OC 66.1 - Comparative analysis of coagulopathy in baboon models of toxigenic versus non-toxigenic Bacillus anthracis sepsis

Tuesday, June 27, 2023

14:45 – 15:00 ET

Room: 524

Session Available As: On-Demand

Presenting Author(s)

Ravi S. Keshari, PhD

Associate Staff Scientist, Cardiovascular Biology
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States

Co-Author(s)

RS

Robert Silasi

Research Assistant Member, Cardiovascular Biology
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States
GR

Girija Regmi

Post-Doctoral Fellow, Cardiovascular Biology
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States
NP

Narcis Popescu

Research Assistant Member, Arthritis and Clinical Immunology
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States
CL

Cristina Lupu

Staff Scientist, Cardiovascular Biology
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States
SK

Susan Kovats

Professor, Arthritis and Clinical Immunology
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States
DF

Darise Farris

Professor, Arthritis and Clinical Immunology
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States
Owen J.T McCarty, PhD, FAHA

Professor and Chair of Biomedical Engineering
Oregon Health & Science University
Portland, Oregon, United States
MC

Mark Coggeshall

Professor, Arthritis and Clinical Immunology
Oklahoma Medical Research Foundation
Oklahoma City, Oklahoma, United States
FL

Florea Lupu, PhD

Professor, Cardiovascular Biology
Oklahoma Medical Research Fundation
Oklahoma city, Oklahoma, United States

Background: Anthrax sepsis associates with robust coagulopathy and inflammation leading to disseminated intravascular coagulation but the relative role of the toxins versus other virulence factors in the disease is not fully understood.

Aims: We compared host responses, including activation of coagulation, complement and inflammation in baboons challenged with the toxigenic Sterne versus non-toxigenic Delta Sterne strains of Bacillus anthracis.

Methods: Baboons were intravenously infused with sublethal doses of live Sterne or Delta Sterne strains for 2h; blood samples and vital signs were collected for 7 days, and activation markers of coagulation, complement and inflammation were measured.

Results: Sterne challenged animals showed a stronger cardiopulmonary dysfunction reflected by tachypnea and tachycardia. They also displayed a stronger activation of coagulation via both intrinsic and extrinsic pathways, reflected by higher levels of inhibitory complexes of Factor (F) XIa, FXIIa, kallikrein, FVIIa and thrombin with antithrombin (AT) (Fig. 1A-C) and increased platelets (Fig. 1D) and fibrinogen consumption. Fibrinolysis markers t-PA and plasmin-antiplasmin complexes were higher during the first 2-4h. Complement activation marker C5b-9 was also significantly higher in Sterne vs. Delta Sterne (Fig. 2A), reflecting a tight crosstalk between coagulation and complement activation. Likewise, markers of cytolysis (lactate dehydrogenase and nucleosomes; Fig. 2B) and neutrophil activation (myeloperoxidase and citrullinated histone H3; Fig. 2C,D) were significantly increased in animals challenged with toxigenic vs. non-toxigenic bacteria suggesting increased cell death and/or impaired clearance of dead cells. The toxigenic strain led to stronger anemia at day 7 than non-toxigenic challenge. Unexpectedly, no significant differences of plasma inflammatory cytokines were observed questioning the dogma that toxins interfere with the innate immune responses.

Conclusion(s): We demonstrate that anthrax toxins contribute to the pathophysiology of the disease by increasing coagulopathy, complement activation, neutrophil activation and cell death. These results suggest that the use of anticoagulants should be considered as therapeutic intervention in anthrax.

Learning Objectives:

the role of coagulation and complement systems in anthrax pathogenesis.
the role of neutrophil activation and cell death in anthrax pathogenesis.
distinguish between host responses to toxigenic versus non-toxigenic Bacillus anthracis bacteria