Mechanism of human rhinovirus infections

Abstract

About 150 human rhinovirus serotypes are responsible for more than 50 % of recurrent upper respiratory infections. Despite having similar 3D structures, some bind members of the low-density lipoprotein receptor family, some ICAM-1, and some use CDHR3 for host cell infection. This is also reflected in the pathways exploited for cellular entry. We found that even rhinovirus serotypes binding the same receptor can travel along different endocytic pathways and release their RNA genome into the cytosol at different locations. How this may account for distinct immune responses elicited by various rhinoviruses and the observed symptoms of the common cold is briefly discussed.

Keywords: Human rhinoviruses; Immune response; Nasal epithelium; Rhinovirus receptors.

Fig. 1

HRV entry and uncoating in ciliated nasal epithelial cells. Left, HRV-A2; middle, HRV-A89; and right, HRV-B14. For clarity, minor group and major group receptors (LDLR and ICAM-1, respectively) are depicted separately although they are co-expressed at the ciliated (apical) side of nasal epithelial cells as well as on the entire plasma membrane of basal cells. After binding to the respective receptor at the ciliated surface, the viruses are internalized and delivered into early endosomes. For HRV-A2, the mildly acidic pH in these compartments leads to dissociation of the virus from its receptor. While LDLR is returned to the apical plasma membrane via perinuclear recycling endosomes, the virus is directed to late endosomes. The low pH ≤ 5.6 in late endosomes converts native viruses into subviral A particles. Subsequently, the viral RNA is released and the remaining empty capsids (subviral B particles) are shuttled to and degraded in lysosomes. In contrast, HRV-A89 together with ICAM-1 is sorted into the recycling pathway. Perinuclear recycling endosomes are similarly acidic as late endosomes resulting in conversion of native HRV-A89 into A and then into B particles. After the transfer of the viral RNA into the cytoplasm, empty capsids are most likely returned to the apical mucous layer. After binding to the same receptor, HRV-B14 is routed from early endosomes into the pathway to lysosomes. However, after undergoing the ICAM-1-dependent conformational modification, the virus ruptures the endosomal membrane leading to RNA uncoating and its penetration into the cytoplasm. Thus, the viral capsid as well as the viral RNA escapes lysosomal degradation. So far, the fate of ICAM-1 is unknown