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.

Our patient reveals the important protective and nonredundant role MDA5 exerts in the human respiratory tract, where it senses and initiates innate immune responses to HRV. Importantly, by carrying out in vitro infection experiments in MDA5-silenced respiratory epithelial cells-and also in the patient's own MDA5-deficient nasal epithelial cells and gene-edited fibroblasts-we have established that the MDA5 genotype is responsible for the increased HRV replication and HRV clinical phenotype in our patient. In contrast, the lack of in vitro susceptibility to influenza virus or RSV in the same cell types suggests that the MDA5 genotype is not responsible for these infections in our patient. These results also indicate that, surprisingly, other viruses such as influenza virus and RSV, which have (ds)RNA intermediates or byproducts that can be recognized by MDA5, are recognized and controlled by other means when MDA5 is deficient. Although it is possible that defective responses to these other viruses might occur in other MDA5-deficient cell types, our results show that this does not occur at the initial site of infection in the lung within respiratory epithelial cells. Additionally, in our patient, the decreased incidence of infections with age coincided with the maturation of antibody responses. This ability of antibodies to compensate for defective innate immunity is similarly observed in other deficiencies of innate immunity. For example, in IRF7 deficiency associated with isolated influenza susceptibility, the absence of repeated influenza infection was associated with initiation of annual seasonal influenza vaccination . Moreover, in TIR AP deficiency associated with isolated staphylococcal susceptibility, staphylococcal lipoteichoic acid (LTA)-specific antibodies were able to prevent disease by rescuing defective TLR2-dependent recognition of LTA (Israel et al., 2017) .