Immunoglobulin A Protease Variants Facilitate Intracellular Survival in Epithelial Cells By Nontypeable Haemophilus influenzae That Persist in the Human Respiratory Tract in Chronic Obstructive Pulmonary Disease

Murphy, Timothy F.; Kirkham, Charmaine; Gallo, Mary C; Yang, Yang; Wilding, Gregory E.; Pettigrew, Melinda M.

doi:10.1093/infdis/jix471

Cited by 16 publications

(12 citation statements)

References 32 publications

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“…This important observation suggests that changes in SSRs, and thus regulation of expression genes by slipped-strand mispairing, are driven by selective pressure in the human airways. This observation is consistent with recent work that shows that passage of NTHi strains through human respiratory epithelial cells selects for expression of IgA proteases that are regulated by slipped-strain mispairing (66).…”

Section: Discussionsupporting

confidence: 93%

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease

Pettigrew

Ahearn

Gent³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Nontypeable (NTHi) exclusively colonize and infect humans and are critical to the pathogenesis of chronic obstructive pulmonary disease (COPD). In vitro and animal models do not accurately capture the complex environments encountered by NTHi during human infection. We conducted whole-genome sequencing of 269 longitudinally collected cleared and persistent NTHi from a 15-y prospective study of adults with COPD. Genome sequences were used to elucidate the phylogeny of NTHi isolates, identify genomic changes that occur with persistence in the human airways, and evaluate the effect of selective pressure on 12 candidate vaccine antigens. Strains persisted in individuals with COPD for as long as 1,422 d. Slipped-strand mispairing, mediated by changes in simple sequence repeats in multiple genes during persistence, regulates expression of critical virulence functions, including adherence, nutrient uptake, and modification of surface molecules, and is a major mechanism for survival in the hostile environment of the human airways. A subset of strains underwent a large 400-kb inversion during persistence. NTHi does not undergo significant gene gain or loss during persistence, in contrast to other persistent respiratory tract pathogens. Amino acid sequence changes occurred in 8 of 12 candidate vaccine antigens during persistence, an observation with important implications for vaccine development. These results indicate that NTHi alters its genome during persistence by regulation of critical virulence functions primarily by slipped-strand mispairing, advancing our understanding of how a bacterial pathogen that plays a critical role in COPD adapts to survival in the human respiratory tract.

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Section: Discussionsupporting

confidence: 93%

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease

Pettigrew

Ahearn

Gent³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The igaB1 gene has been reported to be more prevalent in COPD exacerbation-causing strains, although the in vivo expression levels did not differ from asymptomatic colonization strains that also carried the gene ( 226 ). However, IgA-protease B1 and B2 have been found to promote the intracellular survival of NTHi in human epithelial cells, providing a secondary function (in addition to hydrolysis of IgA antibodies) that could facilitate NTHi growth in inflamed environments ( 227 ). While a majority of the persistent NTHi strains that dwell in COPD patients continuously express one or more variants of the enzyme, it has recently been found that a phase variation to an OFF-state can occur via slipped-strand mispairing over time ( 228 ).…”

Section: Colonization and Adaptation Of Nthi In The Lower Airways Of mentioning

confidence: 99%

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

Jalalvand

Thegerström

et al. 2018

Front. Immunol.

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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.

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“…It has been suggested that IgA-A and IgA-B proteases have different roles in H. influenzae pathogenesis, and may be variably expressed during different phases of host colonization and invasion [ 13 ]. While IgA-A is implied in tissue colonization and invasion, IgA-B cleaves Lysosomal-associated membrane protein 1 (LAMP-1), which has been suggested to be important for bacterial persistence [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Differential distribution of IgA-protease genotypes in mucosal and invasive isolates of Haemophilus influenzae in Sweden

et al. 2018

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BackgroundSeveral different IgA-proteases exist in Haemophilus influenzae. The variants have been suggested to play differential roles in pathogenesis, but there is limited information on their distribution in clinical isolates. The objective of this study was to investigate the distribution of IgA-protease genotypes in H. influenzae and assess the association between IgA-protease genotype and type of clinical infection.MethodsWe performed PCR-screening of the IgA-protease gene variants in two cohorts of clinical H. influenzae. The first cohort consisted of 177 isolates from individuals with respiratory tract infection in January 2010, 2011 and 2012. Information on age, gender and clinical infection was available in this cohort. The second cohort comprised 53 isolates, including NTHi from bloodstream, cerebrospinal fluid (CSF) and urogenital origin as well as encapsulated isolates respresenting all capsule types. We assessed associations between IgA protease genotype and clinical predictors using basic statistical tests of association as well as regression analysis.ResultsThe igaB gene was found in 46% of isolates in the respiratory tract cohort, and no evident trend could be seen during the study years. However, the igaB gene was significantly less common among invasive isolates (19%), p = 0.003 (Fischer’s exact test), even when encapsulated isolates were excluded (21%), p = 0.012. A significantly negative association between bacteraemia and igaB genotype remained after adjusting for covariates. We did not identify a significant association between IgA-protease gene variants and type of respiratory tract infection, but isolates with an igaA2 genotype were overrepresented in pre-school children.ConclusionsThe distribution of IgA-protease gene variants in Swedish H. influenzae highlighted the widespread abundance of the igaB in isolates from cases of respiratory tract infection, but the igaB gene variant was significantly less common in invasive (bloodstream and CSF) isolates of H. influenzae compared with respiratory tract isolates.Electronic supplementary materialThe online version of this article (10.1186/s12879-018-3464-3) contains supplementary material, which is available to authorized users.

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Immunoglobulin A Protease Variants Facilitate Intracellular Survival in Epithelial Cells By Nontypeable Haemophilus influenzae That Persist in the Human Respiratory Tract in Chronic Obstructive Pulmonary Disease

Abstract: IgA proteases B1 and B2 cleave LAMP1 and mediate intracellular survival in respiratory epithelial cells. Intracellular persistence of NTHi selects for expression of IgA proteases B1 and B2. The variants of NTHi IgA proteases play distinct roles in pathogenesis of infection.

Cited by 16 publications

References 32 publications

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease

Haemophilus influenzae genome evolution during persistence in the human airways in chronic obstructive pulmonary disease

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

Differential distribution of IgA-protease genotypes in mucosal and invasive isolates of Haemophilus influenzae in Sweden

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