scholarly journals Insufficient type I IFN immunity underlies life-threatening COVID-19 pneumonia

2021 ◽  
pp. 1-7
Author(s):  
Paul Bastard ◽  
Qian Zhang ◽  
Aurélie Cobat ◽  
Emmanuelle Jouanguy ◽  
Shen-Ying Zhang ◽  
...  
Keyword(s):  
Type I ◽  
Type I Ifn ◽  
Life Threatening

scholarly journals Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Science ◽  
2020 ◽  
Vol 370 (6515) ◽  
pp. eabd4570 ◽  
Author(s):  
Qian Zhang ◽  
Paul Bastard ◽  
Zhiyong Liu ◽  
Jérémie Le Pen ◽  
Marcela Moncada-Velez ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Rare Variants ◽  
Human Fibroblasts ◽  
Severe Infection ◽  
Type I ◽  
Type I Ifn ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Life Threatening ◽  
Dependent Type

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis

2021 ◽  
Vol 218 (12) ◽  
Author(s):  
Jie Chen ◽  
Huie Jing ◽  
Andrea Martin-Nalda ◽  
Paul Bastard ◽  
Jacques G. Rivière ◽  
...  
Keyword(s):  
Poly I:C ◽  
Compound Heterozygous ◽  
Late Time ◽  
Type I ◽  
Type I Ifn ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Viral Susceptibility ◽  
Life Threatening ◽  
The Central Nervous System

Enterovirus (EV) infection rarely results in life-threatening infection of the central nervous system. We report two unrelated children with EV30 and EV71 rhombencephalitis. One patient carries compound heterozygous TLR3 variants (loss-of-function F322fs2* and hypomorphic D280N), and the other is homozygous for an IFIH1 variant (loss-of-function c.1641+1G>C). Their fibroblasts respond poorly to extracellular (TLR3) or intracellular (MDA5) poly(I:C) stimulation. The baseline (TLR3) and EV-responsive (MDA5) levels of IFN-β in the patients’ fibroblasts are low. EV growth is enhanced at early and late time points of infection in TLR3- and MDA5-deficient fibroblasts, respectively. Treatment with exogenous IFN-α2b before infection renders both cell lines resistant to EV30 and EV71, whereas post-infection treatment with IFN-α2b rescues viral susceptibility fully only in MDA5-deficient fibroblasts. Finally, the poly(I:C) and viral phenotypes of fibroblasts are rescued by the expression of WT TLR3 or MDA5. Human TLR3 and MDA5 are critical for cell-intrinsic immunity to EV, via the control of baseline and virus-induced type I IFN production, respectively.

scholarly journals Inborn Errors of Type I IFN Immunity in Patients With Life-Threatening COVID-19

PEDIATRICS ◽  
2021 ◽  
Vol 148 (Supplement 3) ◽  
pp. S72-S73
Author(s):  
Jordan S. Orange
Keyword(s):  
Type I ◽  
Type I Ifn ◽  
Inborn Errors ◽  
Life Threatening

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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