Characterization of the host defense against influenza virus infection and a secondary bacterial pneumonia infection
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PROVIDER: PRJNA851281 | ENA |
REPOSITORIES: ENA
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Project description:Secondary bacterial infections (‘superinfection’) are a major reason for excessive mortality and hospitalizations during influenza virus infections. Here we present a longitudinal study of gene-expression changes in murine lungs during superinfection, with an initial influenza A virus (IAV) infection and a subsequent S. pneumonia (SP) infection. In addition to the well characterized impairment of the innate immune response, we identified superinfection-specific alterations in endothelial functions, including rapid downregulation in angiogenic activity and vascular regulators. Superinfection-specific alterations were also evident in analysis of cellular states related to the host’s immune resistance against pathogens. We found that only a few hours after secondary bacterial challenge, superinfected mice manifested an excessive induction of immune resistance, and in addition, there was a substantial rewiring of the resistance program: interferon-regulated genes are switched from positive to negative correlations with resistance, whereas genes of fatty-acid metabolism are switched from negative to positive correlations with resistance. Thus, the transcriptional resistance state is reprogrammed toward repressed interferon signaling and induced fatty acid metabolism. Our findings suggest new insights into the remodeling of the host defense upon superinfection, providing promising targets for future therapeutic interventions.
2024-03-06 | GSE206534 | GEO
Project description:A leading cause of morbidity and mortality during influenza infection is the development of a secondary bacterial pneumonia, which is appropriately treated with antibiotics. In the absence of a bacterial superinfection, prescribing antibiotics is not indicated but has nevertheless become a common clinical practice for those presenting with a respiratory viral illness. We found that antibiotic use during an antecedent influenza infection impaired the lung innate immunologic defenses toward a secondary challenge with methicillin-resistantStaphylococcus aureus(MRSA). The antibiotics perturbed the gut microbiome causing a fungal dysbiosis that drives an increase in lung eosinophils. We also demonstrate eosinophils, through the release of major basic protein, impair macrophage ability to clear MRSA. Moreover, we provide clinical evidence that eosinophils positively correlate with antibiotic use and worsened outcomes in patients hospitalized for viral infections. Altogether, our work establishes a counterproductive effect of antibiotic treatment during influenza infection that have negative immunologic consequences in the lungs thereby increasing the risk of developing a secondary bacterial infection.
2024-08-21 | GSE259429 | GEO
Project description:Antibiotic use during influenza infection augments lung eosinophils that impair lung immunity against secondary bacterial pneumonia
| PRJNA1081465 | ENA
Project description:Influenza infection is substantially worsened by the onset of secondary pneumonia caused by bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). The bidirectional interaction between the influenza-injured lung microenvironment and MRSA is poorly understood. By conditioning MRSA ex vivo in bronchoalveolar lavage fluid collected from mice at various timepoints of influenza infection, we found that the influenza-injured lung microenvironment dynamically induces MRSA to increase cytotoxin expression while decreasing metabolic pathways. LukAB, a SaeRS two-component system dependent cytotoxin, is particularly important to the severity of post-influenza MRSA pneumonia. LukAB’s activity is likely shaped by the post-influenza lung microenvironment, as LukAB binds to (and is activated by) heparan sulfate (HS) oligosaccharide sequences shed from the epithelial glycocalyx after influenza. Our findings indicate that post-influenza MRSA pneumonia is shaped by bidirectional host-pathogen interactions: host injury triggers changes in bacterial expression of toxins, the activity of which may be shaped by host-derived HS fragments.
2022-11-29 | GSE199707 | GEO
Project description:Novel therapeutic approaches for addressing pneumonia caused by Streptococcus pneumoniae, which exhibit resistance to standard-of-care antibiotics are greatly needed. One viable approach involves precisely stimulating innate immune defenses within the lungs. Using murine models of pneumococcal pneumonia, prior studies demonstrated that intranasal administration of the Toll-like receptor 5 agonist, flagellin, results in a 100-fold decrease in lung infection compared to sole antibiotic therapy, when used as an adjunct treatment to the antibiotic. To promote the transfer of this immunotherapy to clinics and mitigate unwanted systemic inflammation, this project assessed whether the direct delivery of flagellin to the airways through nebulization stimulates respiratory defenses against bacterial infection. Similarly to intranasal administration, nebulized flagellin induced a transient activation of lung innate immunity. In contrast, inhalation by nebulization resulted in an attenuated activation of systemic immune responses. We conclude that flagellin aerosol therapy represents a secure and promising approach in addressing bacterial pneumonia within the context of antimicrobial resistance.
