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New molecular, cellular, and immunologic techniques used to study host–pathogen interactions have led to a reexamination of the role of infection in chronic obstructive pulmonary disease (COPD). There is now considerable evidence that infection plays a major role in the pathogenesis and clinical course of COPD. A vicious circle of infection and inflammation is thought to lead to exacerbations of the disease. New molecular, cellular, and immunologic techniques used to study host–pathogen interactions have led to a reexamination of the role of infection in chronic obstructive pulmonary disease (COPD). Considerable evidence suggests that a vicious circle of infection and inflammation leads to exacerbations of the disease. Historical Perspective In the 1950s and 1960s, according to a theory known as the British hypothesis, repeated airway infection and hypersecretion of mucus were thought to be the causes of chronic obstructive pulmonary disease (COPD). Subsequently, exposure to tobacco smoke was identified as the predominant cause. Researchers were still unable to relate the frequency of exacerbations — acute increases in the respiratory symptoms of COPD that require medical intervention — and hypersecretion of mucus to the progression of airflow obstruction. 1 Instead, the frequency of bacterial isolation from sputum was found to be similar in stable COPD and during exacerbations. On . . .

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. A review of mechanisms of persistence used by non-typeable Haemophilus influenzae to infect the airways of individuals with chronic obstructive pulmonary disease

Moraxella catarrhalis is an exclusively human pathogen and is a common cause of otitis media in infants and children, causing 15%-20% of acute otitis media episodes. M. catarrhalis causes an estimated 2–4 million exacerbations of chronic obstructive pulmonary disease in adults annually in the United States. M. catarrhalis resembles commensal Neisseria species in culture and, thus, may be overlooked in samples from the human respiratory tract. The prevalence of colonization of the upper respiratory tract is high in infants and children but decreases substantially in adulthood. Most strains produce β-lactamase and are thus resistant to ampicillin but susceptible to several classes of oral antimicrobial agents. Recent work has elucidated mechanisms of pathogenesis and focused on vaccine development to prevent otitis media in children and respiratory tract infections caused by M. catarrhalis in adults with chronic obstructive pulmonary disease.

Understanding the causes and factors related to readmission for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) within a nationwide database including all payers and ages can provide valuable input for the development of generalizable readmission reduction strategies. To determine the rates, causes, and predictors for early (3-, 7-, and 30-d) readmission in patients hospitalized with AECOPD in the United States using the Nationwide Readmission Database after the initiation of the Hospital Readmissions Reduction Program, but before its expansion to COPD. We conducted an analysis of the Nationwide Readmission Database from 2013 to 2014. Index admissions and readmissions for an AECOPD were defined consistent with Hospital Readmissions Reduction Program guidelines. We investigated the percentage of 30-day readmissions occurring each day after discharge and the most common readmission diagnoses at different time periods after hospitalization. The relationship between predictors (categorized as patient, clinical, and hospital factors) and early readmission were evaluated using a hierarchical two-level logistic model. To examine covariate effects on early-day readmission, predictors for 3-, 7-, and 30-day readmissions were modeled separately. There were 202,300 30-day readmissions after 1,055,830 index AECOPD admissions, a rate of 19.2%. The highest readmission rates (4.2-5.5%) were within the first 72 hours of discharge, and 58% of readmissions were within the first 15 days. Respiratory-based diseases were the most common reasons for readmission (52.4%), and COPD was the most common diagnosis (28.4%). Readmission diagnoses were similar at different time periods after discharge. Early readmission was associated with patient (Medicaid payer status, lower household income, and higher comorbidity burden) and clinical factors (longer length of stay and discharge to a skilled nursing facility). Predictors did not vary substantially by time of readmission after discharge within the 30-day window. Thirty-day readmissions after an AECOPD remain a major healthcare burden, and are characterized by a similar spectrum of readmission diagnoses. Predictors associated with readmission include both patient and clinical factors. Development of a COPD-specific risk stratification algorithm based on these factors may be necessary to better predict patients with AECOPD at high risk of early readmission.

