Investigating the effects of Bartonella quintana on the host transcriptional cofactor MAL

Bartonella quintana is a Gram-negative facultative intracellular bacterial pathogen that has been infecting humans for more than 4,000 years. Today, B. quintana is considered a re-emerging pathogen. The Bartonella genus contains many species which infect a wide range of mammals, with each Bartonella species highly adapted to one or a few mammalian hosts. In a human host, B. quintana can lead to a range of clinical manifestations, including the disease trench fever. B. quintana infection can be long-term and asymptomatic but can also be life-threatening. Despite being a widespread ancient pathogen capable of causing serious disease, there are many aspects of B. quintana infection that remain poorly characterised. This project investigated the interaction between B. quintana and the host transcriptional cofactor MAL. MAL interacts with the transcription factors SRF and NF-κB to control the expression of hundreds of genes involved in actin, the cytoskeleton, cell motility, and inflammation. There is evidence that B. quintana interferes with cellular processes controlled by the MAL/SRF and MAL/NF-κB pathways. B. quintana potentially induces cytoskeletal rearrangements and cell migration to disseminate within the host and modulates immune responses to evade the immune system. These effects are thought to be mediated by Bartonella effector proteins (Beps), which are injected into host cells via type-IV-secretion systems, as some B. quintana Beps have been shown to target cell signalling pathways known to regulate MAL.

To assess whether B. quintana affects MAL, I developed tissue culture models that allowed the subcellular localisation of MAL within infected host cells to be visualised using fluorescence microscopy. Since the subcellular localisation of MAL is related to its activity, this can be used as a proxy for activation of the MAL/SRF and MAL/NF-κB pathways. B. quintana was found to induce MAL nuclear accumulation in macrophage-like cells, suggesting that B. quintana can activate MAL in human cells. The specific mechanisms by which B. quintana affects MAL’s subcellular localisation and activity were not identified, and I was unable to confirm whether B. quintana activates the MAL/SRF pathway or the MAL/NF-κB pathway. However, these data suggest that the subversion of host cell signalling by B. quintana involves the transcriptional cofactor MAL. Exploring the interactions between B. quintana and host signalling pathways is important in identifying potential targets for the treatment of B. quintana infection and in contributing to our understanding of cell biology.