Human Rhinovirus Impairs the Innate Immune Response to Bacteria in Alveolar Macrophages in Chronic Obstructive Pulmonary Disease

Abstract

Rationale: Human rhinovirus (HRV) is a common cause of chronic obstructive pulmonary disease (COPD) exacerbations. Secondary bacterial infection is associated with more severe symptoms and delayed recovery. Alveolar macrophages clear bacteria from the lung and maintain lung homeostasis through cytokine secretion. These processes are defective in COPD. The effect of HRV on macrophage function is unknown. Objectives: To investigate the effect of HRV on phagocytosis and cytokine response to bacteria by alveolar macrophages and monocyte-derived macrophages (MDM) in COPD and healthy control subjects. Methods: Alveolar macrophages were obtained by bronchoscopy and MDM by adherence. Macrophages were exposed to HRV16 (multiplicity of infection 5), polyinosinic:polycytidylic acid (poly I:C) 30 mg/ml, IFN-b 10 mg/ml, IFN-g 10 mg/ml, or medium control for 24 hours. Phagocytosis of fluorescently labeled Haemophilus influenzae or Streptococcus pneumoniae was assessed by fluorimetry. CXCL8 (IL-8), IL-6, TNF-a (tumor necrosis factor-a), and IL-10 release was measured by ELISA. Measurements and Main Results: HRV significantly impaired phagocytosis of H. influenzae by 23% in MDM (n = 37; P = 0.004) and 18% in alveolar macrophages (n = 20; P , 0.0001) in COPD. HRV also significantly reduced phagocytosis of S. pneumoniae by 33% in COPD MDM (n = 20; P = 0.0192). There was no effect in healthy control subjects. Phagocytosis of H. influenzae was also impaired by poly I:C but not IFN-b or IFN-g in COPD MDM. HRV significantly reduced cytokine responses to H. influenzae. The IL-10 response to H. influenzae was significantly impaired by poly I:C, IFN-b, and IFN-g in COPD cells. Conclusions: HRV impairs phagocytosis of bacteria in COPD, which may lead to an outgrowth of bacteria. HRV also impairs cytokine responses to bacteria via the TLR3/IFN pathway, which may prevent resolution of inflammation leading to prolonged exacerbations in COPD.

Arpin is critical for phagocytosis in macrophages and is targeted by human rhinovirus

“…We found that this was not the case, further emphasising that HRV16 specifically affected the internalisation step. These results are important in the context of COPD where HRV is frequently isolated [20] and, together with other defective functions like cell activation [13,[22][23][24], could be one of the explanations as to why patients show bacterial outgrowths post-HRV infection [13,19]. Phagocytosis is strictly dependent on actin polymerisation (for review, Refs.…”

“…However, mounting evidence shows that HRV can infect the lower respiratory tract in patients with chronic inflammatory diseases including chronic obstructive pulmonary disease (COPD) driving disease exacerbations [17][18][19][20]. How HRV disrupts macrophage/monocyte functions remains unknown, but HRV was reported to induce a defective secondary response in macrophages [13,[22][23][24]. How HRV disrupts macrophage/monocyte functions remains unknown, but HRV was reported to induce a defective secondary response in macrophages [13,[22][23][24].…”

Early respiratory viral infections in infants with cystic fibrosis

“…In addition, viruses can decrease bacterial clearance contributing to the persistence of bacteria within the airway [ 33 ]. In COPD, rhinovirus specifically has been shown to impair bacterial phagocytosis by macrophages [ 34 ]. Others, using in vitro experiments, have shown alveolar macrophages are less able to mount an immune response to bacteria following HRV infection [ 35 , 36 ].…”

Antibiotic-dependent relationships between nasal microbiome and secreted proteome in chronic rhinosinusitis and nasal polyps

“…Activated B cells utilized mTORC1 to activate p70 ribosomal S6 kinase (p70S6K), and this preceded antibody synthesis(Gaudette et al 2020). In contrast, macrophages that released proinflammatory cytokines played an important role in clearing bacteria, and this was accompanied by the production of nitric oxide (NO) and ROS upon contact with pathogens(Tan et al 2016; Finney et al 2019). Several studies have reported that LXR activation exerted anti-inflammatory functions(Higham et al 2013) and inhibited bacterial infection of host macrophages(Pascual-Garcia et al 2013; Matalonga et al 2017).…”