Altered Differentiation and Inflammation Profiles Contribute to Enhanced Innate Responses in Severe COPD Epithelium to Rhinovirus Infection

Abstract

BackgroundRespiratory viral infections are closely associated with COPD exacerbations, hospitalisations, and significant morbidity and mortality. The consequences of the persisting inflammation and differentiation status in virus associated severe disease is not fully understood. The aim of this study was to evaluate barrier function, cellular architecture, the inflammatory response in severe COPD bronchial epithelium to human rhinovirus (HRV) induced pathological changes and innate immune responses.MethodsWell-differentiated primary bronchial epithelial cells (WD-PBECs) derived from severe COPD patients and age-matched healthy controls were cultured in the air-liquid interface (ALI) model. The differentiation phenotype, epithelial barrier integrity, pathological response and cytokine secreting profile of these cultures before and after HRV infection were investigated.ResultsWD-PBECs derived from severe COPD patients showed aberrant epithelium differentiation with a decreased proportion of ciliated cells but increased numbers of club cells and goblet cells compared with healthy controls. Tight junction integrity was compromised in both cultures following HRV infection, with heightened disruptions in COPD cultures. HRV induced increased epithelial cell sloughing, apoptosis and mucus hypersecretion in COPD cultures compared with healthy controls. A Th1/Th2 imbalance and a strong interferon and pro-inflammatory cytokine response was also observed in COPD cultures, characterized by increased levels of IFNγ, IFNβ, IP-10, IL-10 and decreased TSLP and IL-13 cytokine levels prior to HRV infection. Significantly enhanced basolateral secretion of eotaxin 3, IL-6, IL-8, GM-CSF were also observed in both mock and HRV infected COPD cultures compared with corresponding healthy controls. In response to HRV infection, all cultures displayed elevated levels of IFNλ1 (IL-29), IP-10 and TNFα compared with mock infected cultures. Interestingly, HRV infection dramatically reduced IFNλ levels in COPD cultures compared with healthy subjects.ConclusionAn altered differentiation phenotype and cytokine response as seen in severe COPD WD-PBECs may contribute to increased disease susceptibility and an enhanced inflammatory response to HRV infection.

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“…With respect to healthy controls, a Th1/Th2 imbalance and a strong interferon and proinflammatory cytokine response were observed in COPD cultures. In COPD cultures, decreased TSLP and IL-13 cytokine levels prior to HRV infection were observed [ 49 ].…”

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“…Moreover, respiratory viruses also could subvert Th1/Th2 balance in different manners, leading to pathological consequences; for example, PBMC derived from RSV patients stimulated in vitro have been shown to impair IFNγ and IL-2 production, both cytokines of Th1 profile; but able to produce IL-4, a cytokine of the Th2 profile [298,299]. In contrast, rhinovirus infection, which is highly associated with the development of chronic obstructive pulmonary disease (COPD), has been shown to induce the production of Th1 cytokines but no Th2 cytokines in vitro [300]; and during metapneumovirus experimental infection, it has been demonstrated the convergence of Th1, Th2, and Th17 profiles [301]. In the case of severe SARS-CoV-2 infection in humans, there has been reported a marked increase in both Th1 and Th2 cytokines, contrary to pandemic H1N1 influenza infection, with a more discrete cytokine profile [302].…”