Where and Why: The Influence of Host Metabolism on Bacterial Niche Specificity

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

The aim of this work is to determine to how bacteria sense if their environment is optimal for colonisation. In previous work we have shown that the host metabolite, D-serine, affects if bacteria bind to host tissues. The present proposal is important because if these sensing mechanisms can be inhibited, there is the opportunity to develop novel ways of combating pathogens by interfering with their ability to occupy specific niches, and therefore to prevent pathogenesis. For example, our prediction is that strains that can use D-serine for growth are more likely to cause infections in organs where this amino acid is abundant, such as the urinary tract and brain. The diet of patients with a strong susceptibility to such infections (e.g. patients with catheters, women with recurrent bladder infections) could be modified to reduce the concentration of this amino acid in their urine. This push towards overall patient health through diet perfectly fits the BBSRC strategic priority "Food, Nutrition and Health".

Bacteria live and thrive in and on a huge variety of environments including all animals and plants, acting as both the most significant component of the microbiota and the cause of many diseases. The bacterial contribution to health and the environment is enormous with central roles in processes as diverse and important as immune development and nutrient cycling. Many of these roles require bacteria to colonise a defined location, a specific niche. Understanding how and why bacteria colonise particular sites is therefore a fundamental question with profound implications for health, biosecurity and food production. Our work has found that an unusual amino acid, D-serine is produced by humans in some tissues. This D-serine affects how bacteria respond to that environment, so it acts to either promote or discourage colonisation. In other words, D-serine strongly affects the bacteria that colonise particular niches within the human body.

We have discovered the proteins that acts collectively to sense and respond to D-serine. Fascinatingly, one core protein, the D-serine transporter as been shown to be one of the most commonly found sequences in nature. This highlights just how important the protein in for more complex animals, as well as the bacteria. We plan to use our bacteria as a model to help understand this system. We want to know how bacteria detect this amino acid as it will help in our basic understand of why particular diseases are caused. To do this we will dissect the molecular pathway involved using a combination of methods. We will look at how the amino acid is bound and what effects it has on the proteins that bind it. We will then work out how this causes changes in the production of the factors that affect where and how the bacteria colonise. We are confident that our work will provide a major step forward in our understanding of how bacteria cause specific diseases and, more generally, how they interact with humans and other animal hosts.

Technical Summary

The bacterial contribution to health and the environment is enormous with critically important roles in processes as diverse and important as immune development and nutrient cycling. Many of these roles require bacteria to colonise a defined location, a specific niche. Understanding how and why bacteria colonise particular sites is therefore a fundamental question with profound implications for health, biosecurity and food production.

Our recent work has focused on analysing the roles of both bacterial and host metabolism in affecting bacterial gene expression. We have found that the amino acid D-serine drives niche adaptation and bacterial evolution by affecting gene selection in E. coli. How E. coli responds to D-serine can vary according to the specific subtype involved. Pathogenic strains of the bacterium, E. coli cause many serious diseases including hospital-acquired infections such as urinary tract infections (UTIs), meningitis, diarrhea and septicemia. These pathogenic E. coli can be classified as either ExPEC (extra-intestinal pathogenic E. coli) due to their ability to cause disease beyond the gastrointestinal tract and InPEC (intestinal pathogenic E. coli) that are highly niche-specific and are very rarely associated with the colonisation of distal sites. Our data indicate that ExPEC and InPEc strains respond very differently to D-serine, a trait we will investigate in this proposal.

We use E. coli as a model to study this D-serine system and its relevance to niche specificity. The key questions that we plan to address in this proposal are firstly, how do E. coli strains sense and respond to D-serine? And secondly, how does this response vary between different pathotypes to affect niche specificity? To address this we will use a combination of established techniques to understand the molecular and biochemical basis to D-serine sensing. We also plan to test if the same proteins are functional in different bacterial species.

