Impaired control of multiple viral infections in a family with complete IRF9 deficiency

García-Morato, María Bravo; Apalategi, Ane Calvo; Bravo‐Gallego, Luz Yadira; Moreno, Alfonso Blázquez; Simón-Fuentes, Miriam; Garmendia, Jenny V.; Méndez‐Echevarría, Ana; Rabes, T. del Rosal; Domínguez-Soto, Ángeles; López‐Granados, Eduardo; Reyburn, Hugh; Pena, Rebeca Rodríguez

doi:10.1016/j.jaci.2019.02.019

Cited by 60 publications

(60 citation statements)

References 26 publications

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“…No overt immunological abnormality was detected in laboratory tests on these patients except for two recently reported IRF9-deficient patients from the same consanguineous family (Bravo et al 2019). The cells of IRF7-and IRF9-deficient patients are susceptible to IAV infections in vitro, and to laboratory strains of other viruses, such as VSV (Ciancanelli et al 2015;Hernandez et al 2018;Bravo et al 2019). Surprisingly, these patients are exposed, yet resistant to most common pathogens, including viruses such as HPV, RSV, and EBV.…”

Section: Inherited Irf7 and Irf9 Deficienciesmentioning

confidence: 69%

“…Only a few signs of broader vulnerability to viruses, including the vaccine strain of measles, have been observed (Ciancanelli et al 2015;Hernandez et al 2018). No overt immunological abnormality was detected in laboratory tests on these patients except for two recently reported IRF9-deficient patients from the same consanguineous family (Bravo et al 2019). The cells of IRF7-and IRF9-deficient patients are susceptible to IAV infections in vitro, and to laboratory strains of other viruses, such as VSV (Ciancanelli et al 2015;Hernandez et al 2018;Bravo et al 2019).…”

Section: Inherited Irf7 and Irf9 Deficienciesmentioning

confidence: 81%

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Human genetics of life-threatening influenza pneumonitis

Zhang

2020

Hum Genet

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Influenza viruses infect millions of people around the globe annually, usually causing self-limited upper respiratory tract infections. However, a small but non-negligible proportion of patients suffer from life-threatening pulmonary disease. Those affected include otherwise healthy individuals, and children with primary infections in particular. Much effort has been devoted to virological studies of influenza and vaccine development. By contrast, the enormous interindividual variability in susceptibility to influenza has received very little attention. One interesting hypothesis is that interindividual variability is driven largely by the genetic makeup of the infected patients. Unbiased genomic approaches have been used to search for genetic lesions in children with life-threatening pulmonary influenza. Four monogenic causes of severe influenza pneumonitis-deficiencies of GATA2, IRF7, IRF9, and TLR3-have provided evidence that severe influenza pneumonitis can be genetic and often in patients with no other severe infections. These deficiencies highlight the importance of human type I and III IFN-mediated immunity for host defense against influenza. Clinical penetrance is incomplete, and the underlying mechanisms are not yet understood. However, human genetic studies have clearly revealed that seemingly sporadic and isolated life-threatening influenza pneumonitis in otherwise healthy individuals can be genetic.

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Section: Inherited Irf7 and Irf9 Deficienciesmentioning

confidence: 69%

Section: Inherited Irf7 and Irf9 Deficienciesmentioning

confidence: 81%

Human genetics of life-threatening influenza pneumonitis

Zhang

2020

Hum Genet

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“…IRF9 protein expression was undetectable in cells transfected with the c.577+1G>T IRF9 construct, suggesting that either the protein was quickly degraded or the mRNA was not translated. Again, IRF9-deficient cells showed a profound defect in inducing the expression of multiple ISGs [116]. Collectively, these findings show that human IRF9-and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling viral infections, including IAV.…”

Section: Snps In Host Genes Affecting Iav Diseasementioning

confidence: 69%

“…The consequence of this mutation was an impaired activation of IRF-9, and therefore, an impaired transcription of ISGs, many of which show antiviral activities [115]. Similarly, a family in which several members showed a surprising susceptibility to infection by different viruses, including IAV, also showed to be IRF9 deficient [116]. The index patient, a boy with 10 years born at term from healthy consanguineous parents (first cousins of Portuguese origin and residing in Venezuela) encoded a homozygous splicing mutation in the IRF9 gene.…”

