X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Asano, Takaki; Boisson, Bertrand; Onodi, Fanny; Matuozzo, Daniela; Moncada-Vélez, Marcela; Renkilaraj, Majistor Raj Luxman Maglorius; Zhang, Peng; Meertens, Laurent; Bolze, Alexandre; Materna, Marie; Korniotis, Sarantis; Gervais, Adrian; Talouarn, Estelle; Bigio, Benedetta; Seeleuthner, Yoann; Bilgüvar, Kaya; Zhang, Yu; Neehus, Anna-Lena; Ogishi, Masato; Pelham, Simon J.; Voyer, Tom Le; Rosain, Jérémie; Philippot, Quentin; Soler‐Palacín, Pere; Colobran, Roger; Martin‐Nalda, Andrea; Rivière, Jacques G.; Tandjaoui-Lambiotte, Yacine; Chaïbi, Khalil; Shahrooei, Mohammad; Darazam, Ilad Alavi; Olyaei, Nasrin Alipour; Mansouri, Davood; Hatipoğlu, Nevin; Palabıyık, Figen; Özçelık, Tayfun; Novelli, Giuseppe; Novelli, Antonio; Casari, Giorgio; Aiuti, Alessandro; Carrera, Paola; Bondesan, Simone; Barzaghi, Federica; Rovere‐Querini, Patrizia; Tresoldi, Cristina; Franco, José Luis; Rojas, Julián; Reyes, Luis Felipe; Bustos, Ingrid G.; Arias, Andrés A.

doi:10.1126/sciimmunol.abl4348

Cited by 284 publications

(280 citation statements)

References 82 publications

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“…Studies based on whole-genome/exome sequencing analyses have further suggested that rare inborn errors of immunity (IEI), including TLR3- and IRF7-dependent type I interferon (IFN) immunity, can cause life-threatening COVID-19 pneumonia [ 5 ]. Moreover, X-linked recessive TLR7 deficiency accounts for about 1% of cases in male patients younger than 60 years [ 6 ]. In contrast, auto-Abs neutralizing type I IFN accounts for about 15% of critical cases across ages, but 20% in patients > 80 years, and 20% of deaths across all ages [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, their potential susceptibility to SARS-CoV-2 infection is still unknown [ 12 , 13 ]. Herein, we present the detailed clinical, immunological and genetic characterization of a unique IEI patient with critical COVID-19 pneumonia, who has pathogenic mutations in both X-linked TLR7 and autosomal ATM (reported as P6 in a large COVID-19 cohort, with a TLR7 mutation [ 6 ]).…”

Section: Introductionmentioning

confidence: 99%

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X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

et al. 2021

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Background Coronavirus disease 2019 (COVID-19) exhibits a wide spectrum of clinical manifestations, ranging from asymptomatic to critical conditions. Understanding the mechanism underlying life-threatening COVID-19 is instrumental for disease prevention and treatment in individuals with a high risk. Objectives We aimed to identify the genetic cause for critical COVID-19 pneumonia in a patient with a preexisting inborn error of immunity (IEI). Methods Serum levels of specific antibodies against the virus and autoantibodies against type I interferons (IFNs) were measured. Whole exome sequencing was performed, and the impacts of candidate gene variants were investigated. We also evaluated 247 ataxia-telangiectasia (A-T) patients in the Iranian IEI registry. Results We report a 7-year-old Iranian boy with a preexisting hyper IgM syndrome who developed critical COVID-19 pneumonia. IgM only specific COVID-19 immune response was detected but no autoantibodies against type I IFN were observed. A homozygous deleterious mutation in the ATM gene was identified, which together with his antibody deficiency, radiosensitivity, and neurological signs, established a diagnosis of A-T. Among the 247 A-T patients evaluated, 36 had SARS-CoV-2 infection, but all had mild symptoms or were asymptomatic except the index patient. A hemizygous deleterious mutation in the TLR7 gene was subsequently identified in the patient. Conclusions We report a unique IEI patient with combined ATM and TLR7 deficiencies. The two genetic defects underlie A-T and critical COVID-19 in this patient, respectively.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

et al. 2021

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“…The precise role of IFN-I in COVID-19 patients is complex and still emerging. COVID-19 patients that have deficiencies in IFN-I responses as a result of germline mutations or anti-IFN-I autoantibodies are more susceptible to severe disease [149][150][151][152][153]. This is in line with the beneficial role of IFN-I in the control of a variety of viral infections.…”

Section: The Complex Role Of Ifn-i In Covid-19mentioning

confidence: 65%

“…A definitive role for TLR7 in SARS-CoV-2 was recently demonstrated in patients with familial deficiency for TLR7 function. These patients show little to no production of IFN-α2 in their pDCs after stimulation with SARS-CoV-2, though interestingly production of several other inflammatory cytokines was not significantly impacted in this case [153]. Together these studies provide compelling evidence that pDCs sense SARS-CoV2 via TLR7.…”

Section: Sensing Of Sars-cov-2 By Pdcmentioning

confidence: 67%

Type I Interferon Induction and Exhaustion during Viral Infection: Plasmacytoid Dendritic Cells and Emerging COVID-19 Findings

Greene

Zúñiga

2021

Viruses

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Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as “pDC exhaustion”, favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19.

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“…Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, lead-ing to better targeting of care and vaccination [5][6][7]. In addition, characterizing these host factors may help identifying and development of adapted drugs and vaccines [8][9][10]. The scientific community came together with several efforts to investigate how the genomic variation in the host affects disease susceptibil-ity and progress [11,12].…”

Section: Introductionmentioning

confidence: 99%

Poking COVID-19: insights on genomic constraints among immune-related genes between Qatari and Italian populations

Mbarek

Cocca

Al-Sarraj

et al. 2021

Preprint

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Host genomic information, specifically genomic variations, may characterize susceptibility to disease and identify people with a higher risk of harm, leading to better targeting of care and vaccination. Italy was the epicentre for the spread of COVID-19 in Europe, the first country to go into a national lockdown and has one of the highest COVID-19 associated mortality rates. Qatar, on the other hand has a very low mortality rate. In this study, we compared whole-genome sequencing data of 14398 adults and Qatari-national to 925 Italian individuals. We also included in the comparison whole-exome sequence data from 189 Italian laboratory confirmed COVID-19 cases. We focused our study on a curated list of 3619 candidate genes involved in innate immunity and host-pathogen interaction. Two population-gene metric scores, the Delta Singleton-Cohort variant score (DSC) and Sum Singleton- Cohort variant score (SSC), were applied to estimate the presence of selective constraints in the Qatari population and in the Italian cohorts. Results based on DSC SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction

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X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Cited by 284 publications

References 82 publications

X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

X-Linked TLR7 Deficiency Underlies Critical COVID-19 Pneumonia in a Male Patient with Ataxia-Telangiectasia

Type I Interferon Induction and Exhaustion during Viral Infection: Plasmacytoid Dendritic Cells and Emerging COVID-19 Findings

Poking COVID-19: insights on genomic constraints among immune-related genes between Qatari and Italian populations

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