OC 67.4 - Thrombin as an initiator, driver, and effector mechanism of lung pathology following bacterial and viral infection

Tuesday, June 25, 2024

15:30 – 15:45 ICT

Room: 210 A-D

Presenting Author(s)

LG

Laura C. Godin, HBSc

Graduate Student
Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada

Co-Author(s)

AC

Agostina Carestia

Post Doctoral Fellow
Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada
RD

Rachelle P. Davis

Graduate Student
Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada
MT

Madison Turk

Graduate Student/Medical Student
Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada
EK

Esha Kaul

Graduate Student
Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada
SN

Shahnas M. Najimudeen

Research Assistant
Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada
II

Ishara M Isham

Research Assistant
Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada
MA

Mohamed Faizal Abdul-Careem

Professor
Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada
JD

Justin Deniset

Professor
Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada
Craig N. Jenne, PhD

Professor
Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, Canada
Calgary, Alberta, Canada

Background: Viral and bacterial infections of the lung are associated with thrombin generation, platelet activation, and neutrophil recruitment, leading to NET formation and tissue damage. Targeting this pathology could improve patient outcomes.

Aims: To investigate the impact of anticoagulants and anti-platelet drugs as therapeutics for bacterial and viral infection-mediated coagulopathy.

Methods: Mice were infected intranasally with 250 PFU of influenza A virus (IAV) PR8 or 2X10^7 CFU of S. aureus. Groups were treated with acetylsalicylic acid (ASA), low molecular weight heparin (LMWH), or anti-Tissue Factor (TF)-blocking antibody before and after infection. Intravital microscopy of the lung was used to visualize immune cell behavior. Animal weight loss, wet-to-dry lung weight ratios (edema), myeloperoxidase (MPO ) activity, platelet aggregates, neutrophil recruitment, and Neutrophil Extracellular Trap (NET) release were measured.

Results: Platelet aggregation and neutrophil recruitment in the lung following IAV infection were inhibited by pre-treatment with LMWH. LMWH pre-treated, but not ASA pre-treated, showed reduced weight loss, lower WD ratio and MPO activity, and decreased NET release. When LMWH was given as a therapy on day 3 post-infection, protection was lost. In contrast, in S. aureus infection ASA works as both a prophylactic and therapy, decreasing all measures of pathology. LMWH in S. aureus mice worked as prophylactic, but not as therapy administered 6 hours post-infection. IAV and S. aureus infection coagulopathies were inhibited by pre-treatment with an anti-TF antibody, placing TF in a central position contributing to lung pathology (Figure 1).

Conclusion(s): Thrombin plays a critical role in the initiation of infection-mediated lung inflammation. LMWH and TF blockade improve outcomes in influenza before peak inflammation. As such, early treatment of patients at risk for coagulopathy could improve outcomes in influenza infection. Interestingly, only ASA was effective as a therapy post-bacterial infection, indicating the need to match the anticoagulant to a given infection.