# Autosomal dominant OTULIN deficiency and staphylococcal disease

> **NIH NIH R21** · ROCKEFELLER UNIVERSITY · 2022 · $254,250

## Abstract

PROJECT SUMMARY
Staphylococcus aureus is a major bacterial pathogen impacting human health. Yet, while most subjects carry S.
aureus, only a minority develop life-threatening staphylococcal disease. We hypothesize that severe or recurrent
staphylococcal infections, at least in some patients, can result from single-gene inborn errors of immunity (IEI).
We have already shown that IEIs in NF-kB- and TLR2-related genes predispose to staphylococcal infections. As
a basis for this project, a cohort of 100 children and young adults with severe or recurrent S. aureus infections
has been analyzed genetically using whole exome sequencing (WES), which has been pioneered in the lab for
IEIs. Searching for candidate genotypes in a genome-wide manner, by testing various genetic models, we
discovered heterozygous rare non-synonymous variants in OTULIN in 7 patients from 6 kindreds. OTULIN, a
deubiquitinase, is known to regulate inflammation but not to govern anti-staphylococcal immunity. Bi-allelic
deleterious variants in OTULIN cause a severe early-onset condition termed OTULIN-related autoinflammatory
syndrome (ORAS). Interestingly, OTULIN is located on the short arm of the chromosome 5 and is often deleted
in the 5p- (Cri-du-Chat) Syndrome, a genetic disease with a prevalence of 1/30,000. Patients with 5p- Syndrome
are susceptible to bacterial infections. We hypothesize that autosomal dominant OTULIN deficiency operates by
haploinsufficiency and underlies staphylococcal disease. Preliminary results show that the 6 patients’ alleles are
loss-of-function and that expression of OTULIN in dermal fibroblasts from 4 patients carrying heterozygous
OTULIN variants and from 1 patient with 5p- Syndrome (with a missing copy of OTULIN) is about half, when
compared with healthy controls. Moreover, accumulation of linear ubiquitin chains was observed in dermal
fibroblasts from 3 patients, including one with the 5p- Syndrome. Finally, we noticed an accumulation of Caveolin,
which is known to facilitate recruitment of ADAM10, the receptor for the major staphylococcal virulence factor a-
hemolysin. Consistently, we observed a high and selective susceptibility of patients’ fibroblasts to a-hemolysin
cytotoxicity. The aim of the present application is therefore to explore in more depth the specific role of OTULIN
in fibroblasts and monocytes from patients heterozygous for deleterious variants in OTULIN. We will investigate
the impact of OTULIN on the linear ubiquitinome in dermal fibroblasts, with a special emphasis on NF-kB and
markers of inflammation downstream TLR2 using transcriptomic and proteomics approaches. We will also
investigate the innate immune responses in patients’ leukocyte subsets. Finally, we will investigate the intrinsic
immunity of patients to bacterial toxins, including a-hemolysin, in the context of Caveolin dysregulation and
ADAM10 expression. Overall, this study will give weight to the emerging notion that bacterial infection can
preferentially trigger...

## Key facts

- **NIH application ID:** 10373489
- **Project number:** 1R21AI159728-01A1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Bertrand Boisson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $254,250
- **Award type:** 1
- **Project period:** 2022-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373489

## Citation

> US National Institutes of Health, RePORTER application 10373489, Autosomal dominant OTULIN deficiency and staphylococcal disease (1R21AI159728-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10373489. Licensed CC0.

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