For infectious diseases, effective defense mechanisms which constitute an efficient innate host response are the keys to eliminate invading pathogens. According to different studies, the pathogenicity of bacteria is due to different virulence factors that contribute to overcome those mechanisms. Against that, the immune system evolved a large repertoire to fight the pathogen. Nevertheless, an overly strong host response bears the risk of cell and tissue damage. Especially in infections of the lung, the delicate balance between the robust inflam-matory response and the control of it to prevent loss of organ function determines the outcome of the disease. In the therapy of infectious diseases of the lung, antibiotics are used, whereby this treatment is facing increasing resistances. To find an alternative treatment, still remaining gaps in knowledge about the activation of the target cells and thus the signaling pathways of the immune response need to be filled. Alveolar macrophages are the target cells of Legionella pneumophila (L. pneumophila), the causing agent of the legionnaire’s disease, and one of the first targets of Streptococcus pneumoniae (S. pneumoniae), introducing severe pneumonia among others. Lower respiratory tract infections are the third most common cause of death worldwide and the second largest infectious source of death in children worldwide. At this S. pneumoniae is the most common agent of community acquired pneumonia (CAP), whereas the incidence of community acquired Legionnaire’s disease caused by Legionella is at 4-5 % in Germany. Nevertheless, it is the subspecies L. pneumophila which leads to the infection in 70-90 % (depending on the region) of the cases. Macrophages are important immune cells for the first defense against invading pathogens. With the recognition of pathogens by different receptors of the innate immune system, macrophages mainly contribute to the defense against pathogens due to cytokine and chemokine secretion and recruitment of adaptive immune cells. Furthermore, they belong to the phagocytes and directly contribute to the clearance of pathogens. The transcription factor c-myc is known for its role in embryogenesis and regulation of the cell cycle as well as its effect on proliferation and differentiation of cells. Taking into account that c myc regulates approximately 15 % of the genome including promoter regions of important molecules of the innate immune system; it seems to have a crucial impact on the immune response. The results presented in this work could show that c-myc is induced by L. pneumophila and S. pneumoniae in human lung (ex vivo) and particularly in human alveolar macrophages (ex vivo) and in a macrophage-like cell line (in vitro). This induction of c-myc is dependent on the TLR adaptor molecule MyD88 and the Toll-like receptor (TLR) 2 seems to be involved. Furthermore, the Legionella and Pneumococci induced cytokine release is decreased by inhibition or knockdown of c-myc, respectively. The phagocytosis of Legionella by macrophages is compromised by inhibition or knockdown of c-myc. Thereby, it has an effect on the internalization. However, it does not alter the growth of Legionella. Interestingly, the impact of c-myc on the phagocytic ability of macro-phages regarding Pneumococci, including internalization and killing, was only visible by knockdown of c myc, not by inhibition. This might be due to different modes of action or due to unspecific effect of the inhibitor, respectively. Taken together, the results of this study indicate a regulatory role of c-myc in the immune response to infections of the lung with L. pneumophila and S. pneumoniae, upon which the protein is induced over a TLR2 and MyD88 pathway. This leads to increased pro-inflammatory cytokine and chemokine release as well as increased internalization of bacteria.


    Zugriff

    Download

    Verfügbarkeit in meiner Bibliothek prüfen


    Exportieren, teilen und zitieren



    Titel :

    The induction and function of the transcription factor c-myc in macrophages during pneumococcal pneumonia and legionellosis


    Weitere Titelangaben:

    Die Induktion und Funktion des Transkriptionsfaktors c-myc in Makrophagen während einer Pneumokokkenpneumonie und Legionellose


    Beteiligte:

    Erscheinungsdatum :

    2017



    Medientyp :

    Sonstige


    Format :

    Elektronische Ressource


    Sprache :

    Unbekannt



    Klassifikation :

    DDC:    629



    Predicting Transcription Factor Binding Sites Using Structural Knowledge

    Kaplan, T. / Friedman, N. / Margalit, H. | British Library Conference Proceedings | 2005


    Deep Learning Approach to detect Pneumonia

    Gawali, Abhishek / Bide, Pramod / Kate, Vaibhavi et al. | IEEE | 2020



    Silent Hypoxemia in COVID-19 Pneumonia

    Ebihara, Akinori / Kitahara, Asako / Iwamoto, Tokuzen et al. | British Library Conference Proceedings | 2022


    Drosophila transcription factor AP-2-New insights into head development

    Monge, I. / Mitchell, P. J. / Cold Spring Harbour Laboratory | British Library Conference Proceedings | 1997