Lessons learned from the study of human inborn errors of innate immunity

Bucciol, Giorgia; Moens, Leen; Bosch, Barbara; Bossuyt, Xavier; Casanova, Jean‐Laurent; Puel, Anne; Meyts, Isabelle

doi:10.1016/j.jaci.2018.07.013

Cited by 51 publications

(38 citation statements)

References 198 publications

(230 reference statements)

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“…However, there is currently no explanation as to why younger individuals with no co-morbidities in rare cases have developed life-threatening COVID-19. Human inborn errors of immunity can alter the course of various viral infections (131), but in the case of disease progression in SARS-CoV-2 infection, little is known regarding the influence of the host genetic makeup. However, any genetic variant that results in a dysregulated or exaggerated immune response may contribute to lung immunopathology leading to life-threatening clinical manifestations.…”

Section: Human Inborn Errors Of Immunity Predisposing To Coronavirus mentioning

confidence: 99%

Deciphering the Role of Host Genetics in Susceptibility to Severe COVID-19

et al. 2020

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Coronavirus disease-19 (COVID-19) describes a set of symptoms that develop following infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Whilst COVID-19 disease is most serious in patients with significant co-morbidities, the reason for healthy individuals succumbing to fulminant infection is largely unexplained. In this review, we discuss the most recent findings in terms of clinical features and the host immune response, and suggest candidate immune pathways that may be compromised in otherwise healthy individuals with fulminating COVID-19. On the basis of this early knowledge we reason a potential genetic effect on host immune response pathways leading to increased susceptibility to SARS-CoV-2 infection. Understanding these pathways may help not only in unraveling disease pathogenesis, but also in suggesting targets for therapy and prophylaxis. Importantly such insight should instruct efforts to identify those at increased risk in order to institute preventative measures, such as prophylactic medication and/or vaccination, when such opportunities arise in the later phases of the current pandemic or during future similar pandemics.

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Section: Human Inborn Errors Of Immunity Predisposing To Coronavirus mentioning

confidence: 99%

Deciphering the Role of Host Genetics in Susceptibility to Severe COVID-19

et al. 2020

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“…Several PIDs have been associated to the defective expression or function of molecules belonging to innate immune signaling receptors or pathways (1, 2). These discoveries have been accelerated by the introduction of whole exome sequencing (WES) techniques.…”

Section: Introductionmentioning

confidence: 99%

IRF and STAT Transcription Factors - From Basic Biology to Roles in Infection, Protective Immunity, and Primary Immunodeficiencies

2019

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The induction and action of type I interferon (IFN) is of fundamental importance in human immune defenses toward microbial pathogens, particularly viruses. Basic discoveries within the molecular and cellular signaling pathways regulating type I IFN induction and downstream actions have shown the essential role of the IFN regulatory factor (IRF) and the signal transducer and activator of transcription (STAT) families, respectively. However, the exact biological and immunological functions of these factors have been most clearly revealed through the study of inborn errors of immunity and the resultant infectious phenotypes in humans. The spectrum of human inborn errors of immunity caused by mutations in IRFs and STATs has proven very diverse. These diseases encompass herpes simplex encephalitis (HSE) and severe influenza in IRF3- and IRF7/IRF9 deficiency, respectively. They also include Mendelian susceptibility to mycobacterial infection (MSMD) in STAT1 deficiency, through disseminated measles infection associated with STAT2 deficiency, and finally staphylococcal abscesses and chronic mucocutaneous candidiasis (CMC) classically described with Hyper-IgE syndrome (HIES) in the case of STAT3 deficiency. More recently, increasing focus has been on aspects of autoimmunity and autoinflammation playing an important part in many primary immunodeficiency diseases (PID)s, as exemplified by STAT1 gain-of-function causing CMC and autoimmune thyroiditis, as well as a recently described autoinflammatory syndrome with hypogammaglobulinemia and lymphoproliferation as a result of STAT3 gain-of-function. Here I review the infectious, inflammatory, and autoimmune disorders arising from mutations in IRF and STAT transcription factors in humans, highlightning the underlying molecular mechanisms and immunopathogenesis as well as the clinical/therapeutic perspectives of these new insights.

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“…Finally, we previously reported an adult patient heterozygous for a variant in the cytosolic RNA sensor retinoic-acid-inducible-gene (RIG)-I [16]. Surprisingly, among the more than 350 reported primary immunodeficiencies (PIDs), including defects in the innate and the adaptive immune response [17][18][19], defects in IRF7, IRF9, and RIG-I are the only PIDs that seem to selectively predispose to severe influenza in humans [14][15][16]. Thus, the induction of and the response to type I and type III IFNs appear to be particularly important for mounting a protective immune response against influenza virus.…”

Section: Introductionmentioning

confidence: 99%

Defective interferon priming and impaired antiviral responses in a patient with an IRF7 variant and severe influenza

Thomsen

Jørgensen

Gad

et al. 2019

Med Microbiol Immunol

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Influenza infection is common worldwide with many individuals affected each year during epidemics and occasionally pandemics. Previous studies in animal models and a few human cases have established an important role of innate type I and III interferon (IFN) for viral elimination and mounting of antiviral responses. However, genetic and immunological determinants of very severe disseminated influenza virus infection in humans remain incompletely understood. Here, we describe an adult patient with severe influenza virus A (IAV) infection, in whom we identified a rare variant E331V in IFN regulatory factor (IRF)7 by whole-exome sequencing. Examination of patient cells demonstrated a cellular phenotype suggesting functional IRF7 impairment, since priming with IFN was almost abolished and IFN responses to IAV were significantly impaired in patient cells. Moreover, IAV replication was significantly higher in patient cells than in controls. Finally, expression of IRF7 E331V in HEK293 cells demonstrated significantly reduced activation of both IFNA7 and IFNB promoters in a luciferase reporter gene expression assay compared to IRF7 wild type. These findings provide further support for the essential role of IRF7 in amplifying antiviral IFN responses to ensure potent and sustained IFN responses during influenza virus infection in humans.

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Lessons learned from the study of human inborn errors of innate immunity

Cited by 51 publications

References 198 publications

Deciphering the Role of Host Genetics in Susceptibility to Severe COVID-19

Deciphering the Role of Host Genetics in Susceptibility to Severe COVID-19

IRF and STAT Transcription Factors - From Basic Biology to Roles in Infection, Protective Immunity, and Primary Immunodeficiencies

Defective interferon priming and impaired antiviral responses in a patient with an IRF7 variant and severe influenza

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