Michael Levin had just started working as a paediatric infectious-disease doctor in London when he received an urgent call from a hospital in Malta. It was the early 1980s, and a young boy had been brought in with symptoms of a severe infection that was spreading through his body, damaging multiple organs and tissues. But his doctors could find no trace of a pathogen.
The ghost of influenza past and the hunt for a universal vaccine
The boy was flown to Levin’s hospital for further tests. To the surprise of Levin and his colleagues, the culprit was a common bacterium: Mycobacterium fortuitum, which lives in water and soil, and is usually harmless. “Everyone’s exposed to them, but almost no one gets ill,” says Levin, who is now at Imperial College London. Despite aggressive treatment, the boy eventually passed away.
This case illustrates a question that has plagued doctors for decades: why do some people become severely ill from infections that leave others unscathed? What is it about some people’s immune systems that makes them susceptible? And how might these variations affect how doctors try to prevent or treat disease?
As it turned out, the boy from Malta had a brother and a cousin who had also fallen severely ill with mycobacteria infections. After years of searching, Levin and his colleagues eventually identified what made these children so sick: a genetic mutation affecting a receptor for interferon-γ, an immune molecule with myriad functions, including regulating inflammation1. Not long after that, a group in France discovered that similar mutations were responsible for rare cases of severe disease caused by another mycobacterial species — this time, a weakened form used as a tuberculosis vaccine2.
Researchers have since amassed a broad library of mutations in hundreds of genes that underlie ‘inborn errors of immunity’ (IEIs) and that make millions of people around the world susceptible to a wide range of infectious diseases and immune-linked ailments that many people can simply shrug off.
It might seem obvious that differences in each person’s immune system can affect how well they fight off pathogens. But uncovering the specific causes of this variation has enabled researchers to find ways to treat — and even prevent — severe infections that used to seem like random cases of bad luck, says Isabelle Meyts, an oncologist and immunologist who studies IEIs at the university KU Leuven in Belgium.
The discoveries have already begun to change clinical practice, for instance allowing doctors to genetically screen people for relevant mutations or supplement missing immune factors. And scientists are continuing to piece together the many ways in which genetic factors contribute to infectious diseases — especially in life-threatening cases. “What we’re realizing more and more is that there are probably inherited factors that predict who’s going to have severe reactions,” says Michael Abers, a physician-scientist studying infectious disease at Montefiore Einstein in New York City.
From germ to host
The germ theory of disease, popularized by Louis Pasteur in the nineteenth century, was revolutionary. The realization that microorganisms, invisible to the naked eye, could make people ill spurred public-health measures such as better hygiene, vaccines and anti-microbial drugs, which drastically improved outcomes for people with infectious diseases.
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