There is no vaccine that can prevent S. aureus infections while making many people sick

International research – coordinated by medical microbiologist and clinical scientist András Spaan (UMC Utrecht and The Rockefeller University) – has unraveled why some people become seriously ill after infection with the infamous bacterium Staphylococcus aureus. In this groundbreaking study, now published in the journal Science, the researchers describe how a genetic disorder — called OTULIN haploinsufficiency — predisposes people to life-threatening staphylococcal disease. Using advanced techniques, the researchers unraveled the disease at the molecular level and discovered therapeutic leads.

Staphylococcus aureus is a bacteria that makes many people sick, but there is no vaccine that can prevent S. aureus infections. Resistance to commonly used antibiotics, such as methicillin-resistant S. aureus (MRSA) strains, makes treating these infections increasingly difficult. Many people carry the bacteria on their skin and in their nose without causing any problems, but in some the bacteria causes a life-threatening infection. Physicians and researchers do not understand this variability in the course of staphylococcal infections well. Researchers from UMC Utrecht and The Rockefeller University in New York (United States) have therefore set up a study to unravel why some people become seriously ill after infection with S. aureus. The scientists used a genetic approach to analyze a cohort of patients with unexplained severe staphylococcal disease. The results of this study have now been published in Science.

OTULIN gene mutations
First and corresponding author András Spaan (physician microbiologist and clinical scientist at the Department of Medical Microbiology, UMC Utrecht and at the Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University) summarizes: “In our patients with severe staphylococcal disease, we found a more than expected number of rare heterozygous mutations in a gene called OTULIN, which is located on the short arm of chromosome 5 and encodes an enzyme.Patients with this genetic defect had an increased risk of life-threatening necrosis of the skin or lungs. Their illness was usually triggered by S. aureus infections and started in adolescence.”

Haploinsufficiency
It turned out that the condition is caused by haploinsufficiency. Haploinsufficiency is the genetic term to describe a situation where one copy of a gene is inactivated or deleted and the remaining copy of the gene is insufficient to produce adequate levels of the gene product. Spaan: “We soon realized that our discovery had implications for patients with a chromosomal deletion syndrome, the 5p (or Cri-du-Chat) syndrome. The deletion of the short arm of one of their chromosomes contains 5 in most cases OTULIN, making them haploinsufficiency by definition for OTULIN. We have shown that these people are also predisposed to serious infections as a result of haploinsufficiency for OTULIN.”

Cell-intrinsic immunity
Surprisingly, the severe staph infections in the patients could not be explained by a defect in their white blood cells. The researchers found that OTULIN haploinsufficiency causes an increased sensitivity of non-white blood cells, located in the organ tissues, to the virulence factor -toxin of S. aureus. Spaan: “By studying the condition at the genetic, cellular, immunological and clinical level, we were able to establish cause and effect between this genetic defect and the infectious disease. We discovered that OTULIN regulates a key mechanism in the cell-intrinsic immunity against staphylococci in humans. Our description of an innate deficiency of cell-intrinsic immunity against a bacterial pathogen is a first”.

On the way to treatment
The team of researchers used human genetics as a compass to clarify the issue of variability in the course of staphylococcal infections. This approach has not only yielded groundbreaking scientific insights, but could also pave the way for the development of innovative and personalized anti-infectives. Spaan: “We discovered that natural antibodies, directed against the staphylococcal α toxin, can protect the cells of the patients and thereby compensate for the innate defect of their cell-intrinsic immunity. Our study therefore shows the potential of future therapies that act on bacterial toxins, to prevent or treat infections such as those caused by S. aureus.”

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