Award details

The regulation of plant-nematode parasitism

Reference	BB/R011311/1
Principal Investigator / Supervisor	Dr Sebastian Eves-van den Akker
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Plant Sciences
Funding type	Research
Value (£)	979,232
Status	Current
Type	Fellowships
Start date	01/05/2018
End date	30/09/2024
Duration	77 months

Abstract

The most economically important plant-parasitic nematode species have the ability to cause existing plant cells to re-differentiate into a novel tissue that acts as a feeding site. How this is regulated, in the nematode and in the host, is one of the great unanswered questions in the field. This proposal is designed to identify, characterise, and disrupt the regulators of parasitism. The main objectives are designed to address the following hypotheses: Hypothesis 1: The spatio-temporal regulation of the nematode "Parasitism Programme" is controlled by a suite of non-coding DNA motifs and corresponding putative master-regulator transcription factors. Using a combination of whole gland cell RNA sequencing and bioinformatic predictions, I will identify promoter elements that define various aspects of the nematode "parasitism programme". Cognate transcription factors of these promoter elements will be identified by Yeast-1-Hybrid and Co-immunoprecipitation, to provide a series of high-value targets for control. Hypothesis 2: The regulation of feeding site development in the host is a complex, multi-stage process. I will deploy second- and third-generation sequencing technologies to determine the temporally-resolved changes in host gene regulation that are directly linked to progression through the nematode "parasitism programme". This will provide a platform for future exploration of novel tissue re-differentiation in plants. Hypothesis 3: Disrupting the processes of parasitism regulation in the parasite or the host will be detrimental to infection. I will disrupt the processes of parasitism regulation in the nematode and in the host to validate the roles of regulatory proteins/processes during parasitism, and demonstrate their utility as a set of putative targets for the control of plant-parasitic nematodes. This proposal will significantly advance our understanding of a process that is academically fascinating and has global agronomic importance.

Summary

Summary: The regulation of plant-nematode parasitism. Plant-parasitic nematodes are a persistent threat to global food security. The most economically important species have the ability to transform plant cells into permanent and dedicated feeding sites. Plants and parasitic nematodes are locked in an "evolutionary arms race". At the front-line, are the parasite "effectors": molecules secreted into the host plant during infection. Plant-parasitic nematodes use hundreds of effectors to manipulate their host. Often individual effectors target a specific function in the host. The scientific community has focused on trying to understand and block these effector functions. A vulnerability of this approach is that for thousands of years plants have been deploying resistance genes to recognise effectors, and mount an immune response. This means that the parasites are under a strong evolutionary selection pressure to counteract this, developing a number of mechanisms to evade or negate effector recognition (sequence diversity, partitioning effectors in regions of the genome that mutate rapidly, functional redundancy, etc.). Practically, this means that targeting individual effectors to control the parasite is rarely highly successful, and unlikely to be robust. What we need is a series of new targets that have not been the focus of this kind of evolutionary selection pressure. This proposal is designed to deliver new targets by shifting the focus away from individual effectors to "high-level" functions: how is parasitism regulated? The idea is that if we can disrupt the process of parasitism regulation we can disrupt the functions of many effectors at the same time. Two recent breakthroughs in our understanding of parasitism regulation suggest that now is the right time to initiate this shift in focus. In 2016 I identified a regulatory genetic signature of nematode effectors. This signature unifies hundreds of otherwise unrelated effectors. This implies there is some nematode regulatory machinery that recognises this signature, and in so doing orchestrates this aspect of parasitism. I predict that if we could disrupt this "master-regulator", it would in turn disrupt hundreds of associated effectors. In a recent effort I have identified a candidate for such a regulator. The second breakthrough is the discovery that nematodes do not synthesise all effectors at the same time, suggesting that they may be delivered in waves that indicate a complex "parasitism programme" during infection. This sequential programme of effector production suggests that there will be a series of additional regulators that are activated at specific time-points. Disrupting any of these is likely to be severely detrimental to the parasite. Importantly, the plant immune system is "blind" to these master regulators. This means that they are unlikely to be protected by the same mechanisms that make targeting effectors so difficult. Together, this suggests that parasitism master regulators will be an attractive set of targets for control. In this proposal I will identify, validate, and disrupt these master-regulators. The fact that parasitic nematodes predictably execute a "parasitism programme" also gives us some insights into how they transform plant tissues. It suggests that the regulation of feeding site formation in the host is probably a multi stage process, and has the same or a very similar number of stages. This is a new insight into how this tissue is formed and presents an opportunity to understand the fundamental biology that underpins this process. In this proposal I will develop a system to measure changes in the host gene regulation and link these changes to progression through the nematode parasitism programme, ultimately building the foundation to understand this phenomenon.

Impact Summary

The beneficiaries of my proposal are detailed in the relevant sections of the JeS form and the pathways to impact. To summarise, my proposal has substantial potential to impact the academic, societal, and industrial sectors. A series of measures are detailed to realise that impact over the course of the fellowship, and these timescales are detailed in the diagrammatic work plan. Academic impact: The major academic impact of the proposal will come from delivering the outcome of the pan-kingdom linked transcriptome to end-users in an accessible format. By permanently incorporating these data into the A. thaliana community resources (e.g. ePlant), the unusual biology of the nematode feeding site will be viewed by approximately 60,000 plant scientists per month. There is probably no better way to consistently highlight plant-nematode interaction to such a broad audience, and for such a long time. Societal impact: Informing the public, and training the next generation of scientists, is our responsibility. During the fellowship, I will continue to train young plant scientists to address the major global issue of food security. The combination of engagement infrastructures at the University of Dundee and the James Hutton Institute will help appropriately deliver the messages of the outcomes to a broad spectrum of audiences. Industrial impact: Although a challenging aim, the long-term goal of the research is to develop approaches with the potential to increase agricultural stability by combatting plant-parasitic nematodes. The combination of the Drug Discovery Unit at the University of Dundee, the Commercialisation arm of the James Hutton Institute, and the promising link established with a major AgChem company, indicate a number of potential routes to realise industrial impact in the UK and globally.

Committee	Research Committee B (Plants, microbes, food & sustainability)
Research Topics	Plant Science
Research Priority	X – Research Priority information not available
Research Initiative	Fellowship - David Phillips Fellowship (DF) [1995-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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