Rhinoviruses and Their Receptors

Abstract

Human rhinoviruses (RVs) are picornaviruses that can cause a variety of upper and lower respiratory tract illnesses, including the common cold, bronchitis, pneumonia, and exacerbations of chronic respiratory diseases such as asthma. There are currently > 160 known types of RVs classified into three species (A, B, and C) that use three different cellular membrane glycoproteins expressed in the respiratory epithelium to enter the host cell. These viral receptors are intercellular adhesion molecule 1 (used by the majority of RV-A and all RV-B types), low-density lipoprotein receptor family members (used by 12 RV-A types), and cadherin-related family member 3 (CDHR3; used by RV-C). RV-A and RV-B interactions with intercellular adhesion molecule 1 and low-density lipoprotein receptor glycoproteins are well defined and their cellular functions have been described, whereas the mechanisms of the RV-C interaction with CDHR3 and its cellular functions are being studied. A single nucleotide polymorphism (rs6967330) in CDHR3 increases cell surface expression of this protein and, as a result, also promotes RV-C infections and illnesses. There are currently no approved vaccines or antiviral therapies available to treat or prevent RV infections, which is a major unmet medical need. Understanding interactions between RV and cellular receptors could lead to new insights into the pathogenesis of respiratory illnesses as well as lead to new approaches to control respiratory illnesses caused by RV infections.

Keywords: antiviral; cadherin-related family member 3; cellular receptor; intercellular adhesion molecule 1; low-density lipoprotein receptor; rhinovirus.

Figure 1

Structures of RV-A and RV-C colored by radial distance (Å) to the virus center. A black triangle indicates one icosahedral asymmetrical unit on each of the two viruses. A, Structure of RV-A with an enlarged triangle to show outline of the canyon, receptor pocket (dotted oval), receptor footprint (dotted circle, shaded gray), and pore (dark circle). B, Structure of RV-C with an enlarged triangle to show outline of binding pocket (dotted oval) and region of finger-like projection (dotted square, shaded red). A continuous canyon is absent in RV-C. RV = rhinovirus.

Figure 2

Cellular receptors of RV-A, RV-B, and RV-C. ICAM-1 has five consecutive extracellular ligand binding immunoglobulin domains linked by disulfide bonds. The NH₂ domain (D1) interacts with major group RV-A and all RV-B. The LDLR family of glycoproteins (receptors LDLR, VLDLR, and LDLR-related protein) are characterized by distinct repeats of ligand binding domains, EGF domains, and β-propeller modules. The LDLR receptor has seven consecutive extracellular ligand-binding domains followed by three EGF domains, a β-propeller module, and O-linked sugar domain. The NH₂ second and third domains (D2 and D3) interact with minor group RV-A. CDHR3 has six extracellular ligand-binding domains structurally supported by obligate Ca²⁺ ions at the domain junctions. The first two NH₂ domains (D1 and D2) are predicted to interact with RV-C. All RV receptors have a TM and COOH. Their virus contact domains are shaded. CDHR3 = cadherin-related family member 3; COOH = C-terminal cytoplasmic tail; EGF = epidermal growth factor; ICAM-1 = intercellular adhesion molecule 1; LDLR = low-density lipoprotein receptor; NH₂ = N-terminal; TM = transmembrane region. See Figure 1 legend for expansion of other abbreviation.