Role of interferon inducible GTPases in immune defence
Legionella pneumophila is a major cause of Legionnaire’s Disease, an acute form of pneumonia. As part of its pathogenesis, L. pneumophila infects alveolar macrophages and replicates in an intracellular vacuole that avoids fusion with lysosomes. Whereas macrophages propagate bacterial replication, other immune cell types are required for bacterial killing. In particular, we have discovered that monocyte derived cells (MDC) play an important role in controlling L. pneumophila infection in the lung. moDC are recruited to the lung in large numbers early during L. pneumophila infection and we believe that MDC internalize and kill the bacteria in an interferon gamma (IFNγ) dependent manner. Our RNAseq analysis of lung moDC from wild type and IFNγ-deficient mice showed that IFNγ induced the expression of multiple interferon inducible GTPases (GBPs/IRGs). While most GBPs and IRGs are not yet characterised, some localise to intracellular pathogen vacuoles and may induce killing through novel mechanisms. We hypothesise that moDC utilise GBPs and IRGs to kill intracellular L. pneumophila.
The aims of this project is to:
- Investigate the intracellular localization of selected GBPs and IRGs during L. pneumophila infection
- Identify GBPs and IRGs that restrict L. pneumophila intracellular replication
- Test selected GBP- and IRG-deficient mice for susceptibility to L. pneumophila infection
Techniques commonly used in this laboratory:
Bacterial culture, in vitro bacterial infection of cultured cells, enumeration of bacterial replication, RNAi knockdown, confocal laser scanning fluorescence microscopy, construction of stable inducible cell lines, molecular biology including primer design, mutagenesis and PCR, western blotting, immunoprecipitation, mouse infection.
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