PB0599 - Dysregulation of Annexin A2 system triggered by acute SARS-CoV-2 infection in human ACE2 transgenic mice

Monday, June 26, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

AD

ALEKSANDRA K. DRELICH, PhD (she/her/hers)

Research Scientist III
University of Texas Medical Branch, Dept of Microbiology and Immunology
Galveston, Texas, United States

Co-Author(s)

PS

Panatda Saenkham-Huntsinger1

Research Scientist
Departments of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA
Galveston, Texas, United States
BJ

Barbara Judy

Asst. Dir, Research Laboratory
Departments of Pathology, The University of Texas Medical Branch, Galveston, TX 77555, USA
Galveston, Texas, United States
PH

Pinghan Huang

Certificate Student
Departments of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA
Galveston, Texas, United States
PB

Peng Bi-Hung

Assoc Professor of Instruction
Department of Neuroscience, Cell Biology, and Anatomy, The University of Texas Medical Branch, Galveston, TX, USA
Galveston, Texas, United States
TK

Thomas Ksiazek

Professor
Departments of Pathology, The University of Texas Medical Branch, Galveston, TX 77555, USA
Galveston, Texas, United States
CT

Chien-Te Tseng

Professor
Departments of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA
Galveston, Texas, United States

Background: Annexin A2 (ANXA2) is a phospholipid-binding protein that can interact with two molecules of S100A10 at the extracellular membrane to create heterotertrameric complexes that functions as coreceptors for tissue plasminogen activator (t-PA) that tightly regulates the membrane fibrinolysis. Prior clinical studies have identified the presence of autoantibodies to AnxA2 among COVID-19 patients, thereby suggesting ANXA2 might serve as an autoimmunogen to promote the onset of the life-threatening coagulopathy frequently associated with severe SARS-CoV-2 infection.

Aims: To investigate the impact of altered ANXA2 system in the well characterized hACE2 Tg mice, line AC70, in response to acute SARS-CoV-2 infection on the onset of coagulopathy.

Methods: hACE2 Tg mice were challenged intranasally with 105 TCID50 (~ > 10,000 LD50) of SARS-CoV-2 and euthanized at 4 d.p.i. Peripheral blood samples, collected prior to and post infection, were analyzed for hematology and sera subjected to ELISA for detection coagulation biomarkers. Various tissues were harvested for histopathology, immunohistochemistry (IHC), virus titration, and protein extraction. ANXA2 complex was detected using co-immunoprecipitation with anti-S100A10 antibody.

Results: High dose of SARS-CoV-2 resulted in acute onset of lymphopenia and increased neutrophil-to-lymphocyte ratio (NLR) in hACE2 Tg mice, along with altered hemostasis as evidenced by elevated expression of D-dimer, t-PA and PAI-1 (t-PA inhibitor). Increased fibrin deposition was detected within the lung, brain, and heart, whereas autoantibodies to ANXA2 were revealed at the peak-phase of infection. Interestingly, acute SARS-CoV-2 infection downregulated de novo ANXA2 synthesis and reduced AnxA2/S100A10 complex formation, implying an impact on the fibrinolysis/ coagulopathy axis.

Conclusion(s): Using our fully established hACE2 Tg mouse model, we showed acute lethal infection triggered a hypercoagulable state coexisting with fibrinolytic shutdown, accompanied by dysregulation of ANXA2 system. Additional studies are warranted to further explore the impact of ANXA2 mechanism and identify potential therapeutic target for COVID-19.