Award details

Investigating microbial predation as a driver of endosymbiosis and phagocyte evasion

Reference	BB/W002760/1
Principal Investigator / Supervisor	Dr Elizabeth Ballou
Co-Investigators / Co-Supervisors	Professor Jason King
Institution	University of Exeter
Department	Biosciences
Funding type	Research
Value (£)	797,807
Status	Current
Type	Research Grant
Start date	01/04/2022
End date	31/03/2025
Duration	36 months

Abstract

Identifying how environmental microbes developed traits to evade immune cells is critical to understand the causes of opportunistic infections. Zygomycetes are soil-associated fungi with pathogenic potential, causing severe infections in veterinary and human populations. We recently identified, for the first time, an endosymbiosis between the bacterium Ralstonia pickettii and the zygomycete fungus Rhizopus microsporus that blocks engulfment and killing by the soil-dwelling amoeba Dictyostelium discoideum and confers virulence in animals. Endosymbioses between Rhizopus and bacteria such as Ralstonia spp. are widespread in environmental samples and contribute to plant pathogenesis. Endosymbionts are also observed in approximately half of clinical Rhizopus isolates, where phagocyte-related deficiencies are a major predictor of susceptibility. We hypothesize that interactions between bacterium-fungus holobionts and amoeba in soil drives their evolutionary trajectories and opportunistic virulence in mammals. We will use phenotypic, genomic, and molecular tools to dissect the holobiont-phagocyte interaction and investigate host-pathogen interactions at two levels: 1) interactions between bacteria and their fungal hosts, and 2) the effect of endosymbionts on phagocyte evasion and opportunistic virulence. We will take both an unbiased approach to survey bacterial-fungal-amoebal interactions across the genus (Aim 1) and a directed approach to investigate molecular mechanisms for specific bacterial-fungal isolates alone and with amoeba (Aim 2). These mechanistic studies will be coupled to comparative holo-genome and transcriptome analyses to reveal how evolutionary pressures exerted by amoebae drive endosymbiosis and immune evasion (Aim 3). Our unique interdisciplinary approach combines a comparative approach, defining common insights across the fungal genera, with molecular analysis, thereby uncovering the mechanistic details of evolutionary interactions across 3 kingdoms.

Summary

Microbes in the soil are in an arms race, surrounded by friends and foes, that has been going on for millennia. The evidence of this is recorded on their genomes: individual organisms have evolved genetic tools to resist their enemies. But there is also evidence of long-standing partnerships between microbes known as endosymbiosis, where bacteria live inside fungal cells. Partnerships between bacteria and fungi can allow them to escape amoebae that prey on them in the environment. We have shown that, together, a bacterial endosymbiont and its fungal host can make a powerful toxin that blocks amoebae from swallowing the fungus. The bacteria also changes how the fungus can use its genes to respond to different kinds of stress. This is important because amoebae are very similar to the cells in the human immune system that are the first line of defense against infection. The ancient fight going on in the soil is therefore a training ground for when endosymbionts and their fungal hosts infect humans. However, we know very little about how these partnerships arise in the first place, or how they alter how each species behaves. This project brings together three groups with unique expertise in endosymbiosis, fungal pathogenesis, and amoeba biology to investigate three questions: 1) How often do bacteria and fungi collaborate to avoid amoebae? 2) What are the mechanisms for this? 3) How do these partnerships impact the long-term evolution of the individual members, and the team? To answer these questions, we will look at bacterial-fungal partnerships across a wide range of species, looking for differences and commonalities in their shared genomes. We will also watch these partners interact with amoebae in the lab using sophisticated microscopy and mutant analysis to identify the different strategies they can take to evade their ancient enemy. Finally, we will closely examine one of these pairs in depth to understand the mechanisms that allow these partnerships to exist at the molecular level.

Committee	Research Committee B (Plants, microbes, food & sustainability)
Research Topics	Microbiology, Soil Science
Research Priority	X – Research Priority information not available
Research Initiative	UK BBSRC-US NSF/BIO (NSFBIO) [2014]
Funding Scheme	X – not Funded via a specific Funding Scheme

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search