Pathogenesis of rhinovirus infection

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Since its discovery in 1956, rhinovirus (RV) has been recognized as the most important virus producing the common cold syndrome. Despite its ubiquity, little is known concerning the pathogenesis of RV infections, and some of the research in this area has led to contradictions regarding the molecular and cellular mechanisms of RV-induced illness. In this article, we discuss the pathogenesis of this virus as it relates to RV-induced illness in the upper and lower airway, an issue of considerable interest in view of the minimal cytopathology associated with RV infection. We endeavor to explain why many infected individuals exhibit minimal symptoms or remain asymptomatic, while others, especially those with asthma, may have severe, even life-threatening, complications (sequelae). Finally, we discuss the immune responses to RV in the normal and asthmatic host focusing on RV infection and epithelial barrier integrity and maintenance as well as the impact of the innate and adaptive immune responses to RV on epithelial function.

Highlights

► Rhinovirus is a ubiquitous virus and the usual cause of the common cold, yet little is known regarding its pathogenic mechanisms. ► The upper and lower airways are the primary targets of RV, but, surprisingly, this virus causes little cytopathology. ► Many patients will have positive tests to RV, yet remain subclinical. ► The host epithelial barriers and both innate and adaptive immune responses influence the reaction of the host. ► The various immune responses lead to the distinct outcomes from subclinical to severe and even life-threatening infections.

Introduction

Rhinovirus (RV) was first isolated in 1956 by Dr. Winston Price at Johns Hopkins University and was quickly determined to be the most common cause of cold symptoms in adults [1, 2]. It is a positive sense, single-stranded nonenveloped RNA virus of the picornavirus family with well over 100 serotypes discovered to date [3••]. The RNA genome serves as an mRNA, which encodes both structural (capsid) proteins and nonstructural proteins that are involved in viral genome replication and virion assembly. Upon entry into a cell the viral genome is translated into a polyprotein, which in turn undergoes proteolytic cleavage to produce the structural and nonstructural gene products. The RNA genome is packaged within a protein coat consisting of four viral capsid proteins 1, 2, 3, and 4 (VP1, VP2, VP3, and VP4) [3••, 4] (Figure 1). Amino acid differences in one or more of these capsid proteins confer the antigenic differences among individual RV strains or serotypes. The serotypes can be classified as HRV-A, HRV-B, or HRV-C viruses based upon genetic homology [1, 3••, 5].

Over 90% of the known RV serotypes of the HRV-A and HRV-B families utilize ICAM-1 as their cell entry receptor, while the minor group receptor, low-density lipoprotein (LDL), is used by 10 serotypes [4, 6]. HRV binds ICAM-1 near the site of LFA-1 attachment and, as a consequence of binding, the virus loses its protein capsid. Though somewhat controversial, this uncoating process is thought to occur via intermediate particles characterized by the loss of VP4 and the externalization of the hydrophobic N-termini of VP1, and ultimately this leads to transmigration of viral RNA through the host cell membrane [4].

HRV-C has more recently emerged as a virus of interest, particularly in RV-induced exacerbations of asthma [7•]. The genomes of several strains of HRV-C have been recently sequenced, but, to date, the structural information has not as yet shed light on a potential cellular receptor and the receptor it employs to infect epithelial cells remains unclear. On the basis of structural modeling studies, this is unlikely to be either ICAM-1 or the LDL receptor. Gern et al. were the first to grow HRV-C in vitro, utilizing sinus mucosal tissue as the cellular substrate for in vitro HRV-C replication [3••]. At present, HRV-C infection has been studied to only a limited extent and little is known regarding pathogenic mechanisms unique to this RV subtype. Consequently, the remainder of this review will focus on findings involving infection with HRV-A and HRV-B.