Background Reverse vaccinology accelerates the discovery of potential vaccine candidates (PVCs) prior to experimental validation. Current programs typically use one bacterial proteome to identify PVCs through a filtering architecture using feature prediction programs or a machine learning approach. Filtering approaches may eliminate potential antigens based on limitations in the accuracy of prediction tools used. Machine learning approaches are heavily dependent on the selection of training datasets with experimentally validated antigens (positive control) and non-protective-antigens (negative control). The use of one or few bacterial proteomes does not assess PVC conservation among strains, an important feature of vaccine antigens. Results We present ReVac, which implements both a panoply of feature prediction programs without filtering out proteins, and scoring of candidates based on predictions made on curated positive and negative control PVCs datasets. ReVac surveys several genomes assessing protein conservation, as well as DNA and protein repeats, which may result in variable expression of PVCs. ReVac’s orthologous clustering of conserved genes, identifies core and dispensable genome components. This is useful for determining the degree of conservation of PVCs among the population of isolates for a given pathogen. Potential vaccine candidates are then prioritized based on conservation and overall feature-based scoring. We present the application of ReVac, applied to 69  Moraxella catarrhalis and 270 non-typeable Haemophilus influenzae genomes, prioritizing 64 and 29 proteins as PVCs, respectively. Conclusion ReVac’s use of a scoring scheme ranks PVCs for subsequent experimental testing. It employs a redundancy-based approach in its predictions of features using several prediction tools. The protein’s features are collated, and each protein is ranked based on the scoring scheme. Multi-genome analyses performed in ReVac allow for a comprehensive overview of PVCs from a pan-genome perspective, as an essential pre-requisite for any bacterial subunit vaccine design. ReVac prioritized PVCs of two human respiratory pathogens, identifying both novel and previously validated PVCs.

Moraxella catarrhalis is a human respiratory tract pathogen that causes otitis media (middle ear infections) in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. In view of the huge global burden of disease caused by M. catarrhalis, the development of vaccines to prevent these infections and better approaches to treatment have become priorities. In previous work, we used a genome mining approach that identified three substrate binding proteins (SBPs) of ATP-binding cassette (ABC) transporters as promising candidate vaccine antigens. In the present study, we performed a comprehensive assessment of 19 SBPs of 15 ABC transporter systems in the M. catarrhalis genome by engineering knockout mutants and studying their role in assays that assess mechanisms of infection. The capacity of M. catarrhalis to survive and grow in the nutrient-limited and hostile environment of the human respiratory tract, including intracellular growth, account in part for its virulence. The results show that ABC transporters that mediate uptake of peptides, amino acids, cations and anions play important roles in pathogenesis by enabling M. catarrhalis to 1) grow in nutrient-limited conditions, 2) invade and survive in human respiratory epithelial cells and 3) persist in the lungs in a murine pulmonary clearance model. The knockout mutants of SBPs and ABC transporters showed different patterns of activity in the assay systems, supporting the conclusion that different SBPs and ABC transporters function at different stages in the pathogenesis of infection. These results indicate that ABC transporters are nutritional virulence factors, functioning to enable the survival of M catarrhalis in the diverse microenvironments of the respiratory tract. Based on the role of ABC transporters as virulence factors of M. catarrhalis, these molecules represent potential drug targets to eradicate the organism from the human respiratory tract.