Planned Impact

The aims and objectives of the proposed research will contribute to advances in knowledge and understanding at the fundamental level. As our work on niche specificity develops, we will be able to more precisely define potential applications derived from this research. However, in the medium and long term this fundamental knowledge could have significant economic and societal impact as described below.
Health care providers and patients: understanding how these infections are influenced by host metabolism could have profound implications for prevention and treatment of these pathogens. For example, our prediction is that strains that can metabolise D-serine are more likely to cause specific infections of tissues abundant in this amino acid. One outcome might be that the diet of patients with a strong susceptibility to such infections (e.g. patients with catheters, women with recurrent infections) modulated be formulated to reduce the concentration of this amino acid in the urine. Furthermore, understanding the basis to how E. coli O157:H7 colonises disease in humans is very important. Children under five years of age have been shown to be particularly vulnerable to this organism with Shiga toxin (Stx) produced inducing hemolytic uremic syndrome (HUS), resulting in acute kidney injury in 50-70% of patients. Longer-term sequelae include ongoing chronic renal disease (usually requiring kidney replacement) and hypertension, as well as a variety of neuropsychiatric problems. There is no effective therapy that can alter progression from initial O157:H7 infection to HUS. Indeed, treatment with conventional antibiotics increases the likelihood of progression through the release of Stx. Our research will help in understanding the potential for this organism to colonise new sites and niches and the genetic factors involved.
Money saving to the economy and NHS: Research by the Centre for Foodborne Illness Research has found that, one-third of E. coli O157:H7 HUS survivors will suffer life-long medical problems, such as high blood pressure, diabetes, kidney failure and brain damage. These costs are estimated to be ten times greater than those associated with the initial infection alone. Based on data from Canadian studies we estimate that the cost to the UK health system is around £9 million per year. As our research progresses we will aim to develop partnerships with strategic partnerships with groups working on human metabolism to explore the relationship between diet formulation and levels of D-serine in the body. This push towards overall patient health through careful formulation of diets perfectly matches fits the BBSRC strategic priority "Food, Nutrition and Health".
Food manufacturers: As we understand the importance of diet and its influence on infection, there will be the opportunity to develop formulated dietary programs that will require interfacing with food and healthcare manufacturers. This sector is very important across Europe, with over 1750 health-product manufacturers represented by the European Federation of Associations of Health Product Manufacturers (EHPM) alone. The UK has become a leading source of new foods with health propositions. In 2007, 36% of new health product launches in the European Union originated in the UK. Our work will help maintain this competitive advantage.
Antibiotics development industry: There is a clear link between expression of the "sensory" system we have found and virulence factors. This provides a fantastic opportunity to develop novel compounds that block this pathway and effectively switch off key proteins used for attachment. New mechanisms to combat hard to treat infection, particularly gram negative infections are a cross council priority area that still has been sorely neglected despite the urgency of the issue.
Capacity building: the work will feed directly into training at the forefront of research (applied and basic) in respect of Food Security (a BBSRC priority area).

Publications

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Title Artwork and Xmas cards 
Description We worked with an independent scientific artist to generate an image that represented key metabolites affected during infection. This image was used in our broad interest article and was selected by me College as the winner of the "images with impact competition". The image was subsequently used to make Xmas card sent around funders, policy makers and other Universities. 
Type Of Art Image 
Year Produced 2018 
Impact I had several people contact me (members of the public) who were interested in our research having seen the Xmas card. It was a surprisingly effective outreach exercise! 
 
Description To help understand the basis of niche specificity, our recent efforts have focused on analysing the roles of both bacterial and host metabolism in affecting bacterial gene expression. We have found that the amino acid D-serine drives niche adaptation by affecting gene selection in E. coli. D-serine accumulates to mM concentrations in humans as a by-product of metabolism, for example in urine, or as a specific neurotransmitter in the brain. the YhaOJK D-serine "sensing" system, we have discovered is carried by >99% of all E. coli strains sequenced to date. Our working model proposes that three proteins are central to this system: YhaO (a D-serine transporter), YhaK (a co-regulator) and YhaJ (a LysR-type transcriptional regulator, LTR). Moreover, using the full genomes of diverse organisms from the Archaea, Bacteria and Eukarya, the most conserved genetic sequences across the widest divisions of life have recently been determined. One of the genes found to be almost universal was yhaO, encoding part of this D-serine sensing system. This demonstrates that the ability to sense and respond to this amino acid is extremely important for many organisms. In this work, we use E. coli as a model to study this D-serine sensing system and its relevance to niche specificity. The key questions that we are currently addressing in this proposal are how do E. coli strains sense and respond to D-serine? And secondly, how does this response vary between different pathotypes to affect niche specificity?
Exploitation Route Food manufacturers: As we understand the importance of diet and its influence on infection, there will be the opportunity to develop formulated dietary programs that will require interfacing with food and healthcare manufacturers. The UK has become a leading source of new foods with health propositions. In 2007, 36% of new health product launches in the European Union originated in the UK. Dr Roe has a background in food microbiology through a BBSRC-CASE award in conjunction with Unilever and has excellent links with this company. We will liaise with such potential partners through the University Innovation and Marketing office.

Antibiotics development industry: There is a clear link between expression of the "sensory" system we have found and virulence factors. This provides a fantastic opportunity to develop novel compounds that block this pathway and effectively switch off key proteins used for attachment. New mechanisms to combat hard to treat infection, particularly gram negative infections are a cross council priority area that still has been sorely neglected despite the urgency of the issue. Dr Roe has a track record in research of new anti-infective compounds and has links with UK companies including Argenta (a partner in a Wellcome Trust seeding drug discovery application). As we understand the pathway, "bolt-on" projects run by Mres students can perform initial screens for compounds that specifically interfere with activity. All novel IP will be carefully managed though the University Research and innovation officers.
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

URL https://www.gla.ac.uk/researchinstitutes/iii/staff/andrewroe/andrewroe/mainpage/
 
Description Updated teaching to reflect latest research
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact We have incorporated our research into lectures for both graduate and post graduate teaching at the University of Glasgow.This ensures of students have the most up to date information regarding metabolites that affect bacterial gene regulation.
 
Description University Fellowship to Dr James Connolly
Amount £200,000 (GBP)
Organisation Newcastle University 
Sector Academic/University
Country United Kingdom
Start 04/2019 
End 03/2021
 
Description News and views article 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact We wrote an article for the Nature Communications community section called the story behind our paper "iit's a pleasure to discuss the people that made the science a success and the challenges that we faced along the way."
Year(s) Of Engagement Activity 2018
URL https://naturemicrobiologycommunity.nature.com/users/178223-andrew-roe/posts/39063-host-derived-meta...