How does rhinovirus cause the common cold cough?

Abstract

Cough is a protective reflex to prevent aspiration and can be triggered by a multitude of stimuli. The commonest form of cough is caused by upper respiratory tract infection and has no benefit to the host. The virus hijacks this natural defence mechanism in order to propagate itself through the population. Despite the resolution of the majority of cold symptoms within 2 weeks, cough can persist for some time thereafter. Unfortunately, the mechanism of infectious cough brought on by pathogenic viruses, such as human rhinovirus, during colds, remains elusive despite the extensive work that has been undertaken. For socioeconomic reasons, it is imperative we identify the mechanism of cough. There are several theories which have been proposed as the causative mechanism of cough in rhinovirus infection, encompassing a range of different processes. Those of which hold most promise are physical disruption of the epithelial lining, excess mucus production and an inflammatory response to rhinovirus infection which may be excessive. And finally, neuronal modulation, the most convincing hypothesis, is thought to potentiate cough long after the original stimulus has been cleared. All these hypotheses will be briefly covered in the following sections.

Keywords: Airway Epithelium; Cough/Mechanisms/Pharmacology; Respiratory Infection; Viral infection.

Figure 1

(A) Normal healthy airway barrier. In a healthy airway, cells are connected together by tight junction complexes including tight junctions, adherens and gap junctions. Cells are attached to basement membranes by hemidesmosomes and focal contacts. Barrier permeability is minimal and tightly regulated to prevent the excessive release of essential molecules, ions and proteins. The barrier is protective against infection. (B) Human rhinovirus infection in airway epithelial cells. There are two main ways that HRV causes physical disruption of airway barriers, inflammatory-dependent and independent. Both replicating and non-replicating viruses can interfere with airway membrane integrity by disrupting tight junction complexes. This causes a reduction of transepithelial resistance with the potential consequence of contracting a secondary infection. Cytoskeletal remodelling mediated by protein kinase D (PKD) causes an actin reorganisation within infected cells, altering their structure and integrity, further allowing cells to lose their adjoining contacts. Replicating HRV produces a dsRNA intermediate structure which can interact and activate NOD-like receptor X-1 ultimately producing reactive oxygen species. These alone are capable of reducing transepithelial resistance and barrier disruption. Loss of gap junctions and cells leaves gaps within epithelial layers. These allow cytokines, growth factors, immune cells and further viral particles to penetrate deeper layers within the airways, causing dysregulation of cellular signalling. This dysregulation causes further upregulation of various molecules including growth factors, which, in turn, can lead to an increase of receptor expression, such as transient receptor potential channels which have a prolific effect to cause cough (TNF, tumour necrosis factor; IFN, interferon; IL, interleukin).

Figure 2

Sterile-α-motif-pointed domain ETS-factor (SPDEF) and epidermal growth factor receptor (EGFR) regulation of mucus production and goblet cell metaplasia within the airways during upper respiratory tract infection (URTI). Reactive oxygen species (ROS)-induced uncoupling of EGFR permits its translocation to the apical membrane of cells which readily allows its activation. Excessive activation of EGFR promotes various cellular processes including goblet cell metaplasia and upregulation of mucus-associated genes including MUC5AC. Simultaneously, SPDEF is activated to dampen the inflammatory response mounted against the rhinovirus infection through blockade of TLR signal transduction. SPDEF also functions as a transcription modulator and causes upregulation of MUC5AC. Ultimately, increased MUC5AC and goblet metaplasia results in the hyperproduction of mucus, characteristic of rhinovirus infection.