Welcome to the ESID 2022 Meeting Interactive Programme
The meeting will officially run on Central European Summer Time (CEST)
Introduction
COVID-19 in IEI Patients - What Have We Learnt?
SARS-CoV2 Vaccination in IEI
APECED - Susceptibility to COVID-19 and Other Viruses
TCR Repertoire in MIS-C
RECESSIVE INBORN ERRORS OF TYPE I IFN IMMUNITY IN CHILDREN WITH COVID-19 PNEUMONIA
Abstract
Background and Aims
Inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children is much lower and remains unexplained. We tested the hypothesis that recessive inborn errors of type I IFN immunity could underlie COVID-19 pneumonia in patients < 16 years of age.
Methods
We performed an enrichment analysis focusing on rare variants in 15 candidate genes on our international cohort of 112 pediatric patients with moderate to critical COVID-19 pneumonia and 1,224 children and adults with asymptomatic or paucisymptomatic infection. We validated our findings studying the response to SARS-CoV-2 infection in patient’s fibroblasts.
Results
We identified 12 children aged 1.5 to 13 years with four of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2, are highly vulnerable to SARS-CoV-2. These 15 deficiencies are not found in children and adults with benign SARS-CoV-2 infection without pneumonia (p = 1.2x10-11).
Conclusions
Our findings suggest that three of the 14 known AR inborn errors of type I IFN immunity underlie COVID-19 pneumonia in ~4% of children. We also found XR TLR7 deficiency in ~6% of children and 8.9% of boys with pneumonia. We provide evidence that recessive and complete defects at these four loci can underlie ~10% of cases of COVID-19 pneumonia in hospitalized children.
IDENTIFICATION OF HOST GENETIC VARIANTS IN THE CYTOSOLIC DNA SENSOR POL III IN PATIENTS WITH CRITICAL COVID-19
Abstract
Background and Aims
The underlying pathogenesis explaining why some individuals develop life-threatening COVID-19 disease remains incompletely understood. In this study we aim to identify gene variants predisposing specifically to vary rare cases of critical COVID-19 in young individuals without co-morbidities.
Methods
By whole exome sequencing we have identified potential disease-causing host gene variants in younger patients with critical COVID-19.
Results
We have revealed an accumulation of mutations in genes encoding the innate cytosolic DNA sensor RNA polymerase III (POL III) in younger patients with critical COVID-19. In peripheral blood mononuclear cells (PBMCs) isolated from patients with identified POL III gene variants, we have shown reduced type I interferon (IFN) responses to SARS-CoV-2 and the POL III agonist poly(dAdT). Likewise, inhibition of POL III in the pulmonary cell line A549 resulted in reduced IFN response to SARS-CoV-2. Currently, we are further scrutinizing the impact of POL III gene variants on the development of critical COVID-19 by investigating how the DNA sensor POL III is sensing infections with RNA-viruses, like SARS-CoV-2. We hypothesize that mitochondrial DNA released into the cytosol due to SARS-CoV-2-induced cellular stress during infection is sensed by POL III and mediating induction of IFN expression.
Conclusions
By regulating the IFN response to SARS-CoV-2 POL III seems to be important for prevention of development of critical COVID-19. Studies to examine the molecular mechanism, whereby host DNA may serve an antiviral role during SARS-CoV-2 infection are ongoing. Hence, this study provides new knowledge on the role of cytosolic DNA sensing and POL III in severe viral infections.