Establishment of novel macrophage cell lines to study the pathogenesis of respiratory bacterial pathogens in lung alveolar macrophages

Macrophages are important immune cells in the first line of defence against infectious pathogens.

To understand macrophage-bacteria interactions mice are frequently used. Macrophages can be best investigated using purified cells from organs or by producing them from bone marrow in tissue culture, but the availability of such cells is limited.

Lung alveolar macrophages (AMs) play central roles in defence against respiratory bacterial pathogens. Infection of AMs can result in direct pathogen elimination, however, bacteria may overcome macrophage killing mechanisms allowing pathogen replication or persistence inside the cell. The activation of a plethora of pathogen sensing mechanisms play key roles in these processes and their understanding is key to the efficient treatment of respiratory infections.

The therapy of bacterial infections of the airways can be still problematic and macrophages play key roles in these processes as bacteria can be unavailable to drugs when persist or replicate in macrophages.

We described a novel, continuously growing, murine model of lung alveolar macrophages (AMs), providing unrestricted amounts of primary macrophages (MPI cells). Using this system we have demonstrated the very high sensitivity of MPI cells and AMs to respiratory pathogens and have shown the existence of unique immune mechanisms in AMs.

The sensing of respiratory bacteria by AMs involves various immune receptors, however, the understanding of their contribution to pathogenesis mechanisms is hampered by the restricted availability of AMs.

Here we will transfer the MPI cell technology to the Kings College London (KCL) and the Institut Pasteur, Korea (IPK) to study bacterial pathogenesis in lung macrophages. We will establish new MPI cell lines from relevant genetically modified mice lacking various bacterial pathogen recognition sensors. To better understand respiratory macrophage-bacteria interactions we will establish MPI cells from these g mice available at KCL, the Sanger Institute and the IPK.

To make the cells accessible to other researchers we will make a repository of the new cell lines and/or distribute them through commercial vendors to the wider community.

We have ongoing in vivo and in vitro studies with the above listed pathogens. We will use the established new cell lines to complement these studies and obtain mechanistic data regarding the activation of innate immune pathways to the sensing and the treatment of respiratory bacterial infections.