The Role of Non-Typeable Haemophilus influenzae Biofilms in Chronic Obstructive Pulmonary Disease

Abstract

Non-typeable Haemophilus influenzae (NTHi) is an ubiquitous commensal-turned-pathogen that colonises the respiratory mucosa in airways diseases including Chronic Obstructive Pulmonary Disease (COPD). COPD is a progressive inflammatory syndrome of the lungs, encompassing chronic bronchitis that is characterised by mucus hypersecretion and impaired mucociliary clearance and creates a static, protective, humid, and nutrient-rich environment, with dysregulated mucosal immunity; a favourable environment for NTHi colonisation. Several recent large COPD cohort studies have reported NTHi as a significant and recurrent aetiological pathogen in acute exacerbations of COPD. NTHi proliferation has been associated with increased hospitalisation, disease severity, morbidity and significant lung microbiome shifts. However, some cohorts with patients at different severities of COPD do not report that NTHi is a significant aetiological pathogen in their COPD patients, indicating other obligate pathogens including Moraxella catarrhalis, Streptococcus pneumoniae and Pseudomonas aeruginosa as the cause. NTHi is an ubiquitous organism across healthy non-smokers, healthy smokers and COPD patients from childhood to adulthood, but it currently remains unclear why NTHi becomes pathogenic in only some cohorts of COPD patients, and what behaviours, interactions and adaptations are driving this susceptibility. There is emerging evidence that biofilm-phase NTHi may play a significant role in COPD. NTHi displays many hallmarks of the biofilm lifestyle and expresses key biofilm formation-promoting genes. These include the autoinducer-mediated quorum sensing system, epithelial- and mucus-binding adhesins and expression of a protective, self-produced polymeric substance matrix. These NTHi biofilms exhibit extreme tolerance to antimicrobial treatments and the immune system as well as expressing synergistic interspecific interactions with other lung pathogens including S. pneumoniae and M. catarrhalis. Whilst the majority of our understanding surrounding NTHi as a biofilm arises from otitis media or in-vitro bacterial monoculture models, the role of NTHi biofilms in the COPD lung is now being studied. This review explores the evidence for the existence of NTHi biofilms and their impact in the COPD lung. Understanding the nature of chronic and recurrent NTHi infections in acute exacerbations of COPD could have important implications for clinical treatment and identification of novel bactericidal targets.

Induction of Mucosal IgA–Mediated Protective Immunity Against Nontypeable Haemophilus influenzae Infection by a Cationic Nanogel–Based P6 Nasal Vaccine

“…NTHi forms biofilms, which act as reservoirs of NTHi and cause infections in the upper and lower respiratory tracts ( 31 , 32 ). NTHi biofilms increase resistance to antibiotics and trigger chronic and recurrent infections, including otitis media ( 31 , 32 ).…”

“…NTHi forms biofilms, which act as reservoirs of NTHi and cause infections in the upper and lower respiratory tracts ( 31 , 32 ). NTHi biofilms increase resistance to antibiotics and trigger chronic and recurrent infections, including otitis media ( 31 , 32 ). Because our results showed that P6-specific IgA bound effectively to the surfaces of NTHi cells ( Figure 2A ), we hypothesized that the antibody binding might physically inhibit NTHi biofilm formation.…”

Single cell RNA-seq identifies inflammation-induced loss of CFTR-expressing airway ionocytes in non-eosinophilic asthma

“…Insights into the pathogenesis of non-eosinophilic asthma may be gained by examining the crossover with cellular and pathological markers of other chronic airways diseases including COPD, CF, and subsets of non-CF bronchiectasis. These diseases also show strong neutrophilic infiltrates in the airways, a dominant mixture of Type 1 and Type 17 cytokine responses, mucous hypersecretion, and high airway bacterial colonization (4–9, 44). Indeed, the characteristic airway colonizers of CF, Pseudomonas aeruginosa and Haemophilus influenzae, are also found in high abundance in COPD and non-CF bronchiectasis and are microbiome markers of non-eosinophilic asthma (45–49).…”

The Role of Extracellular Vesicles as a Shared Disease Mechanism Contributing to Multimorbidity in Patients With COPD

“…Respiratory infections are the primary driver of COPD exacerbations, which lead to worsening of symptoms and increased risk of hospitalisation and mortality (93)(94)(95)(96). Respiratory viruses, including rhinovirus, respiratory syncytial virus (RSV) and influenza, are commonly associated with COPD exacerbations whilst colonisation of bacteria such as nontypeable Haemophilus influenzae (NTHi), Streptococcus pneumoniae and Moraxella catarrhalis in the airways of COPD patients is common during both stable disease and exacerbations (12,13,(97)(98)(99)(100). In particular, acquisition of new bacterial strains appears to be associated with an increased risk of COPD exacerbations (101,102).…”

“…For example, OMVs of M. catarrhalis can bind to TLR2 on epithelial cells and are subsequently internalized, causing a pro-inflammatory response and increased levels of IL-8 ( 138 ). Furthermore, OMVs have been implicated in the formation of biofilms that increase tolerance to antimicrobial treatments and the immune system ( 99 , 139 ). While the presence of NTHi and M. catarrhalis have been associated with a heightened risk of COPD exacerbation, the mechanisms for this remains unclear.…”