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.

Host immunity to many viruses, including those targeting the respiratory tract, can be initiated in mice by the RIG-I-like helicase receptors (RLR) melanoma differentiation-associated protein 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). MDA5 and RIG-I, which are encoded by the IFIH1 and DDX58 genes, function as intracellular cytosolic sensors of double-stranded (ds)RNA viral replicative intermediates or byproducts. Both sensors send signals through the adaptor mitochondrial antiviral-signaling protein (MAVS, also known as IPS-1, Cardif, and VISA) to activate IFN production and IFN-regulated gene transcription. This can inhibit virus replication and modulate cellular immune responses. MDA5 has a major role in recognizing and limiting picornavirus replication in mice and in vitro in human cells (Gitlin et al., 2006; Kato et al., 2006; Wang et al., 2009 Wang et al., , 2010 Wang et al., , 2011 Slater et al., 2010; McCartney et al., 2011; Triantafilou et al., 2011; Jin et al., 2012) . Together with RIG-I, MDA5 can also recognize and limit replication of other positive sense single-stranded RNA viruses of the coronavirus, calicivirus, and flavivirus families (Loo et al., 2008; McCartney et al., 2008; Roth-Cross et al., 2008; Li et al., 2010; Züst et al., 2011; Errett et al., 2013) , (ds)RNA viruses of the orthoreovirus family (Loo et al., 2008) , negative sense single-stranded (ss)RNA viruses of the paramyxovirus and orthomyxovirus families (Kato et al., 2006; Shingai et al., 2007; Gitlin et al., 2010; Baños-Lara et al., 2013; Grandvaux et al., 2014; Kim et al., 2014) , and even a DNA virus of the poxvirus family (Delaloye et al., 2009; Pichlmair et al., 2009) . However, those studies were conducted in vivo in MDA5-deficient mice and in vitro using mouse and human cells. In contrast, the role of MDA5 deficiency in the course of natural infections in humans is not yet known.