The Interplay Between Immune Response and Bacterial Infection in COPD: Focus Upon Non-typeable Haemophilus influenzae

Abstract

Chronic obstructive pulmonary disease (COPD) is a debilitating respiratory disease and one of the leading causes of morbidity and mortality worldwide. It is characterized by persistent respiratory symptoms and airflow limitation due to abnormalities in the lower airway following consistent exposure to noxious particles or gases. Acute exacerbations of COPD (AECOPD) are characterized by increased cough, purulent sputum production, and dyspnea. The AECOPD is mostly associated with infection caused by common cold viruses or bacteria, or co-infections. Chronic and persistent infection by non-typeable Haemophilus influenzae (NTHi), a Gram-negative coccobacillus, contributes to almost half of the infective exacerbations caused by bacteria. This is supported by reports that NTHi is commonly isolated in the sputum from COPD patients during exacerbations. Persistent colonization of NTHi in the lower airway requires a plethora of phenotypic adaptation and virulent mechanisms that are developed over time to cope with changing environmental pressures in the airway such as host immuno-inflammatory response. Chronic inhalation of noxious irritants in COPD causes a changed balance in the lung microbiome, abnormal inflammatory response, and an impaired airway immune system. These conditions significantly provide an opportunistic platform for NTHi colonization and infection resulting in a "vicious circle." Episodes of large inflammation as the consequences of multiple interactions between airway immune cells and NTHi, accumulatively contribute to COPD exacerbations and may result in worsening of the clinical status. In this review, we discuss in detail the interplay and crosstalk between airway immune residents and NTHi, and their effect in AECOPD for better understanding of NTHi pathogenesis in COPD patients.

Keywords: COPD; airway; exacerbation; immune response; infection; inflammation; non-typeable Haemophilus influenza.

Figure 1

Cigarette and tobacco smoke has several effects on gene regulation. Nicotine and other compounds in the smoke alter gene expression by two pathways, firstly, chromatin remodeling (Left) and secondly, DNA methylation (Right). Chromatin remodeling involves activation of kinases signaling pathways, activation and nuclear translocation of transcription factor NF-κB (RelA/p65), and complex formation with CBP/p300 on specific DNA sites. CBP/p300 is intrinsically a histone acetyltransferase (HAT). Subunit p65 is further phosphorylated at Ser276 and Ser311, respectively, by MSK1 and PKCζ, whereas CBP acetylates p65 at Lys310. The phosphorylation and acetylation enhance the interaction within the NF-κB/CBP/p300 complex while stabilizing the DNA binding of NF-κB. The complex of NF-κB/CBP/p300 then modifies the histones through CBP-mediated acetylations of histone H3 (at Lys9) and H4 at Lys 8 and Lys12, and phosphorylation of H3 at Ser10 by MSK1 and PKCζ. This results in the structure change of chromatin, from a condensed structure (repressed) to an activated open conformation. The transcription of target genes is therefore increased. In the second mechanism, several side effects resulting from cigarette smoking such as DNA damage and nicotine signaling could trigger the hypermethylation or decreased methylation of target DNA. This may lead to DNA methylation anomalies and thus altered DNA expression. Resulting hypoxia due to high concentrations of carbon monoxide also contributes to altered gene expression. The aberrant gene expression by cigarette smoke mostly occurs in pro-inflammatory genes with resulting increased production of inflammatory mediators, and amplified inflammation in the COPD lung upon exposure.

Figure 2

Non-typeable H. influenzae-dependent immune responses in the lower airway of COPD patients result in inflammation. Airway epithelium exposed to cigarette or tobacco smoke display an increased permeability with compromised tight junctions, and airway remodeling (goblet cell hyperplasia and small airway squamous metaplasia). Cigarette smoke causes the activation of airway epithelium and alveolar macrophages. The activated airway structural and resident immune cells release an array of chemotactic factors responsible for recruitment of inflammatory and immune cells to the lung. Activated epithelium produces TGF-β and FGF that triggers the production of ECM molecules by fibroblasts. Increased deposition of ECM causes progression of fibrosis and air flow limitation. The chemokines CXCL1 and IL-8, and LTB₄ attract the circulating neutrophils through the receptors CXCR2 and BLT₁, respectively. Meanwhile, CXCL1 and CCL2 targeting the receptors CXCR2 and CCR2 on blood monocytes are also released. Recruited blood monocytes differentiate into macrophages in the airway tissue. Activated alveolar macrophage and epithelium cell also release inflammasome (1L-1β and IL-18) for neutrophils survival and activation of helper T cells Th17. The chemokine IL-23 are released by macrophages to attract T helper cell subset Th17, and ILC3. Both Th17 and ILC3 will release IL-17 and IL-22 that will act on the alveolar epithelium to release CXCL1 and IL-8 for enhanced recruitment of neutrophils, resulting in neutrophilic inflammation. Activated neutrophils are thereafter degranulated and release myeloperoxidase (MPO), lipocalin, neutrophil elastase (NE), cathepsin-G (CG), proteinase-3 (Prot-3), and matrix metalloprotease (MMP) 8 and 9. The granulated products are proteolytic and elastilolytic to aveolar, causing alveolar destruction and emphysema. In addition, NE, CG, and Prot-3 are also targeting goblet cells and submucosal glands to induce hypersecretion of mucus. Dendritic cells carrying the receptors CCR2 and CCR6 are recruited to airway tissue via chemottractants CCL2 and CCL20. The dendritic cells uptake the antigen (smoke residues), and present the antigens to the naïve T cells at lymph nodes. Uncommitted T lymphocytes are thereafter primed to the presented antigen and activated by IL-12 derived from dendritic cells (professional antigen presenting cells; APC). Mature/activated T cells expressing receptor CXCR3 are chemotactic toward CXCL9, CXCL10, and CXCL11 and are recruited to the lung tissue. Cytotoxic CD8+ T cell subtype Tc1 releases perforin and granzyme B resulting in epithelial apoptosis contributing to emphysema progression. For the humoral immune response, B cells are activated by Th2, enter the circulation via high-endothelial venule (HEV)-like vessel and transported to lung tissue, and organized into lymphoid follicles at peripheral airway. B cell-derived plasma cells from lymphoid follicles release IgA, and secreted into airway lumen as secretory IgA (sIgA) via the polymeric immunoglobulin receptor. Mucosal antibodies play an important role to eradicate pathogens and noxious antigens via immune exclusion. However, the airway defense by sIgA is diminished by NTHi IgA protease that degrade the antibodies. TLR2 and TLR4 of the airway phagocytes and epithelium following exposure to cigarette smoke are not responding to P6 and LOS of NTHi. This results in defective phagocytosis and delayed bacterial clearance from the airway. The suppressed TLR4 induction in T cells has also lead to Th2 predominant immune response, with low production of IFN-γ and reduced T cell-mediated immune killing of NTHi. Moreover, NTHi downregulates Foxp3 of Tregs and thus impairs the anti-inflammatory/pro-inflammatory balance of Tregs. The extensive immunosuppressive activity by Tregs diminishes the response of effector T to NTHi stimulation. Lastly, plasma cells from COPD patients fail to produce NTHi-specific antibodies and compromised immunoglobulin class switching. The impairment of the host immune response in COPD toward NTHi infection are labeled in blue. In total, NTHi infection in COPD lung adversely reduces the production of IL-1β, IL-6, IL-8, CXCL-10, IL-22, TNF-α, antimicrobial peptide (AMP), and IFN-γ. This may explain the inefficient eradication of airway pathogens in COPD patients whereby persistent NTHi infection concomitantly escalates the inflammation and thus exacerbation in COPD.