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Human IFNAR2 deficiency: Lessons for antiviral immunity.

ABSTRACT: Type I interferon (IFN-?/?) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-?/? 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-?/? receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-?/?. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-?/? 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-?/? in human antiviral immunity.

SUBMITTER: Duncan CJ

PROVIDER: S-EPMC4926955 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Human IFNAR2 deficiency: Lessons for antiviral immunity.

Duncan Christopher J A CJ Mohamad Siti M B SM Young Dan F DF Skelton Andrew J AJ Leahy T Ronan TR Munday Diane C DC Butler Karina M KM Morfopoulou Sofia S Brown Julianne R JR Hubank Mike M Connell Jeff J Gavin Patrick J PJ McMahon Cathy C Dempsey Eugene E Lynch Niamh E NE Jacques Thomas S TS Valappil Manoj M Cant Andrew J AJ Breuer Judith J Engelhardt Karin R KR Randall Richard E RE Hambleton Sophie S

Science translational medicine 20150901 307

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 ...[more]

PMID: 26424569

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Project description:Influenza virus infections particularly when followed by bacterial superinfections (BSI) result in significant morbidities and mortalities especially during influenza pandemics. Type I interferons (IFNs) regulate both anti-influenza immunity and host susceptibility to subsequent BSIs. These type I IFNs consisting of, among others, 14 IFN-?'s and a single IFN-?, are recognized by and signal through the heterodimeric type I IFN receptor (IFNAR) comprised of IFNAR1 and IFNAR2. However, the individual receptor subunits can bind IFN-? or IFN-?'s independently of each other and induce distinct signaling. The role of type I IFN signaling in regulating host susceptibility to both viral infections and BSI has been only examined with respect to IFNAR1 deficiency. Here, we demonstrate that despite some redundancies, IFNAR1 and IFNAR2 have distinct roles in regulating both anti-influenza A virus (IAV) immunity and in shaping host susceptibility to subsequent BSI caused by S. aureus. We found IFNAR2 to be critical for anti-viral immunity. In contrast to Ifnar1 -/- mice, IAV-infected Ifnar2 -/- mice displayed both increased and accelerated morbidity and mortality compared to WT mice. Furthermore, unlike IFNAR1, IFNAR2 was sufficient to generate protection from lethal IAV infection when stimulated with IFN-?. With regards to BSI, unlike what we found previously in Ifnar1 -/- mice, Ifnar2 -/- mice were not susceptible to BSI induced on day 3 post-IAV, even though absence of IFNAR2 resulted in increased viral burden and an increased inflammatory environment. The Ifnar2 -/- mice similar to what we previously found in Ifnar1 -/- mice were less susceptible than WT mice to BSI induced on day 7 post-IAV, indicating that signaling through a complete receptor increases BSI susceptibility late during clinical IAV infection. Thus, our results support a role for IFNAR2 in induction of anti-IAV immune responses that are involved in altering host susceptibility to BSI and are essential for decreasing the morbidity and mortality associated with IAV infection. These results begin to elucidate some of the mechanisms involved in how the individual IFNAR subunits shape the anti-viral immune response. Moreover, our results highlight the importance of examining the contributions of entire receptors, as individual subunits can induce distinct outcomes as shown here.

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Human IFNAR2 deficiency: Lessons for antiviral immunity.

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Human IFNAR2 deficiency: Lessons for antiviral immunity.

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