Section: Snps In Host Genes Affecting Iav Diseasementioning

confidence: 99%

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Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

Nogales¹,

DeDiego

2019

Pathogens

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A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can affect gene expression or protein function by different mechanisms. Furthermore, they have been linked to multiple human diseases, highlighting their medical relevance. Therefore, the identification and analysis of this kind of polymorphisms in the human genome has gained high importance in the research community, and an increasing number of studies have been published during the last years. As a consequence of this exhaustive exploration, an association between the presence of some specific SNPs and the susceptibility or severity of many infectious diseases in some risk population groups has been found. In this review, we discuss the relevance of SNPs that are important to understand the pathology derived from influenza A virus (IAV) infections in humans and the susceptibility of some individuals to suffer more severe symptoms. We also discuss the importance of SNPs for IAV vaccine effectiveness. multiple mechanisms, although there are some differences between strains. For that genome plasticity, IAV take advantage of multiple strategies, such as alternative splicing, frameshift mechanisms, and overlapping open reading frames (ORFs) [7][8][9]. In addition, the coding capability of the viral genome is extended by encoding multifunctional proteins that act at different steps during virus infection. of synthetized vRNP, ensuring that the vRNPs are available for packaging [24]. Moreover, NEP has also other functions during IAV infection, contributing to viral budding and to regulate viral RNA synthesis. NS1 is a multifunctional protein and a key viral factor that counteracts the host antiviral responses. NS1 has been shown to inhibit the production of interferon (IFN), the activity and expression of multiple interferon-induced genes (ISG) and the processing and nuclear transport of host mRNAs causing cellular shut-off [25,26]. Segment 3 of IAV also encodes two proteins, the polymerase component PA and PA-X. PA is translated directly from the PA mRNA, whereas PA-X is translated using a +1 frameshift mechanism from the same open reading frame (ORF) [9]. Synergistically with NS1, PA-X is also able to block the cellular antiviral responses by inhibiting host protein expression. Moreover, the PA-X protein has been shown to modulate host inflammation, immune responses, apoptosis, and virus pathogenesis [25][26][27][28][29][30].

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Severe COVID‐19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals

2022

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Since the emergence of the COVID‐19 pandemic in early 2020, a key challenge has been to define risk factors, other than age and pre‐existing comorbidities, that predispose some people to severe disease, while many other SARS‐CoV‐2‐infected individuals experience mild, if any, consequences. One explanation for intra‐individual differences in susceptibility to severe COVID‐19 may be that a growing percentage of otherwise healthy people have a pre‐existing asymptomatic primary immunodeficiency (PID) that is unmasked by SARS‐CoV‐2 infection. Germline genetic defects have been identified in individuals with life‐threatening COVID‐19 that compromise local type I interferon (IFN)‐mediated innate immune responses to SARS‐CoV‐2. Remarkably, these variants – which impact responses initiated through TLR3 and TLR7, as well as the response to type I IFN cytokines – may account for between 3% and 5% of severe COVID‐19 in people under 70 years of age. Similarly, autoantibodies against type I IFN cytokines (IFN‐α, IFN‐ω) have been detected in patients' serum prior to infection with SARS‐CoV‐2 and were found to cause c . 20% of severe COVID‐19 in the above 70s and 20% of total COVID‐19 deaths. These autoantibodies, which are more common in the elderly, neutralise type I IFNs, thereby impeding innate antiviral immunity and phenocopying an inborn error of immunity. The discovery of PIDs underlying a significant percentage of severe COVID‐19 may go some way to explain disease susceptibility, may allow for the application of targeted therapies such as plasma exchange, IFN‐α or IFN‐β, and may facilitate better management of social distancing, vaccination and early post‐exposure prophylaxis.

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Impaired control of multiple viral infections in a family with complete IRF9 deficiency

Cited by 60 publications

References 26 publications

Human genetics of life-threatening influenza pneumonitis

Human genetics of life-threatening influenza pneumonitis

Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

Severe COVID‐19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals

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