2024-10-11 | GSE252037 | GEO
Project description:Introduction: Diagnosis of severe influenza pneumonia remains challenging because of the lack of correlation between presence of influenza virus and patient’s clinical status. We conducted gene expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure (e.g. bacterial pneumonia, non-infective systemic inflammatory response syndrome). Methods: Whole blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene expression beadarrays. Differentially expressed genes were determined by linear mixed model analysis and over-represented biological pathways determined using GeneGo MetaCore. Results: The gene expression profile of H1N1 influenza A pneumonia was distinctly different from bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene expression profile is characterized by up-regulation of genes from cell cycle regulation, apoptosis and DNA-damage response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene expression profile of influenza infection persisted through five days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection who subsequently developed bacterial co-infection, the influenza gene-expression signature remained unaltered, despite the presence of a super-imposed bacterial infection. Conclusions: The whole blood expression profiling data indicates that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed up identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly. Daily PAXgene samples for up to 5 days for; influenza A pneumonia patients (n=8), bacterial pneumonia patients (n=16), mixed bacterial and influenza A pneumonia patients (n=3), systemic inflammatory response patients (SIRS, n=13). Days 1 and 5 PAXgene samples for healthy control individuals
2012-08-14 | E-GEOD-40012 | biostudies-arrayexpress
Project description:Background: Pneumococcal secondary infection following influenza A virus (IAV) pneumonia is a synergistic complication with high mortality. While varying invasiveness of pneumococcal serotypes is an important pathogenic factor, serotype-specifc immediate-early transcriptional responses of the IAV-perturbed alveolar epithelium have not been adressed. We comprehensively analyzed gene transcription in alveolar type II epithelial cells (AECII) isolated from mice infected with IAV and/or S. pneumoniae (S.pn.) serotypes 4, 7F and 19F. Results: IAV, 14 days post infection, rendered the lung susceptible to invasive secondary S.pn. infection with serotypes 4 and 7F but not 19F. Only secondary 7F infection induced exacerbated cytokine/chemokine responses. IAV/7F infection induced superior protein expression of type I and II interferons, acesserbated expression in IAV/serotype 4 infection. Inference of a scale-free-like ARACNE gene co-expression network revealed interferon-response network modules in AECII and network-mapping unfolded S.pn. serotype-specific transcriptional network responses/usage. Secondary S.pn. infection abrogated the IAV-induced pneumocyte proliferative configuration and preceeding IAV infection rendered the transcriptional response to 7F infection comparable to that towards serotype 4. This related especially to network genes correlating with the expression of two master regulators of interferon responses: Irf7 and Stat1. Epigenetic ATAC-seq analysis of AECII in resolved IAV infection identified enhanced expression of ARACNE network genes Hist1h2bf, Igtp, Mki67, Rasl10b, H2-Q6 and H2-Q7 to be associated with increased chromatin accessability at promoter regions. Conclusions: We show that AECII sustainably retain an IAV-associated transcriptional configuration with epigenetic involvement, that serotype-specifically affects proliferation and accelerates and enhances the AECII transcriptional response, mainly to interferons, in secondary S.pn. infection.
2023-12-31 | GSE225343 | GEO
Project description:Introduction: Diagnosis of severe influenza pneumonia remains challenging because of the lack of correlation between presence of influenza virus and patient’s clinical status. We conducted gene expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure (e.g. bacterial pneumonia, non-infective systemic inflammatory response syndrome). Methods: Whole blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene expression beadarrays. Differentially expressed genes were determined by linear mixed model analysis and over-represented biological pathways determined using GeneGo MetaCore. Results: The gene expression profile of H1N1 influenza A pneumonia was distinctly different from bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene expression profile is characterized by up-regulation of genes from cell cycle regulation, apoptosis and DNA-damage response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene expression profile of influenza infection persisted through five days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection who subsequently developed bacterial co-infection, the influenza gene-expression signature remained unaltered, despite the presence of a super-imposed bacterial infection. Conclusions: The whole blood expression profiling data indicates that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed up identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly.
2012-08-15 | GSE40012 | GEO
Project description:Metatranscriptomic analysis identifies a state of pathogen dominance and suppressed pulmonary immune signaling in critically ill COVID-19 patients with secondary bacterial pneumonia.
2024-09-20 | GSE246795 | GEO
Project description:RNA-sequencing of primary and secondary bacterial pneumonia
| PRJNA821208 | ENA