Presenter of 1 Presentation
HUMAN OTULIN HAPLOINSUFFICIENCY IMPAIRS CELL-INTRINSIC IMMUNITY TO STAPHYLOCOCCAL ΑLPHA-TOXIN
Abstract
Background and Aims
Staphylococcus aureus is a major bacterial pathogen with a global impact on human health. The molecular basis of interindividual clinical variability upon exposure to and infection with S. aureus is unclear. Most cases of severe staphylococcal disease remain unexplained.
Methods
We aimed to discover human genetic and immunological determinants of severe staphylococcal disease in a genome-wide manner. We tested for genetic homogeneity in a cohort of patients with unexplained life-threatening staphylococcal disease in the exomes of 105 cases and 1,274 controls.
Results
We found enrichment for rare heterozygous OTULIN variants in patients with severe staphylococcal disease. OTULIN is a linear deubiquitinase and negative regulator of NF-κB-signaling encoded by a gene on chromosome 5p. Probands heterozygous for deleterious OTULIN variants suffered from episodes of life-threatening skin or pulmonary necrosis. Their disease was typically triggered by S. aureus infections. Haploinsufficiency was the mechanism of dominance and was both biochemically and clinically phenocopied in patients with the more common 5p- (Cri-du-Chat) chromosomal deletion syndrome. Blood leukocyte subsets were developmentally and functionally unaffected. In dermal fibroblasts, OTULIN haploinsufficiency increased the levels of linear ubiquitin, but TNF-receptor NF-κB-signaling remained intact. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts — but not leukocytes — facilitated the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contributed to incomplete clinical penetrance.
Conclusions
By disrupting cell-intrinsic immunity to α-toxin in fibroblasts, human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease of the skin and lungs.