Oral Presentation Lorne Infection and Immunity 2020

STING-associated vasculopathy with onset in infancy (SAVI) caused by the point mutation Arg284Ser in STING (#19)

Katherine R Balka 1 2 , Rohit G Saldanha 3 4 , Sophia Davidson 2 , Brynn K Wainstein 3 4 , Melanie Wong 5 , Rebecca Macintosh 6 , Christine K Loo 7 , Martin A Weber 7 8 , Vasanth Kamath 7 , Fiona Moghaddas 2 , Dominic De Nardo 1 2 , Paul E Gray 3 4 , Seth L Masters 2
  1. Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
  2. Inflammation Division, Walter and Eliza Hall Institute of Medical Research , Parkville , VIC, Australia
  3. Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide , South Australia, Australia
  4. School of Women and Children’s Health, University of New South Wales,, Sydney, NSW, Australia
  5. Children's Hospital at Westmead, Sydney, NSW, Australia
  6. Department of Medical Genetics, Sydney Children’s Hospital, Sydney, VIC, Australia
  7. Department of Anatomical Pathology, Prince of Wales Hospital, Sydney, NSW, Australia
  8. School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia

The cGAS-STING pathway is important for promoting an innate immune response against cytosolic microbial and/or endogenous double-stranded DNA (dsDNA). Stimulation of cGAS-STING induces the activation of interferon regulatory factor 3 (IRF3) and NF-kB leading to production of type I interferons (IFNs) and inflammatory cytokines. Aberrant STING activation is implicated in the pathology of multiple inflammatory diseases. Mutations in TMEM173, the gene encoding STING, have been shown to cause an autoinflammatory condition termed STING-associated vasculopathy with onset in infancy (SAVI), where overactive STING promotes constitutive inflammation. SAVI patients present early in life and are characterised by cutaneous vasculopathy and lung disease, amongst other pathologies.

 

We identified a child initially presenting with Pneumocystis jirovecii infection, who continued to suffer long-term with failure to thrive, global developmental delay, cutaneous lesions, frequent vomiting and life-threatening pulmonary hypertension. Whole genome sequencing (WGS) was undertaken to determine the underlying genetic cause for the condition which revealed a de novo mutation at p.Arg284Ser in STING. Analysis of mRNA expression from patient peripheral blood mononuclear cells (PBMCs) revealed up-regulation of IFNb, IFN-stimulated genes (ISGs) and inflammatory cytokines. Modelling Arg284Ser STING in vitro validated Arg284Ser as a pathogenic STING mutation. The patient was treated with Ruxolitinib, a Janus kinase (JAK) inhibitor targeting ISG production downstream of type I IFNs. The patient responded well to JAK inhibition, correlating with the resolution of the IFN gene signature ex vivo. This study provides further evidence for JAK inhibition as a therapy for patients with gain-of-function STING mutations and IFN-associated inflammatory conditions.