Research Projects (Third party funds)

AECII and Coinfection

Analysing influenza A virus-mediated changes in the reactivity of alveolar type II epithelial cells as an underlying mechanism of increased susceptibility to secondary pneumococcal infections

Studies regarding the extraordinarily high death toll of the 1918/19 Influenza A virus (IAV) outbreak (the ‘Spanish flu’) have revealed a high incidence of bacterial superinfections. Retrospective analyses revealed that most of the several million deaths during this pandemic were caused by severe complications due to secondary infections with bacterial pathogens. A clear predisposition of IAV infected individuals to life-threatening infections with bacteria also occurred during later IAV epidemics in the 1950’s and 1960’s and in a substantial number of patients during the 2009 H1N1 swine flu outbreak. Epidemiological data clearly attest a strong fatal synergism between IAV and a number of bacterial pathogens, in which Streptococcus pneumoniae (the pneumococcus) is one of the most important players. We have previously established a murine model of IAV/pneumococcal superinfection showing that previous IAV infection predisposes to the development of fatal invasive pneumococcal disease (IPD). In this context we could show that pathogenesis of pneumococcal superinfection is strongly serotype-dependent. So far, the mechanisms underlying this transiently dysfunctional antibacterial defense are incompletely understood.

©HZI©HZIThe respiratory epithelium constitutes a thin and highly permeable barrier between the outside environment and the body. Nowadays the immunological potential of alveolar epithelial cells becomes increasingly recognized. Interestingly, we found alveolar type II epithelial cells (AECII) to integrate pathogen- and microenvironment-derived signals and constitute an important link to adaptive immunity during IAV infection. However, it is not known if and how IAV-induced physiological changes of AECII are contributing to increased susceptibility to pneumococcal superinfection. Using comparative ex vivo transcriptome analyses of AECII (uninfected, IAV- and/or S. pneumoniae –infected) we aim to obtain a comprehensive view on virus-induced changes in the genetic program and immunological profile of these cells. Additional ex vivo approaches will address the question if and to what extent physical and immunological barrier mechanisms of AECII are altered after IAV infection.  With these investigations we will significantly extend our understanding of the processes involved in the synergism between IAV and S. pneumoniae as a first step towards elucidating options for effective treatment, diagnosis and prophylaxis.

Partners

Prof. Birgitta Henriques Normark (Karolinska Institutet, Sweden)

 Prof. Achim D. Gruber (Freie Universität Berlin, Germany)

Groups

Funding agency

DFG - German Research Foundation

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