Rhinovirus-Induced Exacerbations of Asthma and COPD

Hershenson, Marc B.

To address the question of whether preexisting allergic airways disease alters the response to viral infection, and whether the interferon response to rhinovirus is required for viral clearance (or part of a maladaptive response to a relatively innocuous infection), we developed a mouse model of human RV infection [68] [69] [70] [71] [72] [73] . Before describing this model, however, I like to say a little bit about the basic biology of rhinovirus. RV is an RNA virus from the Picornaviridae family. Rhinovirus is composed of a single strand of positivesense RNA enclosed in a small icosahedral capsid. There are greater than 100 known serotypes of rhinovirus. The major subgroup (88 serotypes) utilizes ICAM-1 as a receptor [74] ; the minor group (11 serotypes) uses the family of low density lipoprotein receptors (LDL-R, VLDL-R, and LDL-R related protein) [75] . Other surface molecules, including TLR2, may serve as a coreceptor and also be required for viral responses [76] . Rhinoviruses may also be classified not only on the basis of their host receptor but according to their resistance to antiviral drugs. According to this classification, there are 74 type A viruses and 25 type B viruses [77] . A third group of rhinoviruses, type C, has recently been discovered [78] [79] [80] . Rhinoviruses have also been classified according to their genome sequences [81] . Interestingly, RV16, a major group virus commonly used for experimental human infection, and RV1, which has been used in animal models of rhinovirus infection (see below), are closely related. At this time, the only cell type conclusively shown to be infected by RV in humans is the airway epithelial cell. Typically, RV infects small clusters of cells in the epithelial layer [30] . Rhinovirus is internalized by clathrin-mediated endocytosis [82] [83] [84] [85] . The endosome acidic pH triggers viral uncoating and RNA insertion. RV replication occurs entirely in the cytoplasm. During viral replication, negative sense RNA and doublestranded RNA intermediates are formed. dsRNA produced during viral infection represents an important stimulus for the host innate immune response. dsRNA is recognized and engaged by three pattern recognition receptors, toll-like receptor (TLR)-3, localized to the endosomal and plasma membranes, and cytoplasmic proteins RIG-I, and MDA-5 which are intracellular receptors for viral dsRNA [86, 87] .