Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

Lamborn, Ian T.; Jing, Huie; Zhang, Yu; Drutman, Scott; Abbott, Jordan K.; Munir, Shirin; Bade, Sangeeta; Murdock, H. Moses; Santos, Celia; Brock, L. G.; Masutani, Evan; Fordjour, Emmanuel Y.; McElwee, Joshua; Hughes, Jason D.; Nichols, David P.; Belkadi, Abdelaziz; Oler, Andrew J.; Happel, Corinne S.; Matthews, Helen; Abel, Laurent; Collins, Peter L.; Subbarao, Kanta; Gelfand, Erwin W.; Ciancanelli, Michael J.; Casanova, Jean Laurent; Su, Helen C.

doi:10.1084/jem.20161759

Cited by 124 publications

(118 citation statements)

References 84 publications

(103 reference statements)

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“…While the revised version of this paper was under review, an independent study showed an association between IFIH1 deficiency and life-threatening infections with HRV and other respiratory viruses in a child carrying another homozygous missense IFIH1 variant (24). This observation further supports a causal role for IFIH1 deficiency in extreme susceptibility to common respiratory viruses.…”

Section: Discussionmentioning

confidence: 67%

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Asgari

Schlapbach

Anchisi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

127

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Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses. V iral respiratory tract infections are the most common childhood infections worldwide, with close to 100% of children being infected during the first years of life. Whereas the vast majority of viral respiratory infections are mild and self-limiting, more severe disease leads to the hospitalization of about 3% of individuals in each birth cohort (1). In-hospital mortality rates are limited to <1% with intensive care support; still these infections account for 21% of childhood mortality worldwide (2, 3). The main viral pathogens causing lower respiratory tract infections are human respiratory syncytial virus (RSV), enteroviruses [including human rhinoviruses (HRV)], adenoviruses, human metapneumovirus, coronavirus, influenza, and parainfluenza viruses, with RSV being responsible for the majority of the hospitalized pediatric cases (4, 5).A number of risk factors including socioeconomic and environmental influences, preterm birth, chronic diseases, and immunosuppression are associated with more severe clinical presentation (6). However, ∼1 out of 1,000 children without any known risk factor will require intensive care support due to life-threatening manifestations of common viral respiratory infections. In the absence of established differences in pathogen virulence, we hypothesized that human genetic variation contributes to unusual susceptibility to severe disease due to common viruses. Supporting evidence is provided by a recent study, which showed that rare variants in IRF7 resulted in life-threatening influenza in an otherwise healthy child (7).We combined exome sequencing, transcriptomic analysis, and in vitro functional testing to identify and characterize potentially causal genetic variants in a prospective cohort of previously healthy children requiring intensive care support for common respiratory viral infections. We report the identification of a pathogen-restricted immunodeficiency due to loss-of-function variants in IFIH1, which result in defective innate recognition of RNA viruses, preventing the activation of an efficie...

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Section: Discussionmentioning

confidence: 67%

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Asgari

Schlapbach

Anchisi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

127

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“…Moreover, pollen exposure reduces the expression of MDA5, and MDA5 deficiency can predispose to recurrent rhinovirus infections. 39 Furthermore, exposure to pollen resulted in a reduced translocation of phosphorylated IRF3 and IRF7 into the nucleus following activation by double-stranded RNA suggesting a mechanistic link between pollen exposure, reduction in enhanceosome complexes and reduced CCL5 and IFN-λ release. IRF3 has also been shown to play a role in triggering apoptosis, a defense mechanism of virally infected cells to reduce viral load and replication and thus prevent spreading of the infection.…”

Section: Discussionmentioning

confidence: 95%

Pollen exposure weakens innate defense against respiratory viruses

Gilles

Blume

Wimmer

et al. 2019

Allergy

101

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Background Hundreds of plant species release their pollen into the air every year during early spring. During that period, pollen allergic as well as non‐allergic patients frequently present to doctors with severe respiratory tract infections. Our objective was therefore to assess whether pollen may interfere with antiviral immunity. Methods We combined data from real‐life human exposure cohorts, a mouse model and human cell culture to test our hypothesis. Results Pollen significantly diminished interferon‐λ and pro‐inflammatory chemokine responses of airway epithelia to rhinovirus and viral mimics and decreased nuclear translocation of interferon regulatory factors. In mice infected with respiratory syncytial virus, co‐exposure to pollen caused attenuated antiviral gene expression and increased pulmonary viral titers. In non‐allergic human volunteers, nasal symptoms were positively correlated with airborne birch pollen abundance, and nasal birch pollen challenge led to downregulation of type I and ‐III interferons in nasal mucosa. In a large patient cohort, numbers of rhinoviruspositive cases were correlated with airborne birch pollen concentrations. Conclusion The ability of pollen to suppress innate antiviral immunity, independent of allergy, suggests that high‐risk population groups should avoid extensive outdoor activities when pollen and respiratory virus seasons coincide.

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“…However, contrary to published reports, we observed several episodes of severe viral infections in one patient, suggesting the possibility that JAK inhibitors might significantly increase the risk of infections possibly in cases of more severe lung involvement or in the presence of genetic modifiers, not investigated in our patient, with consequent deterioration of t he lung disease. Interestingly, the most frequent virus isolated was rhinovirus, which may be a direct consequence of effective type I IFN inhibition by ruxolitinib at least in respiratory epithelial cells, where IFN-β is required to control rhinovirus [16,17]. On the other end, these infections might result from a cumulative effect of the drug with the reported developmental and in vitro proliferative defects of STING mutant T lymphocytes [18,19].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

et al. 2019

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Objectives Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib. Methods We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis. Results We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid Stefano Volpi and Antonella Insalaco contributed equally.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00645-0) contains supplementary material, which is available to authorized users. treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease. Conclusions We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

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Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

Abstract: Human MDA5 deficiency features recurrent severe human rhinovirus (HRV) infections. MDA5 serves a protective and nonredundant role in protecting against HRV in the respiratory tract, through its effects on virus sensing and triggering of antiviral IFN signaling.

Cited by 124 publications

References 84 publications

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations

Pollen exposure weakens innate defense against respiratory viruses

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

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