Streptococcus pneumoniae causes high mortality as a major pneumonia-inducing pathogen. In pneumonia, control of innate immunity is necessary to prevent organ damage. We assessed the role of microRNAs (miRNAs) as regulators in pneumococcal infection of human macrophages. Exposure of primary blood-derived human macrophages with pneumococci resulted in transcriptional changes in several gene clusters and a significant deregulation of 10 microRNAs. Computational network analysis retrieved miRNA-146a as one putatively important regulator of pneumococci-induced host cell activation. Its induction depended on bacterial structural integrity and was completely inhibited by blocking Toll-like receptor 2 (TLR-2) or depleting its mediator MyD88. Furthermore, induction of miRNA-146a release did not require the autocrine feedback of interleukin 1β and tumor necrosis factor α released from infected macrophages, and it repressed the TLR-2 downstream mediators IRAK-1 and TRAF-6, as well as the inflammatory factors cyclooxygenase 2 and interleukin 1β. In summary, pneumococci recognition induces a negative feedback loop, preventing excessive inflammation via miR-146a and potentially other miRNAs.
Lower respiratory infections, such as community-acquired pneumonia (cAp), and chronic obstructive pulmonary disease (copD) rank among the most frequent causes of death worldwide. improved diagnostics and profound pathophysiological insights are urgent clinical needs. in our cohort, we analysed transcriptional networks of peripheral blood mononuclear cells (pBMcs) to identify central regulators and potential biomarkers. We investigated the mRnA-and miRnA-transcriptome of pBMcs of healthy subjects and patients suffering from CAP or AECOPD by microarray and Taqman Low Density Array. Genes that correlated with PBMC composition were eliminated, and remaining differentially expressed genes were grouped into modules. One selected module (120 genes) was particularly suitable to discriminate AECOPD and CAP and most notably contained a subset of five biologically relevant mRNAs that differentiated between CAP and AECOPD with an AUC of 86.1%. Likewise, we identified several microRNAs, e.g. miR-545-3p and miR-519c-3p, which separated AECOPD and CAP. We furthermore retrieved an integrated network of differentially regulated mRNAs and microRNAs and identified HNF4A, MCC and MUC1 as central network regulators or most important discriminatory markers. in summary, transcriptional analysis retrieved potential biomarkers and central molecular features of cAp and AecopD. Community acquired pneumonia (CAP) is clinically defined by a sudden onset of severe illness that is accompanied by signs of lower respiratory tract infection, fever, cough and dyspnoea 1. When left untreated, severe secondary effects such as organ damage and occurrence of bacteria in the blood (bacteremia) can ensue. While subject to variance due to region, season and population characteristics, the incidence of CAP is estimated to lie between 1.5 and 14 cases per 1,000 persons per year, with children under 5 years of age and the elderly of more than 65 years being most strongly affected 2. Immunocompromised persons also bear a higher risk of CAP contraction. The leading underlying cause of CAP is infection with the gram-positive bacterium Streptococcus pneumoniae, accounting for 30-35% of CAP cases worldwide 3. The initial colonization of the nasopharynx and the upper respiratory tract often remains asymptomatic. Aspiration into the alveoli can cause severe respiratory or systemic disease, depending on the host immune status and the pneumococcal serotype 1. As CAP is a multifaceted disease with a host of potential causative agents, the robust identification of microR-NAs that are functionally involved in pneumonia depends on the pathogen. In severe Influenza A Virus (H1N1)
Immune response in the lung has to protect the huge alveolar surface against pathogens while securing the delicate lung structure. Macrophages and alveolar epithelial cells constitute the first line of defense and together orchestrate the initial steps of host defense. In this study, we analysed the influence of macrophages on type II alveolar epithelial cells during Legionella pneumophila-infection by a systems biology approach combining experimental work and mathematical modelling. We found that L. pneumophila-infected THP-1-derived macrophages provoke a pro-inflammatory activation of neighboring lung epithelial cells, but in addition render them hypo-responsive to direct infection with the same pathogen. We generated a kinetic mathematical model of macrophage activation and identified a paracrine mechanism of macrophage-secreted IL-1β inducing a prolonged IRAK-1 degradation in lung epithelial cells. This intercellular crosstalk may help to avoid an overwhelming inflammatory response by preventing excessive local secretion of pro-inflammatory cytokines and thereby negatively regulating the recruitment of immune cells to the site of infection. This suggests an important but ambivalent immunomodulatory role of macrophages in lung infection.
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