category of disease – or, as during COVID-19, a discovery that changes global health strategies.

“We pull on a thread – one patient, one infection – and it unravels into a whole network of understanding,” he explains. “Sometimes the thread leads to millions of people. COVID proved that.”

Casanova’s legacy extends beyond discovery. He’s training a new generation of physician-scientists to ask the same deep questions – and to follow patients all the way to mechanism and treatment.

“I’m proud of the science, but I’m just as proud of the people we’ve trained,” he says. “This is a long game. We need 100 more physician-scientists asking these questions. If we can train the next generation to think this way – to think from patient to pathway – we can solve most of infectious disease.”

The future of infection

As Casanova’s laboratory grows and the method spreads, the number of questions also rises. There are more than 3,000 known infectious diseases. For most of them, we still don’t understand why one person survives while another does not. That uncertainty leaves millions vulnerable – and prevents medicine from seeing the deeper logic behind disease.

Casanova believes the tools to solve this mystery now exist. What’s needed is scale. More scientists, more sequencing, more collaboration. The next step is not just to explain rare cases, but to make host-based precision medicine a routine part of infectious disease care.

“We’ve only scratched the surface,” Casanova says. “For the vast majority of infectious diseases, we don’t know the human genetic and immunological determinants. But we now know how to find them.”

The goal isn’t to replace the germ theory – but to complete it. Understanding who gets sick, and why, is the unfinished half of the infection puzzle.

“I often say: Pasteur explained what causes infection,” he says. “We’re explaining who gets sick – and why. That’s the next revolution.”

Looking ahead, Casanova sees his life’s work not as a conclusion but a blueprint – one that future generations will have to scale up and carry forward.

“The next 30 years will be about scale. We need to train more scientists. Build more collaborations. Use sequencing, immunology, and systems biology to understand every infection.”

Because the next pandemic will come. And Casanova believes that the most powerful form of preparedness isn’t just a vaccine – it’s knowledge.

“Our goal is simple. When the next pandemic comes – and it will – we want to be ready,” he says. “Not just with a vaccine, but with knowledge of who is at risk, and how we can protect them.”