Oxford Research - "Chronic Lyme Disease": a model for persistent pathogen involvement in chronic disease

We are delighted to announce that Lyme Resource Centre aims to collaborate with a number of partners including Oxford University to undertake research on the physiology of patients with chronic Lyme disease. If funding can be obtained, it is hoped that the project will run for 3 years from 2022-2024.

The full project will cost £1.6 million, but we can start with just the first year at a cost of £400,000. We are currently in the process of investigating multiple avenues to obtain funding.

You can help support this and other research by donating to our Research fund at http://www.lymeresourcecentre.com/donate

At a "Lyme and Tick-borne Disease Workshop" by the National Institute for Health Research in November 2019, a representative from Public Health England stated that "research on treatments will not happen in my lifetime". It became starkly clear to patients that if they were going to get help with future treatment they would have to organise research in other ways. We are therefore delighted to take part in this project. 

Oxford University logo   UCD logo   Mater Misericordiae Hospital logo   Lyme Resource Centre logo   SoftCell Biological Research logo

Summary

Chronic Lyme disease (CLD) can be a life long illness for patients who are misdiagnosed or inadequately treated. Although thought to involve Borrelia and a number of other ‘co-infections’, we still have limited understanding of what drives the illness to enter a chronic state. This proposal will be the first to explore in detail how the microbiome-metabolome-immune axis links to symptoms, physiology and treatment in people with CLD.

We propose an intensive prospective study of 40 patients to correlate clinical improvement over a six month period with an antibiotics intervention strategy successfully used at University College Dublin to treat over 400 CLD patients with evidence of significant clinical improvement. We will link changes in symptoms to levels of blood pathogens and alterations in the gut microbiome. The former, involving a comprehensive assessment of the blood biome, will be carried out by our industrial collaborator SoftCell Biological Research, who have previously observed elevated levels of L-form pathogens in many chronic diseases. As the immune system appears to be compromised in CLD patients, changes in gut health in response to treatment will be measured and immune cell function studied using state of the art single cell approaches. Energy metabolism is emerging as an important player in the functioning of the immune system with growing links to fatigue. We will determine the mtDNA genotypes of all patients and run pilot studies linking variant levels to treatment outcomes. Modulation of the plasma metabolome and Raman spectral profiles of peripheral blood mononuclear cells (PBMC) are abnormal in patients with ME/CFS, and this observation will be explored and changes correlated with symptom improvement.

Our comprehensive assessment of patient physiology will attempt to determine the cellular and tissue compartments most affected in CLD. This will be of great value in identifying the key areas to target for future treatment strategies.

Investigators

Principal Investigator:

  • Dr Karl Morten, University of Oxford (Women's and Reproductive Health)
    Karl Morten

Co-Investigators:

  • Prof. Jack Lambert, University College Dublin (School of Medicine)
    Jack Lambert
  • Prof. James McCullagh, University of Oxford (Oxford Chemistry)
    James McCullagh
  • Dr Wei Huang, University of Oxford (Engineering Science)
    Wei Huang
  • Mr Stephen Taylor, University of Oxford (Weatherall Inst of Molecular Medicine)
    Stephen Taylor
  • Dr Jethro Johnson, University of Oxford (Kennedy Institute)
    Jethro Johnson
  • Prof. Kim Midwood, University of Oxford (Kennedy Institute)
    Kim Midwood
  • Prof. Peter O'Gorman, Mater Misericordiae University Hospital, Dublin
    Peter O'Gorman
  • Dr. Janey Cringean, Lyme Resource Centre, Scotland
    Janey Cringean

Objectives

To achieve our overall goal, we have the following objectives for this research:

  1. Evaluate the number of Chronic Lyme Disease patients who show a clinical response to long term antibiotic treatment including an estimate of time with reduced symptoms. This pilot study will inform on the potential of this approach in the treatment of Chronic Lyme Disease.
  2. Determine the change in blood pathogen (blood biome) load following antibiotic intervention and link to measures of clinical improvement. The blood biome will also be compared to healthy controls pre-treatment.
  3. Determine changes in the gut microbiome following antibiotic intervention linking to measures of clinical improvement. The gut microbiome will also be compared to healthy controls pre-treatment.
  4. Assess immune cell profile and activation status pre-treatment comparing to healthy controls. Determining the effect of antibiotics on immune cell function and linking to clinical improvement.
  5. Determining changes in the plasma and peripheral blood mononuclear cell (PBMC) metabolites post antibiotics treatment and linking to clinical improvement. Metabolites showing differences will be explored further investigating links with pathogens and cellular metabolism.
  6. Determining if the gut or blood brain barrier (BBB) are leaky in Chronic Lyme Disease patients compared to healthy controls and whether a reduction in leakiness correlates with an improvement in symptoms post antibiotic treatment. Establishing if gut and/or brain are potentially key sites in the disease.
  7. Culturing and characterising L-form organisms from individual Chronic Lyme patient's blood samples and looking for matches with organisms detected by whole genome sequencing (WGS) of the initial blood. These two different approaches carried out independently in the laboratories of SoftCell Biological Research will provide strong evidence for the presence of specific patient associated pathogens. In addition L-form cultures from individual patients will be used for the future in vitro evaluation of antibiotic drug panels prior to trials in patients.
  8. Evaluate the potential of Raman Spectroscopy as a diagnostic tool in Chronic Lyme Disease exploring PBMC's and plasma. Chronic Lyme data sets will be compared with our ME/CFS and Multiple Sclerosis data sets using machine learning and the data visualisation tool Zegami. Raman Spectroscopy and Zegami have already shown a strong ability to distinguish the two patient groups from each other and healthy controls.
  9. Determine if mitochondrial DNA (mtDNA) variants correlate with a positive or negative response to antibiotic treatment. Assessing the impact of our antibiotics treatment regime on mtDNA variant mitochondrial function in in-vitro models.

Project Partners

Industrial Project Partners

  • Dr Gregory Prince, SoftCell Biological Research
    Gregory Prince

Non-Industrial Project Partners

  • Dr Joanna Elson, University of Newcastle
    Joanna Elson
  • Prof Brad Sutherland, University of Tasmania
    Brad Sutherland
  • Dr Amy Chadwick, University of Liverpool
    Amy Chadwick
  • Mr Carl Fratter, Oxford Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust
    Carl Fratter
  • Prof Paul Klenerman, University of Oxford
    Paul Klenerman