The genetic underpinnings of severe staph infections

20 May 2022

In a large collaborative effort, an international team of researchers describes a genetic mutation that predisposes individuals to severe staphylococcus infections. The research, which includes key contributions from Leuven, appears in the latest edition of Science.

A Staphylococcus aureus infection is usually harmless, but in rare cases people do get life-threatening illnesses. A new study links this to abnormalities in the OTULIN gene. (Image: Rockefeller University)

Staphylococcus aureus is usually harmless. Many of us host colonies of this bacterium in our noses and on our skin without suffering more than the occasional rash. But some strains of staph—particularly MRSA—can turn deadly, leading to pneumonia and sepsis that claims 20,000 lives in the U.S. each year. Now a new study describes a mutation that predisposes some individuals to severe staph infection.

Genetic defect

The research, published in Science, describes a mutation in the OTULIN gene in patients who suffer life-threatening staph infections. “In a collaborative effort, several unrelated patients were identified with identical severe clinical presentations and we found a common genetic cause of the disease”, says Dr. Frederik Staels, MD, and PhD student at UZ Leuven and KU Leuven.

"We have characterized severe Staphylococcus aureus infection at the genetic, cellular, immunological, and clinical levels," says Dr. András Spaan, a clinical microbiologist working at Utrecht University and The Rockefeller University, who was one of the coordinators of this large international effort. "By integrating these levels, we have been able to establish causality and provide clues for future pharmaceutical interventions."

Key pieces of the puzzle were provided by families treated by Leuven doctors Isabelle Meyts, Rik Schrijvers, and Carine Wouters, who were investigated by Leuven researchers Stephanie Humblet-Baron and Adrian Liston.

The study indicated that about 30 percent of people with this OTULIN mutation are at risk for developing severe disease. This risk was reduced in patients that had acquired specific anti-staph antibodies, while patients without such neutralizing antibodies remained at very high risk of developing severe infections.

“This work highlights again that extreme manifestations of infection or inflammation are seldom or never a case of bad luck, even in adults,” says Prof. Dr. Isabelle Meyts, pediatric immunologist at UZ Leuven. The work also sheds light on the underlying cause of inflammation in patients with Cri-du-Chat syndrome, a rare genetic disorder affecting 1 in 50,000 newborns. “People with this syndrome are missing one copy of the gene. Our new findings suggests that they are similarly predisposed to severe consequences of Staphylococcus infections.”

"Studies on these disorders can act as a compass," Prof. Humblet-Baron says. “It brings new mechanistic insights about the interaction between hosts and pathogens, which can also benefit the general population with better understanding about staph infection pathogenesis.”

“From a clinical point of view, this work is of great relevance to physicians confronted with patients manifesting severe, life-threatening episodes of skin and/or lung inflammation, necessitating prompt recognition and treatment,” says Prof. Dr. Carine Wouters, pediatric rheumatologist at UZ Leuven.

Last edit: 20 May 2022