Infection, immunity and inflammation

Our immune system protects us against infection, but may cause disease if not properly regulated. Understanding how the immune response is triggered and controlled is thus an important area of research. 

At the Plymouth Institute of Health and Care Research (PIHR) we bring together basic scientists and clinicians to link our laboratory-based studies with clinical applications to drive improved diagnostic and therapeutic strategies for infectious disease and other conditions, including cancer and neurodegeneration.

Combating sepsis

Inflammation is the cornerstone of innate immune defence against infection but may also cause tissue damage and pathology if not properly regulated. An example is sepsis, a clinical emergency that carries a high mortality. Sepsis is a consequence of disregulation of the inflammatory response. Moreover, inflammatory responses underlie a variety of diseases and chronically may trigger conditions such as atherosclerosis and neurodegeneration. Therefore, understanding the regulation of inflammation is key to developing effective treatments for sepsis and prevention of many disease states. 

Our group has been investigating how cells of the innate immune system respond to infectious stimuli to produce inflammatory mediators. We are elucidating these mechanisms to find targets for new anti-inflammatory therapies.

Professor Simon Jackson

Liver research

The Hepatology Research Group uses state of the art laboratory facilities based in the Derriford Research Facility and the world class clinical research strengths of the Faculty of Health and Plymouth Hospitals NHS Trust. We work in unison with the South West Liver Unit, at Plymouth Hospitals NHS Trust, providing a full range and secondary, tertiary and community Hepatology services to the South West region, including assessment for liver transplantation, TIPS and liver cancer therapy. The research team run several commercially sponsored clinical trials in hepatitis C therapy, non-alcoholic steatohepatitis (NASH), primary biliary cholangiopathy (PBC), alcoholic liver disease and liver failure amongst others, through the clinical research facilities of The Lind Research Centre at Derriford Hospital.  

The broad themes of the hepatology research group are: 

  • Protection from hepatitis C virus infection (Cramp)
  • Lipid metabolism and the pathogenesis and treatment of non-alcoholic steatohepatitis (Sheridan)
  • Alcoholic hepatitis (Dhanda)
  • Molecular virology of hepatitis C and other hepatitis viruses (Felmlee).

In 2020, the group opened an observational clinical trial at UHP to test biomarkers of outcome of patients hospitalised with COVID-19. Other research highlights include the identification, using next generation sequencing, of six genes expressed in the liver that had rare genetic signatures in the small number of people who appear resistant to the Hepatitis C Virus.

Macrophages

Macrophages are at the forefront of immune defence against pathogens and tumours. They exhibit a degree of functional plasticity which, when dysregulated, contribute to inflammatory pathology and cancer. Research centres on the role of mucosal macrophages in homeostasis and pathology; with the specific aim of manipulation of plasticity and functional activation/suppression as a future cell-based therapeutic regimen in the treatment of gut diseases (Crohn’s disease, ulcerative colitis, colorectal cancer) and oral mucosal diseases (chronic periodontitis and oral squamous cell carcinoma).

Studies of macrophages are hampered by the limited life-span and restricted numbers of primary tissue macrophages that can be obtained for experiments. We have established a novel, continuously growing, non-transformed model of lung alveolar macrophages (AMs), cells that play key roles in important diseases such as lung infection, asthma and chronic obstructive pulmonary disease. This new system has already made possible the identification of several, previously unknown, innate immune phenomena in AMs and we are now analysing the underlying molecular details to allow development of drugs that can influence AM activity in various pathology states.

(Feyer, Foey)

Microbial diagnostics and infection control

By 2050 it is estimated that 10 million people worldwide will die as a result of being infected with drug-resistant bacteria. Bacteria which were previously susceptible to antibiotic treatment have evolved to develop resistance to commonly used antibiotics, rendering them ineffective to combat infection. Now there are fewer antibiotics available to treat patients with certain infections. Hence, there is a global drive not only to discover new antibiotics to combat these bacteria but also to develop new types of diagnostics that can help diagnose infection at the point of care.

This research focuses on designing low cost, rapid (five minutes), point of care nucleic acid-based biosensor assays for detection of AMR resistance genes and other pathogens that work within minutes from sample to result.

Doctor Tina Joshi

Plugging the gaps in the antibiotic discovery pipeline

The WHO have declared that antibiotic resistance is one of the major threats to human health and the Chief Medical Officer recently raised this issue nationally. However, there is still a real need to discover novel antibiotics. Infections caused by drug resistant pathogens are a significant cause of morbidity and mortality and pan-resistant organisms are becoming less rare. 

The antibiotic-resistant pathogens research group runs a programme of natural product screening for discovery of bacteriocins, antimicrobial peptides produced by bacteria. The programme is supported by use of next generation sequencing methods to determine bacterial genome sequences and generate metagenomic datasets that can be interrogated with various software tools for identification of putative bacteriocins. Lead compounds are being developed towards clinical use with commercially focused funding from BBSRC and other sources.

(Upton, Warburton).

Self-disseminating vaccines

Throughout history most pathogens have been acquired by transmission from animal reservoirs (called a zoonotic infection). Ebola virus infection in humans (from chimpanzees and gorillas) and bovine tuberculosis infection in cattle (from badgers) are two examples of ongoing zoonotic diseases from wild animal populations. Vaccination of such animal populations in the wild is impossible using conventional approaches due to the need for inoculation of individual animals. An exciting new method we are testing is to insert regions from Ebola virus and TB into harmless viruses normally carried by these animals, and to use them as 'disseminating' vaccines that are able to spread through the entire population. This has the added value of also protecting the wild animals.

Skeletal pathology

The skeleton constantly remodels in response to changes in mechanical load, serum calcium and micro-damage. This dynamic process generates a bone mass and structure optimised to current physical and mineral requirements. At a cellular level remodelling is performed by osteoblasts that secrete and mineralise new bone matrix and osteoclasts that resorb bone. Osteoblast and osteoclast activity is tightly regulated such that during each remodelling cycle osteoblast formation is temporally coupled to resorption ensuring there is little net bone loss. However, this balance is disrupted in many skeletal disorders such as post-menopausal osteoporosis, breast and prostate cancer. 

Our work aims to understand the mechanisms leading to the disruption of bone cell activity and assess the beneficial impact of potential novel nutritional factors on tumour and bone cell function.