In:
Science, American Association for the Advancement of Science (AAAS), Vol. 376, No. 6599 ( 2022-06-17)
Abstract:
Staphylococcus aureus is a bacterial pathogen with a global impact on human health. Most individuals carry S. aureu s on their skin and in their nostrils, but a minority develop life-threatening staphylococcal disease. The molecular basis of interindividual clinical variability upon exposure to and infection with S. aureus is unclear. Inherited or acquired disorders affecting innate, myeloid immunity confer a predisposition to staphylococcal disease but account for only a small proportion of cases. Most cases of severe staphylococcal disease remain unexplained. RATIONALE Single-gene inborn errors of immunity are being implicated in a growing number of life-threatening infectious diseases. We performed a genome-wide study to identify the human genetic determinants of severe staphylococcal disease. We tested for genetic homogeneity in a cohort of patients with unexplained life-threatening staphylococcal disease by searching for variant enrichment in the exomes of 105 cases and 1274 controls. We considered rare variants and tested an autosomal dominant mode of inheritance with incomplete penetrance. RESULTS We found enrichment for heterozygous OTULIN variants in patients with severe staphylococcal disease. OTULIN is a linear deubiquitinase and negative regulator of nuclear factor κB (NF-κB) signaling encoded by a gene on chromosome 5p. Biallelic OTULIN mutations cause an early-onset autoinflammatory condition called OTULIN-related autoinflammatory syndrome (ORAS). Probands heterozygous for deleterious OTULIN variants suffered from life-threatening skin or pulmonary necrosis. Their disease was typically triggered by S. aureus infection and occurred from adolescence onward. Clinically, penetrance was incomplete, and expressivity was variable. The dominance mechanism was haploinsufficiency, which 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 tumor necrosis factor (TNF) receptor–mediated NF-κB signaling remained intact. Through cross-talk with CYLD, OTULIN haploinsufficiency caused the accumulation of caveolin-1 complexes modified with lysine-63–linked polyubiquitin (K63-Ub) chains. Caveolin-1 accumulation in the patients’ dermal fibroblasts, but not leukocytes, enhanced the cytotoxicity of the staphylococcal virulence factor α-toxin. Upon α-toxin binding to its receptor, disintegrin and metalloprotease domain–containing protein 10 (ADAM10), the receptor was retained at the cell surface, enhancing cytotoxicity in the patients’ dermal fibroblasts. Impaired cell-intrinsic immunity to α-toxin owing to OTULIN haploinsufficiency was rescued by α-toxin–neutralizing antibodies. CONCLUSION By disrupting cell-intrinsic immunity to α-toxin in fibroblasts and, perhaps, other nonleukocytic cells, human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease of the skin and lungs.Naturally elicited α-toxin–neutralizing antibodies in heterozygotes may contribute to incomplete clinical penetrance. The study of OTULIN haploinsufficiency, a rare inborn error of immunity, helped clarify a phenotype seen in individuals with 5p− syndrome, a more common chromosomal abnormality. OTULIN haploinsufficiency is characterized by skin and pulmonary necrosis after S. aureus infection. The disorder is phenocopied in patients with 5p −syndrome. The cytotoxic damage to fibroblasts inflicted by the staphylococcal α-toxin is facilitated by caveolin-1 accumulation and ADAM10 retention at the cell surface. OTULIN haploinsufficiency is rescued by naturally elicited α-toxin–neutralizing antibodies. Autoinflammation in biallelic OTULIN deficiency is driven by excessive NF-κB activation in myeloid cells. WT, wild-type allele; MT, mutant allele; del, deletion; LUBAC, linear ubiquitin assembly complex; M1-Ub, M1-linked ubiquitin.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abm6380
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2022
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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