Oral Presentation Australian Society for Microbiology Annual Scientific Meeting 2021

Human Plasminogen Exacerbates Clostridioides difficile Enteric Disease and Alters the Spore Surface (#64)

Milena Awad 1 , Melanie Hutton 1 , Juinn Quek 2 , William Klare 3 , Steven Mileto 1 , Kate Mackin 1 , Diane Ly 4 5 , Viola Oorschot 2 6 , Marijana Bosnjak 1 , Grant Jenkin 7 , Paul Conroy 2 , Nick West 8 , Alex Fulcher 6 , Adam Costin 2 , Christopher Day 9 , Michael Jennings 9 , Robert Medcalf 10 , Martina Sanderson-Smith 4 5 , Stuart Cordwell 3 , Ruby Law 2 , James Whisstock 2 11 12 , Dena Lyras 1
  1. Microbiology, Monash University, Clayton, Vic, Australia
  2. Australian Research Council Centre of Excellence in Advanced Molecular Imaging and Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Vic, Australia
  3. School of Life and Environmental Sciences and Charles Perkins Centre , The University of Sydney, Sydney, NSW, Australia
  4. School of Chemistry and Molecular Bioscience and Molecular Horizons , University of Wollongong, Wollongong, NSW, Australia
  5. Illawarra health and Medical Research Institute, Wollongong, NSW, Australia
  6. Monash Micro Imaging , Monash University, Clayton, VIC, Australia
  7. Monash Infectious Diseases, Monash Health, Clayton, Vic, Australia
  8. School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, University of Queensland, St Lucia, QLD, Australia
  9. Institute for Glycomics , Griffith University, Gold Coast, QLD, Australia
  10. Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Monash University, Clayton, VIC, Australia
  11. European Molecular Biology Laboratory Australia, Monash University, Clayton, VIC, Australia
  12. South East University-Monash Joint Institute , Institute of Life Sciences, Southeast University, Nanjing, China

Plasmin, a host protease important in wound healing, has been shown to aid pathogen invasion and promote pathogen host evasion. However, the role of this protease during gut infection is not known. Clostridioides difficile enteric disease causes major morbidity and mortality globally. Spores are crucial for infection, however, their role in the host is poorly understood. Here we show that the zymogen human plasminogen is recruited to the toxin-damaged gut, resulting in immune dysregulation, tissue degradation and reduced survival. Plasminogen specifically binds to C. difficile spores and active plasmin degrades their surface, facilitating rapid germination. We developed and structurally characterized antibodies that inhibit human plasminogen activation and tested their therapeutic efficacy. Remarkably, plasminogen activation inhibition reduced disease severity. Collectively, our data reveal a new disease mechanism in which human plasminogen is recruited to the damaged gut during infection, exacerbating C. difficile-mediated disease in mice. Human plasminogen binds to C. difficile spores and upon activation to plasmin, remodels the spore surface, facilitating rapid spore germination. Finally, inhibitors of plasminogen activation may have utility for the treatment of C. difficile or other infection-mediated gastrointestinal diseases.