Severe influenza pneumonitis in children with inherited TLR3 deficiency

Lim, Hye Kyung; Huang, Sarah X.L.; Chen, Jie; Kerner, Gaspard; Gilliaux, Olivier; Bastard, Paul; Dobbs, Kerry; Hernandez, Nicholas; Goudin, Nicolas; Hasek, Mary; Reino, Eduardo J. Garcia; Lafaille, Fabien G.; Lorenzo, Lazaro; Luthra, Priya; Kochetkov, Tatiana; Bigio, Benedetta; Boucherit, Soraya; Rozenberg, Flore; Vedrinne, C.; Keller, Michael D.; Itan, Yuval; Garcı́a-Sastre, Adolfo; Célard, M.; Orange, Jordan S.; Ciancanelli, Michael J.; Meyts, Isabelle; Zhang, Qian; Abel, Laurent; Notarangelo, Luigi D.; Snoeck, Hans-Willem; Casanova, Jean‐Laurent; Zhang, Shen-Ying

doi:10.1084/jem.20181621

Cited by 160 publications

(169 citation statements)

References 108 publications

(235 reference statements)

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“…Four IEIs-GATA2 (Bigley et al 2011;Pasquet et al 2013;Sologuren et al 2018), IRF7 (Ciancanelli et al 2015), IRF9 (Hernandez et al 2018), and TLR3 (Lim et al 2019) deficiencies-have been shown to cause life-threatening influenza pneumonitis (Table 1). Autosomal dominant (AD) GATA2 deficiency is the only one of these IEIs leading to a pleiotropic syndromic disorder that manifests as a lack of multilymphoid and granulocyte-macrophage progenitors in the bone marrow, smaller numbers of dendritic cells (DCs), monocytes, T, B and NK lymphocytes in peripheral blood, and higher susceptibility to viral, mycobacterial, and fungal infections.…”

Section: Inherited Gata2 Deficiencymentioning

confidence: 99%

“…Unlike patients with GATA2 deficiency, those with autosomal recessive (AR) IRF7 and AR IRF9 deficiencies have an almost isolated susceptibility to influenza (Ciancanelli et al 2015;Hernandez et al 2018;Lim et al 2019), albeit only a few patients have been studied so far (Table 1). 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).…”

Section: Inherited Irf7 and Irf9 Deficienciesmentioning

confidence: 99%

“…The human genetics and cellular mechanisms of HSE are discussed in detail in another review in this issue by Zhang [2020]. In 2019, the first association between heterozygous TLR3 mutations and influenza pneumonitis was reported (Lim et al 2019).…”

Section: Inherited Tlr3 Deficiencymentioning

confidence: 99%

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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 Gata2 Deficiencymentioning

confidence: 99%

Section: Inherited Irf7 and Irf9 Deficienciesmentioning

confidence: 99%

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Human genetics of life-threatening influenza pneumonitis

Zhang

2020

Hum Genet

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“…Interestingly, genetic susceptibility to devastating influenza does not appear to be a polygenic trait, but is determined by defects in single genes that govern non-redundant pathways of type I (α/β) and type III (λ) interferon (IFN) responses. Critical genes identified so far are either involved in induction of type I and type III IFNs (TLR3, IRF7) (Ciancanelli et al 2015;Lim et al 2019), IFN production by plasmacytoid dendritic cells (GATA2) (Sologuren et al 2018) or are part of the IFN signaling pathway required for antiviral action (IRF9) . Surprisingly, however, no clear defects have yet been found in type I and type III IFN-stimulated genes (ISGs).…”

Section: Introductionmentioning

confidence: 99%

Mx genes: host determinants controlling influenza virus infection and trans-species transmission

Haller

Kochs

2019

Hum Genet

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The human MxA protein, encoded by the interferon-inducible MX1 gene, is an intracellular influenza A virus (IAV) restriction factor. It can protect transgenic mice from severe IAV-induced disease, indicating a key role of human MxA for host survival and suggesting that natural variations in MX1 may account for inter-individual differences in disease severity among humans. MxA also provides a robust barrier against zoonotic transmissions of avian and swine IAV strains. Therefore, zoonotic IAV must acquire MxA escape mutations to achieve sustained human-to-human transmission. Here, we discuss recent progress in the field.

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“…In AD disorders due to HI, the mutant copy is not functional and does not interfere with the WT product, and the single functional WT copy produces too little protein to fulfill its function. HI is more commonly associated with loss-of-expression alleles and DN with normally or highly expressed alleles, but rare examples have been reported of HI with normal levels of the mutant protein (30), and of negative dominance (ND) with a lack of detectable mutant protein (31). Autosomal dominance by GOF defines a third category, in which the mutant protein is produced (32).…”

Section: Haploinsufficient Genes Are Under Stronger Selection Than Domentioning

confidence: 99%

Negative selection on human genes causing severe inborn errors depends on disease outcome and both the mode and mechanism of inheritance

Rapaport

Boisson

Gregor

et al. 2020

Preprint

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Background: Genetic variants underlying severe diseases are less likely to be transmitted to the next generation, and are thus gradually and selectively eliminated from the population through negative selection. Here, we study the determinants of this evolutionary process in genes underlying severe diseases in humans. Results:We propose a novel approach, CoNeS, integrating known negative selection scores through principal component projection. We compare evidence for negative selection at 319 genes underlying inborn errors of immunity (IEI), which are life-threatening monogenic disorders. We find that genes underlying autosomal dominant (AD) or X-linked IEI are under stronger negative selection than those underlying autosomal recessive (AR) IEI, which are under no stronger selection than genes not known to be disease-causing. However, we find that genes with mutations causing AR IEI that are lethal before reproductive maturity and that display complete penetrance are under stronger negative selection than other genes underlying AR IEI.We also find that genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. Finally, we replicate these results in a study of 1,140 genes causing inborn errors of neurodevelopment. Conclusions:These findings collectively show that the clinical outcomes of inborn errors, together with the mode and mechanism of inheritance of these errors, determine the strength of negative selection acting on severe disease-causing genes. These findings suggest that estimating the intensity of negative selection with CoNeS may facilitate the selection of candidate genes in patients suspected to carry an inborn error.

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Severe influenza pneumonitis in children with inherited TLR3 deficiency

Cited by 160 publications

References 108 publications

Human genetics of life-threatening influenza pneumonitis

Human genetics of life-threatening influenza pneumonitis

Mx genes: host determinants controlling influenza virus infection and trans-species transmission

Negative selection on human genes causing severe inborn errors depends on disease outcome and both the mode and mechanism of inheritance

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