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Host-pathogen interaction profiling of nontypeable Haemophilus influenzae and Moraxella catarrhalis coinfection of bronchial epithelial cells.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease and the third leading cause of death globally. Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) are common pathogens in individuals with COPD. Acquisition of NTHi or Mcat can cause acute exacerbations of COPD. NTHi and/or Mcat can also persist for months in the lower airways and lead to chronic inflammation. We hypothesized that infection by NTHi or Mcat, singly or during coinfection, requires regulation of specific bacterial and host cell pathways. We investigated this phenomenon using an in vitro cell culture model consisting of lung carcinoma H292 cell lines, infected with NTHi, Mcat, or both species. Samples were fractionated into “apical fluid”, containing free floating bacteria, and adhered/invaded bacteria on or within H292 cells. We used transcriptomic profiling with RNA-seq and various bioinformatic analyses to disentangle host-pathogen interactions in epithelial cell infection from the perspective of each species. Several biological pathways were differentially regulated across all conditions (31, NTHi; 22, Mcat; and 169, Human). NTHi transcriptomic profiles differed during single and coinfection; examples included downregulation of iron-sulfur metabolism (IscR regulon) and differential regulation of quorum sensing in coinfection compared to single infection. Mcat was comparatively less affected by the presence of NTHi during coinfection. H292 epithelial cells responded broadly to all infections with distinct responses to single and coinfection. Enriched host pathways included influenza/interferon/Wnt and proinflammatory responses. These findings suggest common and distinct processes involved in NTHi and/or Mcat induced COPD pathogenesis and have implications for therapeutic intervention.

ORGANISM(S): Moraxella catarrhalis Homo sapiens Haemophilus influenzae

PROVIDER: GSE283527 | GEO | 2025/05/27

REPOSITORIES: GEO

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Project description:Objectives: Therapies being safe, effective and not vulnerable to develop resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by the use of host-directed drugs to counteract microbial infections. This study sought to identify cellular genes and pathways differentially expressed during airways epithelial infection by nontypable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). Based on the proposed relationship between NTHi intracellular location and persistence, the antimicrobial potential of a panel of drugs perturbing host pathways used by NTHi to enter epithelial cells was investigated. Methods: We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing A549 cell whole genome expression profiling, and identified a panel of host target candidates which were pharmacologically modulated. Interfering drugs were tested for their bactericidal effect, cytotoxicity, effect on the interplay NTHi-epithelial cell, and effect on NTHi respiratory infection in vivo, by assessing lung bacterial loads in a murine intranasal infection model. Results: The sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi; the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts both intracellularly and in the lungs of infected mice. Conclusions: PDE4 inhibition is currently prescribed in COPD; resveratrol is a geroprotector attractive for COPD treatment by preventing lung aging. This work provides evidence for the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection. Haemophilus influenzae clinical strain NTHi375 induced gene expression in A549 human type II pneumocyte cell line was measured at 2 h post-infection. Non infected cells were used as a control. Four independent experiments were performed for each condition.

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Host-pathogen interaction profiling of nontypeable Haemophilus influenzae and Moraxella catarrhalis coinfection of bronchial epithelial cells.

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