Human IFNAR2 deficiency: lessons for antiviral immunity

Christopher J. A. Duncan; Siti M. B.  Mohamad; Dan Frushard Young; Andrew J. Skelton; T. Ronan  Leahy; Diane Carolyn Munday; Karina M. Butler; Sofia Morfopoulou; Julianne R. Brown; Mike Hubank; Jeff Connell; Patrick J. Gavin; Cathy McMahon; Eugene Dempsey; Niamh E. Lynch; Thomas S. Jacques; Manoj Valappil; Andrew J. Cant; Judith Breuer; Karin R. Engelhardt; Richard Edward Randall; Sophie Hambleton

doi:10.1126/scitranslmed.aac4227

Human IFNAR2 deficiency: lessons for antiviral immunity

Christopher J. A. Duncan, Siti M. B. Mohamad, Dan Frushard Young, Andrew J. Skelton, T. Ronan Leahy, Diane Carolyn Munday, Karina M. Butler, Sofia Morfopoulou, Julianne R. Brown, Mike Hubank, Jeff Connell, Patrick J. Gavin, Cathy McMahon, Eugene Dempsey, Niamh E. Lynch, Thomas S. Jacques, Manoj Valappil, Andrew J. Cant, Judith Breuer, Karin R. EngelhardtRichard Edward Randall, Sophie Hambleton

Research output: Contribution to journal › Article › peer-review

Abstract

Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human antiviral immunity.

Original language	English
Article number	307ra154
Number of pages	7
Journal	Science Translational Medicine
Volume	7
Issue number	307
DOIs	https://doi.org/10.1126/scitranslmed.aac4227
Publication status	Published - 30 Sept 2015

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SDG 3 Good Health and Well-being

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© 2015, Publisher / the Author(s). This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at stm.sciencemag.org / https://dx.doi.org/10.1126/scitranslmed.aac4227
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Duncan, C. J. A., Mohamad, S. M. B., Young, D. F., Skelton, A. J., Leahy, T. R., Munday, D. C., Butler, K. M., Morfopoulou, S., Brown, J. R., Hubank, M., Connell, J., Gavin, P. J., McMahon, C., Dempsey, E., Lynch, N. E., Jacques, T. S., Valappil, M., Cant, A. J., Breuer, J., ... Hambleton, S. (2015). Human IFNAR2 deficiency: lessons for antiviral immunity. Science Translational Medicine, 7(307), Article 307ra154. https://doi.org/10.1126/scitranslmed.aac4227

@article{e3a90a4e57fd41b3876f7ef56ae773b7,

title = "Human IFNAR2 deficiency: lessons for antiviral immunity",

abstract = "Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human antiviral immunity.",

author = "Duncan, \{Christopher J. A.\} and Mohamad, \{Siti M. B.\} and Young, \{Dan Frushard\} and Skelton, \{Andrew J.\} and Leahy, \{T. Ronan\} and Munday, \{Diane Carolyn\} and Butler, \{Karina M.\} and Sofia Morfopoulou and Brown, \{Julianne R.\} and Mike Hubank and Jeff Connell and Gavin, \{Patrick J.\} and Cathy McMahon and Eugene Dempsey and Lynch, \{Niamh E.\} and Jacques, \{Thomas S.\} and Manoj Valappil and Cant, \{Andrew J.\} and Judith Breuer and Engelhardt, \{Karin R.\} and Randall, \{Richard Edward\} and Sophie Hambleton",

note = "C.J.A.D. was supported by the Academy of Medical Sciences (AMS-SGCL11), the British Infection Association, and the UK NIH Research (NIHR); S.M.B.M. was supported by the Universiti Sains Malaysia Fellowship; K.R.E. and S.H. were supported by the Sir Jules Thorn Trust (12/JTA); D.F.Y., D.C.M., and R.E.R. were supported by the Wellcome Trust (101788/Z/13/Z); and A.J.S. was supported by the Medical Research Council–Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing and NIHR Newcastle Biomedical Research Centre. J.B. receives funding from the UCLH/UCL NIHR Biomedical Research Centre. S.M. is supported by the FP7 PATHSEEK grant. J.R.B. is supported by an NIHR fellowship.",

year = "2015",

month = sep,

day = "30",

doi = "10.1126/scitranslmed.aac4227",

language = "English",

volume = "7",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

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Duncan, CJA, Mohamad, SMB, Young, DF, Skelton, AJ, Leahy, TR, Munday, DC, Butler, KM, Morfopoulou, S, Brown, JR, Hubank, M, Connell, J, Gavin, PJ, McMahon, C, Dempsey, E, Lynch, NE, Jacques, TS, Valappil, M, Cant, AJ, Breuer, J, Engelhardt, KR, Randall, RE & Hambleton, S 2015, 'Human IFNAR2 deficiency: lessons for antiviral immunity', Science Translational Medicine, vol. 7, no. 307, 307ra154. https://doi.org/10.1126/scitranslmed.aac4227

TY - JOUR

T1 - Human IFNAR2 deficiency

T2 - lessons for antiviral immunity

AU - Duncan, Christopher J. A.

AU - Mohamad, Siti M. B.

AU - Young, Dan Frushard

AU - Skelton, Andrew J.

AU - Leahy, T. Ronan

AU - Munday, Diane Carolyn

AU - Butler, Karina M.

AU - Morfopoulou, Sofia

AU - Brown, Julianne R.

AU - Hubank, Mike

AU - Connell, Jeff

AU - Gavin, Patrick J.

AU - McMahon, Cathy

AU - Dempsey, Eugene

AU - Lynch, Niamh E.

AU - Jacques, Thomas S.

AU - Valappil, Manoj

AU - Cant, Andrew J.

AU - Breuer, Judith

AU - Engelhardt, Karin R.

AU - Randall, Richard Edward

AU - Hambleton, Sophie

N1 - C.J.A.D. was supported by the Academy of Medical Sciences (AMS-SGCL11), the British Infection Association, and the UK NIH Research (NIHR); S.M.B.M. was supported by the Universiti Sains Malaysia Fellowship; K.R.E. and S.H. were supported by the Sir Jules Thorn Trust (12/JTA); D.F.Y., D.C.M., and R.E.R. were supported by the Wellcome Trust (101788/Z/13/Z); and A.J.S. was supported by the Medical Research Council–Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing and NIHR Newcastle Biomedical Research Centre. J.B. receives funding from the UCLH/UCL NIHR Biomedical Research Centre. S.M. is supported by the FP7 PATHSEEK grant. J.R.B. is supported by an NIHR fellowship.

PY - 2015/9/30

Y1 - 2015/9/30

N2 - Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human antiviral immunity.

AB - Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human antiviral immunity.

UR - https://www.scopus.com/pages/publications/84942843900

U2 - 10.1126/scitranslmed.aac4227

DO - 10.1126/scitranslmed.aac4227

M3 - Article

C2 - 26424569

SN - 1946-6234

VL - 7

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 307

M1 - 307ra154

ER -

Human IFNAR2 deficiency: lessons for antiviral immunity

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Prof Randall Wellcome Trust: The interaction of paramyxoviruses with the interferon system

Richard Randall

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Human IFNAR2 deficiency: lessons for antiviral immunity

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