Analysis of influenza-mediated alterations in alveolar type II epithelial cell (AECII) responsiveness as a mechanism underlying enhanced susceptibility to secondary pneumococcal infection

• Applicant: Professorin Dr. Dunja Bruder
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326600522

Type II alveolar epithelial cells (AECII) are resident cells of the lower respiratory tract with an increasingly recognized immunological potential. They are targeted by the influenza A virus (IAV) for replication and rapidly react to viral infection with the production of cytokines and chemokines. However, not only viral infections trigger AECII responses, but they also respond to bacterial ligands and have been shown to essentially contribute to anti-bacterial defense. Epidemiological data from historic as well as recent influenza pandemics clearly documents strongly enhanced susceptibility to secondary bacterial infection following influenza, especially with S. pneumoniae. While this synergism was originally explained by epithelial destruction through the viral infection, we know today that IAV has a long-term modulating effect on host respiratory immunity. The proposed project aims at uncovering IAV-mediated changes in the responsiveness of AECII towards bacterial triggers as an underlying mechanism. AECII have so far been neglected as possible players in the viral/bacterial synergism, despite their role in anti-bacterial defense - which is however insufficiently characterized to date. Therefore we will first characterize the AECII anti-pneumococcal response in detail to subsequently assess IAV-mediated alterations present after recovery from the viral infection. This will take place on the one hand on a global gene transcriptional level through microarray analyses of primary AECII isolated from infected mice. On the other hand we aim at increasing our understanding of the direct interaction of AECII with the bacterium by analyzing bacterial penetration of AECII and induction of apoptosis both in situ and ex vivo with primary cells from naïve as well as previously IAV infected hosts. Importantly, here we will also take into account bacterial factors influencing the AECII/pneumococcal interaction by including different strains of selected S. pneumoniae serotypes. Taken together, these analyses will shed light on how a resolved IAV infection imprints the respiratory epithelium, affecting its responsiveness to pneumococcal encounters and thereby enhancing susceptibility to secondary bacterial infections. By taking AECII into account as new players in respiratory immune modulation following influenza, we are aiming towards a complete understanding of the processes underlying the synergism between IAV and S. pneumoniae - an understanding which will be the crucial basis for the development of strategies for treatment and prophylaxis in the future.

• DFG Programme: Research Grants