The contribution of metabolic switching to an emerging human pathogen from the genus Photorhabdus

Lead Research Organisation: University of Warwick
Department Name: Warwick Medical School

Abstract

Programme overview:
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.

Project overview:
Factors such as global warming and the encroachment of humans into previously wild habitats are believed to be driving the emergence of new human pathogens. Given the overwhelming numbers of insect hosts, the pathogens of these organisms far exceed those of recognised human disease agents.

Members of the bacterial genus Photorhabdus represent one such globally ubiquitous insect pathogen group. They are symbionts carried by certain insect pathogenic nematodes, which carry them from insect host to the next insect host. This partnership is so effective that they are as biological pest control agents. However over recent years cases of human infection by certain strains have emerged. These are caused by P. asymbiotica strains, with serious clinical manifestations.

Interestingly, they are also carried by the same types of nematodes and can also complete the "normal" insect infection cycle like all other Photorhabdus. For this reason, we have been studying how these strains are able to switch hosts from insect to man. Previous studies suggest they effect this switch mainly through changes in their metabolic activities when grown at 37'C. In fact, the insect host restricted strains are not even able to grow above 34'C, necessarily excluding mammals as hosts. While we have genome sequences, gene expression and metabolic activity data for these strains, we still do not understand how these changes are facilitated in a dynamic way. Thus, we now wish to create and test computational models of temperature dependant metabolic activity when they are provided with different nutrients available in insect or human hosts.

The PhD student will learn the complex skillsets of metabolic modelling to construct and validate the organismal models in silico. They will then use molecular microbiology studies and microscopy to test predictions of the model in the laboratory. The interdisciplinary synergy in these studies will give us a deep understanding of host range switching in an emerging human pathogen, and provide the student with a good grasp of diverse approaches to biomedical science studies. These approaches encompass the development of quantitative skills, whole organism physiology of the bacterial pathogen in question and of course, how to synergise interdisciplinary skills.

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