Section snippets

Upper and lower respiratory tract disease pathogenesis

In nonasthmatic individuals, symptoms of RV infection are generally limited to the upper respiratory tract. Rhinorrhea and nasal obstruction, the most prominent symptoms, are associated with a neutrophilic inflammatory response that causes increased vascular permeability and stimulation of mucus hypersecretion. Cough is a less common but bothersome manifestation of RV URI. The pathogenesis of cough may involve irritation from posterior pharyngeal drainage or direct infection of the large

Clinical and subclinical infections

Early studies utilizing tissue culture isolation to detect RV in the nasal secretions of patients with cold symptoms undoubtedly under-reported the frequency of RV infections. Since the advent of nucleic acid-based detection, it is possible to more reliably discern the actual prevalence of RV infection. However, the application of sensitive PCR-based detection techniques immediately led to a quandary regarding the issue of the prevalence of asymptomatic infection with RV. This confirmed earlier

Pathogenic influences of RV on the epithelium

While other respiratory viruses such as influenza and respiratory syncytial virus destroy the airway epithelial barrier, studies demonstrate that RV by itself does not cause cytopathology. For these studies, monolayers of adenoid tissue were infected with RV and, at the time of peak secreted viral titers, no detectable damage or other cytopathic effect was observed [23]. This is consistent with the failure to observe cytopathology in RV-infected nasal or bronchial biopsy tissue. Infection does,

Immune response to rhinovirus

In the absence of an ability to ascribe the presence and extent of symptoms to either virus titer or cytopathology, we propose that it is the characteristics of the host response to RV that are the primary determinant of symptoms. The host response to the virus includes those mediated by the innate, humoral, and cellular immune systems. To some extent these distinct responses represent a continuum with the progressive evolution of more severe (and more symptomatic) responses, although the

Innate immunity

In the absence of preexisting humoral immunity (discussed below) or presumably other mucosal surface-associated factors, RV will infect the epithelium and this will initially lead to the induction of an innate immune response. This occurs very rapidly as evinced by our studies showing appearance of type I interferon along with a drop in airway pH less than 24 hours after experimental infection [26]. Early innate detection of RV depends on the host's ability to recognize RV-associated pattern

Humoral immune responses

The therapeutic importance of humoral immune responses to RV is increasingly recognized. In experimental RV inoculation, B cell responses in the form of mucosal RV serotype-specific IgA were detected by day 3 and IgG at days 7–8 [40]. A role for this humoral response is suggested by observations that the presence of serotype-specific neutralizing IgG antibodies precludes subsequent challenge infection following experimental inoculation with an RV of that serotype [41]. It should be emphasized

Cellular immune responses

In the absence of neutralizing antibodies or an effective innate immune response, RV-specific T-cells become central in virus eradication. The rapidity with which viral titers begin to decline after an RV infection, usually at ∼72 hours, precludes the possibility that this reflects the de novo activation of naïve RV serotype-specific T cells. This observed timeframe is only consistent with activation of preexisting effector/memory T cells, which must therefore respond to shared epitope(s)

Mechanism of asthma exacerbations in association with RV infections

Any discussion of RV-associated disease pathogenesis must appreciate the striking capacity of this virus to drive asthma exacerbations. Among children, 80–85% of asthma exacerbations are associated with upper respiratory viral infections [46, 47] and RV consistently accounts for ∼60–70% of these virus-associated exacerbations [48, 49, 50, 51, 52, 53, 54, 55]. For example, in our studies, viral infections were identified in 61% of children aged 3–18 years hospitalized with an asthma

Summary

A debate remains as to whether it is the inherent pathogenicity of RV that leads to the associated symptoms, or whether it is the environment in which the virus replicates that determines the induction of symptoms. We argue that it is that various facets of the immune response to the virus that are important in restricting the infection but simultaneously drive the symptoms of RV infection, as the virus itself is not cytopathic. Whether features of physical barrier function, the innate immune

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors would like to acknowledge Dr. Judith Woodfolk for her gracious review and edits of this paper. Also, we appreciate the work of Zach Kennedy for the illustrations included within this review.

Dr. Larry Borish is funded by NIH RO1 AI057483 and R21 AI1090413. Dr. Thomas Braciale has funding from NIH R01 AI15608, R01 HL33391, U19 AI83024 and R21 AI1090413. Dr. Ron Turner has received funding from Henkel, Inc, Johnson and Johnson Pharmaceutical Research and Development, NIH 5R43 AI085683,

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