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.

Studies in single patients can establish causality between genotype and phenotype in humans, provided that the mutant genotype is only found in the affected patient, the specific variant impairs corresponding protein function, and cellular phenotype can be recapitulated or rescued at the molecular level (Casanova et al., 2014; Ciancanelli et al., 2015) . By these criteria, we have shown that human MDA5 protects against respiratory infections caused by HRV. HRV accounts for a substantial disease burden of acute lower respiratory infections requiring hospitalization, especially in infants and children where it surpasses that of influenza (Gaunt et al., 2011) . Additionally, HRV is primarily responsible for half of upper respiratory infections, but has not been adequately studied as it is often dismissed as innocuous (Heikkinen and Järvinen, 2003; Global Burden of Disease Study 2013 Collaborators, 2015 . This has impeded clinical recognition of additional patients with genetic susceptibility to severe respiratory disease associated with the common cold. Whether MDA5 provides physiological protection against other respiratory viruses that we did not test such as human coronaviruses and adenovirus, or against systemic RNA viruses that our patient has not been exposed to such as poliovirus and Hepatitis A virus, is not yet known. Interestingly, our patient has not had hand-foot-mouth disease, nor has she had detectable nonrespiratory enteroviruses associated with acute viral gastroenteritis, possibly due to a differential dependence of MDA5 virus-sensing on the virus or cell type, as well as protective effects of intravenous immunoglobulin treatment that variably contains neutralizing antibodies to enteroviruses (Galama et al., 2000; Arora et al., 2011) . The type 1 diabetes mellitus that she developed at two yr of age might have been precipitated by persistent infection with pancreatropic enteroviruses which have been detected in pancreatic autopsy specimens from recent-onset disease (Jaïdane et al., 2010; Rodriguez-Calvo and von Herrath, 2015) . Moreover, her intrauterine growth retardation was compatible with congenital infection by untested viruses that might be poorly controlled in multiple organ systems when MDA5 is lacking. Nonetheless, respiratory infections are the most frequent type of infection among the general population, and thus, exposure history most likely accounts for what seems at first glance to be a "site-specific" susceptibility.