Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

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

underlying respiratory disease are absent. Thus, unlike other primary immunodeficiencies characterized by susceptibility to highly pathogenic microbes, the lack of strong purifying selection is not unexpected for MDA5. It is still possible that heterozygous variants that impair activity also exert protective advantage as has been suggested by genome-wide association studies of type 1 diabetes mellitus (Smyth et al., 2006; Nejentsev et al., 2009) . As shown by our knockdown experiments, MDA5 function appears to be partially redundant with RIG-I function for controlling HRV replication, where other sensors can contribute to protection when MDA5 function is lacking. Although other genetic variants in the patient might have contributed to her susceptibility to influenza virus or RSV, this seems less likely since replication of influenza virus or RSV in her nasal epithelial cells was comparable to that in cells from healthy controls. Alternatively, it instead seems possible that in the setting of chronic lung disease-which is probably multifactorial from ventilator-induced lung injury, recurrent HRV infections in infancy, or other cofactors-secondary complications including susceptibility to other viruses such as influenza and RSV and bacterial superinfections ensued. Thus, in some individuals, a selective genetic susceptibility to HRV could under certain circumstances contribute more broadly to the pathogenesis of severe respiratory disease during childhood. Furthermore, in light of the known association of HRV infections as a trigger of asthma exacerbations, it will be interesting to explore whether loss-of-function mutations in IFIH1 are associated with worsened asthma outcome in susceptible individuals.