Our Research

Mild infections caused by Staphylococcus aureus and Group A Streptococcus (also known as Streptococcus pyogenes) are the rule, but only a small minority of otherwise healthy people develops severe, life-threatening and invasive infections. The molecular basis of clinical variability upon infections with S. aureus and Group A Streptococcus are unclear. The pathogens cause life-threatening disease in humans only. S. aureus and Group A Streptococcus employ an arsenal of virulence factors to cause disease in a human-specific manner. The molecular underpinnings of the human specific host-pathogen interactions remain incompletely understood. One driver of severe infectious diseases in humans is the individual’s genetic makeup. Single-gene inborn errors of immunity are a heterogeneous group of genetic disorders. These causative genetic defects explain, at the molecular level, the interindividual variability in the course of a growing number of infections. We hypothesize that single-gene defects of human antistaphylococcal or anti streptococcal immunity increase an individual’s susceptibility to distinct staphylococcal or streptococcal virulence factors, thereby underlying their life-threatening infections.

 

Our landmark paper (Spaan et al., Science, 2022) showcases the analytical and experimental strategy we have developed to integrate the studies of human genetics and host-pathogen interactions. Building on our previously established expertise in the field of microbial toxins, we discovered a single-gene inborn error of immunity that selectively predisposes to the detrimental effects of a major staphylococcal toxin. The deficiency, named OTULIN haploinsufficiency, is phenocopied in individuals with 5p- syndrome, a chromosomal deletion syndrome encompassing OTULIN. Human OTULIN haploinsufficiency causes the accumulation of caveolin in non-hematopoietic cells, which increases the susceptibility of these cells to the staphylococcal pore-forming toxin alpha-toxin. The disorder, clinically manifested by necrosis of the skin and lungs, is the first known defect of non-hematopoietic cell-intrinsic immunity to a bacterial infection. The work is a proof of concept for our original approach: it has delivered the discovery of a crucial pathway of immunity against a human-specific bacterial pathogen. By integrating microbiology and immunology with human genetics, our search for inborn errors of immunity serves as a compass for the clarification of human-specific host-pathogen interactions.

 

Yet, OTULIN haploinsufficiency collectively explains only a few patients with severe staphylococcal infections. With the help of our funders, we are now able to take this challenge to the next level by searching for other, yet unknown, inborn errors of antistaphylococcal immunity.​ To date, and in contrast to S. aureus , no inborn errors of immunity are known to specifically underlie invasive Group A Streptococcal infections. We have recently launched an exciting program to discover inborn errors of human antistreptococcal immunity. By combining our clinical expertise with fundamental scientific approaches, we aim to establish causality between the individual genetic make-up of our real-world patients and the interactions with their pathogens.