Insights on persistent airway infection by non-typeable Haemophilus influenzae in chronic obstructive pulmonary disease

Abstract

Non-typeable Haemophilus influenzae (NTHi) is the most common bacterial cause of infection of the lower airways in adults with chronic obstructive pulmonary disease (COPD). Infection of the COPD airways causes acute exacerbations, resulting in substantial morbidity and mortality. NTHi has evolved multiple mechanisms to establish infection in the hostile environment of the COPD airways, allowing the pathogen to persist in the airways for months to years. Persistent infection of the COPD airways contributes to chronic airway inflammation that increases symptoms and accelerates the progressive loss of pulmonary function, which is a hallmark of the disease. Persistence mechanisms of NTHi include the expression of multiple redundant adhesins that mediate binding to host cellular and extracellular matrix components. NTHi evades host immune recognition and clearance by invading host epithelial cells, forming biofilms, altering gene expression and displaying surface antigenic variation. NTHi also binds host serum factors that confer serum resistance. Here we discuss the burden of COPD and the role of NTHi infections in the course of the disease. We provide an overview of NTHi mechanisms of persistence that allow the pathogen to establish a niche in the hostile COPD airways.

Keywords: chronic obstructive pulmonary disease; immune evasion; mechanisms of persistence; non-typeable Haemophilus influenzae; persistent infection.

Figure 1.

Identification of NTHi in the clinical microbiology laboratory. Shaded area represents additional laboratory testing required to reliably differentiate NTHi from H. haemolyticus, currently indistinguishable by standard laboratory testing. Factor V = nicotinamide-adenine-dinucleotide (NAD), Factor X = hemin.

Figure 2.

Representation of NTHi primary site colonization of the nasopharynx (green) and secondary site infections of the middle ear and lower airways (red). NTHi colonizes the nasopharynx as a commensal organism. In children, NTHi ascends the Eustachian tube to infect the middle ear causing otitis media. During otitis media, the middle ear space, which is normally air filled, contains an inflammatory exudate due to the invading NTHi, resulting in a classic inflamed and bulging tympanic membrane. In adults with COPD, NTHi descends to the lower airways to infect the small airways of the lung. Airflow is restricted in the bronchioles and alveoli of the COPD airways due to chronic inflammation and swelling and collapsed alveolar sacks due to tissue destruction, respectively. NTHi infection of the COPD lower airways contributes to airway inflammation and increased mucous production, further contributing to restricted airflow.

Figure 3.

Model of persistent NTHi infection in the COPD small airways. In the small airways of individuals with COPD NTHi attaches to respiratory epithelial cells via multiple adhesins. Known host cell-NTHi adhesin receptors include ICAM-1, CEACAM-1, β-glucan receptor (βGR), platelet activating factor receptor (PAFR) and a vitronectin receptor that binds host vitronectin bound by NTHi. NTHi adhesins also bind to ECM proteins exposed as a result of epithelial cell damage. NTHi binds to the host ECM indirectly by binding host plasminogen (A) and through direct interactions of NTHi adhesins and host laminin (B), collagen IV (C), fibronectin (D), proteoglycans (E) and vitronectin (F). Attachment to respiratory epithelia permits intracellular invasion and evasion from host immune effectors. Attachment to respiratory epithelial and the ECM permits NTHi biofilm formation. Biofilm residency contributes to evasion from host immune effectors including resident alveolar macrophages and recruited neutrophils. Biofilms offer resistance to NET, of which components can be incorporated into the NTHi biofilms. NTHi utilizes intracellular invasion, biofilm formation and additional virulence persistence mechanisms to evade host immune recognition and clearance.