How does membrane lipid remodelling enable intracellular survival of B. cenocepacia?

The Burkholderia cepacia complex (Bcc) represents a large group of human pathogens which cause lung infection in immunocompromised individuals including cystic fibrosis patients. Bcc infections can be lethal and difficult to treat due to high intrinsic resistance to a wide range of clinically available antibiotics. As such, there is an urgent need to identify new targets for novel antimicrobial drugs for Bcc. In our continued effort to better understand the physiology of bacterial membrane lipids in bacterial pathogens, we have recently found that Bcc bacteria can change membrane lipids in infection. Thus, in response to nutrient availability during infection, these bacteria produce sugar-containing lipids to replace membrane phospholipids. A key gene involved in this so-called membrane lipid remodelling process is plcP. Importantly, this gene is essential for successful infection of Bcc in an insect infection model as well as human and murine macrophage models. This PlcP-mediated lipid remodelling pathway is therefore a promising new drug target for future development of novel antibiotics for treating Bcc infection. Capitalising on our discovery, we propose to systematically investigate the interplay of nutrients, membrane lipid remodelling and innate immunity in Bcc infection, using a synthesis of molecular and cellular microbiology, biochemistry and 'omics' tools. The results of this project have the potential for help developing new drug targets for treating Bcc infection in human.

The Burkholderia cepacia complex (Bcc) represents a large group of opportunistic human pathogens which cause lung infection. Bcc infections can be lethal and difficult to treat due to high intrinsic resistance to a wide range of clinically available antibiotics. Bcc bacteria are intracellular pathogens which can establish persistent infection within macrophages. However, the molecular and cellular mechanisms underpinning their intracellular persistence are not completely elucidated.

We have recently found that Bcc bacteria uses a so-called membrane lipid remodelling strategy, whereby the bacteria synthesise alternative lipids to replace membrane phospholipids, in order to establish intracellular infection in both insect models and macrophage models. One of the key genes involved in this process is plcP, a mutant of which renders B. cenocepacia unable to establish infection. Since plcP expression is regulated by nutrient availability, such as phosphorus, these data support the crucial interplay between nutrients, membrane lipid remodelling and the innate immune system for B. cenocepacia infection, and provide the first evidence that nutrients availability mediated lipid remodelling is an important yet overlooked secret for the success of B. cenocepacia as an intracellular pathogen. Capitalising on our recent discovery, we aim to 1) identify temporal and spatial expression and transcriptional regulation of PlcP during infection and 2) uncover the molecular and cellular mechanisms underpinning the role of PlcP in intracellular survival. Our results will pave the way for future development of membrane lipid remodelling as a drug target for treating Bcc infections.