The Roslin Institute
The melioidosis pathogen Burkholderia pseudomallei is a facultative intracellular pathogen of humans and animals that enters non-phagocytic cells, escapes from endosomes and propels itself within and between cells by continuous polymerisation of actin at one bacterial pole (known as actin based motility). Actin-based motility is also a feature of infection by the closely related glanders pathogen B. mallei and the avirulent saprophyte B. thailandensis.
With previous BBSRC support, I have unravelled how B. pseudomallei stimulates actin assembly to propel itself within and between eukaryotic cells. I characterised a factor required for intracellular actin-based motility (BimA), surveyed its diversity in natural populations and identified functional orthologues in other Burkholderia species . BimA is required for intracellular survival, intercellular spread and virulence and acts in a manner distinct from most other pathogen-associated factors required for actin-based motility. Moreover, I recently found that BimA from closely-related Burkholderia species use distinct strategies to nucleate actin. B. thailandensis BimA recruits and activates a cellular complex that assembles actin (Arp2/3) via a unique central acidic domain, whereas B. pseudomallei BimA exhibits an intrinsic Arp2/3-independent ability to nucleate actin in a manner akin to eukaryotic formin- and spire-family proteins.
My ongoing research is aimed at further understanding the mechanisms by which BimA proteins from related Burkholderia species function as actin nucleators. Towards this aim I am trying to understand how posttranslational modifications of the proteins affect function as well as define any differences in the host cell proteins they may interact with. I am also investigating the role of BimA and actin-based motility in the evasion of intracellular recognition and killing mechanisms in host cells.