Nontypeable Haemophilus influenzae (NTHi) persists in the lower airways of adults with chronic obstructive pulmonary disease (COPD) for months to years, increasing airway inflammation that accelerates the progressive loss of lung function. Understanding the mechanisms of persistence in human airways by NTHi is critical in developing novel interventions. Chronic obstructive pulmonary disease (COPD) is a common debilitating disorder that is the third most common cause of death globally. Chronic lower airway infection by nontypeable Haemophilus influenzae (NTHi) in adults with COPD increases airway inflammation, causes increased symptoms, and accelerates progressive loss of lung function. Little is known about the mechanisms by which NTHi survives in COPD airways. To explore this question, the present study analyzes, in detail, 14 prospectively collected, serial isolates of a strain that persisted for 543 days in a patient with COPD, including analysis of four gap-free complete genomes. The NTHi genome underwent inversion of a ~400-kb segment three times during persistence. This inversion event resulted in switching of expression of the HMW1A and HMW2A adhesins as the inversion sites are in the promoter regions of HMW1 and HMW2. Regulation of the level of expression of HMW 1 and HMW2 in the human airways was controlled by the ~400-kb inversion and by 7-bp repeats in the HMW promoters. Analysis of knockout mutants of the persistent strain demonstrated that HMW1 and HMW2 proteins both function in the adherence of NTHi to human respiratory epithelial cells during persistence and that HMW1 also facilitates invasion of epithelial cells. An inverse relationship between biofilm formation and HMW1 expression was observed during persistence. This work advances understanding of the mechanisms of persistence of NTHi in COPD airways, which can inform the development of novel interventions to treat and prevent chronic NTHi infection in COPD. IMPORTANCE Nontypeable Haemophilus influenzae (NTHi) persists in the lower airways of adults with chronic obstructive pulmonary disease (COPD) for months to years, increasing airway inflammation that accelerates the progressive loss of lung function. Understanding the mechanisms of persistence in human airways by NTHi is critical in developing novel interventions. Here, in detail, we studied longitudinally collected sequential isolates of a strain of NTHi that persisted in an adult with COPD, including analysis of four gap-free genomes and knockout mutants to elucidate how the genome adapts in human airways. The NTHi genome underwent a genome rearrangement during persistence and this inversion impacted regulation of expression of key virulence phenotypes, including adherence to respiratory epithelial cells, invasion of epithelial cells and biofilm formation. These novel observations advance our understanding of the mechanisms of persistence of NTHi in the airways of adults with COPD.

Rhinovirus causes many types of respiratory illnesses, ranging from minor colds to exacerbations of asthma. Moraxella catarrhalis is an opportunistic pathogen that is increased in abundance during rhinovirus illnesses and asthma exacerbations and is associated with increased severity of illness through mechanisms that are ill-defined. We used a co-infection model of human airway epithelium differentiated at the air-liquid interface to test the hypothesis that rhinovirus infection promotes M. catarrhalis adhesion and survival on the respiratory epithelium. Initial experiments showed that infection with M. catarrhalis alone did not damage the epithelium or induce cytokine production, but increased trans-epithelial electrical resistance, indicative of increased barrier function. In a co-infection model, infection with the more virulent rhinovirus-A and rhinovirus-C, but not the less virulent rhinovirus-B types, increased cell-associated M. catarrhalis . Immunofluorescent staining demonstrated that M. catarrhalis adhered to rhinovirus-infected ciliated epithelial cells and infected cells being extruded from the epithelium. Rhinovirus induced pronounced changes in gene expression and secretion of inflammatory cytokines. In contrast, M. catarrhalis caused minimal effects and did not enhance RV-induced responses. Our results indicate that rhinovirus-A or C infection increases M. catarrhalis survival and cell association while M. catarrhalis infection alone does not cause cytopathology or epithelial inflammation. Our findings suggest that rhinovirus and M. catarrhalis co-infection could promote epithelial damage and more severe illness by amplifying leukocyte inflammatory responses at the epithelial surface.

This prospective study examined the changes in bacterial isolates from sputum samples obtained monthly from 81 outpatients with chronic obstructive pulmonary disease. There were 374 acute exacerbations of lung disease, which were significantly associated with the acquisition of a new strain of Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae (relative risk for any new strain, 2.15). An exacerbation was diagnosed at 33 percent of the clinic visits that coincided with the appearance of a new bacterial strain in the sputum. This prospective study shows a relation between clinical deterioration and the presence of a new bacterial strain. Morbidity and mortality among patients with chronic obstructive pulmonary disease are related in large part to acute exacerbations, which occur one to three times per year. 1 – 6 Our understanding of the cause and pathogenesis of these exacerbations is incomplete, and the role of bacterial pathogens is controversial. 7 – 10 In studies performed decades ago, investigators followed patients with chronic obstructive pulmonary disease longitudinally, with periodic collection of sputum samples for culture, to determine whether there was an association between the isolation of bacterial pathogens in sputum and the occurrence of exacerbations. 5 , 6 , 11 In these studies, the rate of isolation of . . .