Clash of the Kingdoms: How the quest for nutrients leads to pathogenicity

Streptomyces is a harmless soil bacterium that is often found around the roots of plants, interacting with them but without causing disease. Streptomyces also interacts with other soil organisms such as amoeba, single celled organisms that behave like the phagocytic cells in the human body, eating bacterial cells. Currently we know very little about how these different species interact at the molecular level. Recently we were able to identify that a group of genes (the mce genes, which stands for Mammalian Cell Entry genes)that are found in Streptomyces and are very closely related to genes in its distant cousin Mycobacterium tuberculosis, the bacterium that causes TB. We showed that these genes encode a transport system and are important for Streptomyces to gather nutrients from plant roots and also to interact with the amoebae. Yet in M. tuberculosis they are required for them to colonise human lung cells and grow within those cells.
In this proposal we will fully characterise this transport system and study the molecular details of what the proteins encoded by these genes do, what substrates they bind and take up, and what effect they have on plant and amoeba both physically and also genetically. The findings of this study will have implications for our understanding of how human and animal pathogens have evolved from non-pathogenic bacteria and how bacteria can colonise plants and out-compete plant pathogens to stop them from causing disease. There are also possibilities that these genes can be used in the biotechnology industry to help make useful drugs, such as steroids from plant waste products.

The rise of antibiotic resistance and the recognition that this represents a great threat to human health and wellbeing has pushed researchers to look towards alternative intervention therapies. The desire for increased vaccine efficacy and novel strategies to interfere with the infection process are ultimately led by a thorough understanding of the basic process of host-pathogen interaction.

Comprehending these processes through a deeper understanding of evolutionary conserved host-pathogen interaction mechanisms offers a great opportunity to identify and exploit novel potential therapeutic avenues. This proposal is focussed on a known virulence factor in Mycobacterium (the mce locus) that is present in the non-pathogenic bacterium Streptomyces, which functions and facilitates interaction with amoebae and plants. This will be used as a model system for understanding the evolutionary transition from a nutrient acquisition system in a saprophyte to a virulence factor in a pathogen and in the longer term will help us to identify novel intervention strategies to disrupt these processes.

Industrial applications:
The industrial biotechnology market in the UK has recently been estimated at £81 billion per annum, employing 800,000 people across the pharmaceutical, food & drink, bioconversion and waste-treatment industries. The mce locus has great industrial potential and been shown by us and others to encode a sterol transport system. Given that hydrophobic molecules are difficult to biotransform/bioconvert, the mce locus offers great potential for exploitation in biotechnology for the transport and processing of recalcitrant substrates and for the bioconversion of relatively low value plant sterols in to high value steroid drugs. The importance of this locus in Rhodococcus for a similar process has previously been demonstrated, however the diversity of substrate binding proteins within these loci across the actinobacteria offers great potential for exploitation in synthetic biology and biotechnology to develop novel uptake systems for biotechnology.

Agricultural applications:
A better understanding of how the mce locus facilitates plant-microbe interactions has great potential for exploitation in biocontrol strains of bacterial for use in sustainable agriculture, enhancing plant growth, suppressing disease and increasing nutrient availability. In the UK, potatoes alone are worth £780 million annually to the economy. Given the rising importance of global food security, studies such as this can have significant impact on our understanding plant pathogens, the rhizosphere and sustainable agriculture processes.

Outreach/public engagement:
Studies like this can capture the public's imagination and demonstrate how basic science, such as how bacteria interacting with plants and amoebae, can be transformed in to tangible outputs in industry (Bioconversions), agriculture (plant growth promotion/disease suppression) and medicine (understanding host-pathogen interaction and development of vaccines and novel intervention strategies). The initial study of Mce in Streptomyces (Clark et al., 2013; Nature Scientific Reprorts) has captured the wider imagination of the public and has been the subject of blog posts (http://microbelog.wordpress.com/?s=mce and http://defectivebrain.fieldofscience.com/2013/03/microtwjc-evolution-of-virulence.html) and the subject of a student run Journal club that is hosted on the social media site 'Twitter' on a fortnightly basis (http://microtwjc.wordpress.com/2013/03/), which I and the first author (Dr Laura Clark) took part in when our paper was discussed.