OC 10.1 - Alterations in tryptophan metabolism in mice and humans infected with SARS-CoV-2 contribute to a prothrombotic milieu

Saturday, June 22, 2024

13:00 – 13:15 ICT

Room: 209 A-D

Presenting Author(s)

Saravanan Subramaniam, M.Pharm., PhD

Assistant Professor
Department of Pharmaceutical Sciences, School of Pharmacy, MCPHS University, Boston, USA
Boston, Massachusetts, United States

Co-Author(s)

Marc Arthur Napoleon

Graduate student
Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
Boston, Massachusetts, United States
SL

Saran Lotfollahzadeh

Postdoc
Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
Boston, Massachusetts, United States
MH

Mohamed Hassan Kamal

Assistant Professor
Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
Boston, Massachusetts, United States
HK

Helena Kurniawan

Residency
Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
Boston, Massachusetts, United States
ME

Murad Elsadawi

Residency
Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
Boston, Massachusetts, United States
FD

Florian Dhouam

Assistant Professor
Department of Microbiology, National Institute of Emerging Infectious Diseases, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
Boston, Massachusetts, United States
NL

Norman Lee

Research Assistant Professor
Department of Microbiology, National Institute of Emerging Infectious Diseases, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
Boston, Massachusetts, United States
MB

Markus Bosmann

Associate Professor
Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
Boston, Massachusetts, United States
SW

Stephen Whelan

Associate Professor
Chemical Instrumentation Center, Department of Chemistry, Boston University, Boston, MA, 02118, USA
Boston, Massachusetts, United States
EB

Eric Burk

Clinical Assistant Professor
Department of Pharmacology and Toxicology, Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA
Boston, Massachusetts, United States
GZ

Grace Zhao

Assistant Professor
Department of Pharmacology and Toxicology, Massachusetts College of Pharmacy and Health Sciences, Boston, MA 02115, USA
Boston, Massachusetts, United States
VK

Vijay Kolachalama

Associate Professor
Department of Biostatistics, School of Public Health, Boston University, MA, 02118, USA Computational Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
Boston, Massachusetts, United States
KR

Katya Ravid

Professor
Department of Medicine and Whitaker Cardiovascular Institute, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
Boston, Massachusetts, United States
VC

Vipul Chitalia

Professor and Director
Center of Cross-Organ Vascular Pathology (COVP), Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University Medical Center, Boston, MA 02118, USA
Boston, Massachusetts, United States

Background: COVID-19 disturbs blood coagulation balance, triggering thrombosis and contributing to organ failure. The role of prothrombotic metabolites and their therapeutic targetability in COVID-19-associated coagulopathy remain elusive.

Aims: We aimed at characterizing tryptophan metabolism and related prothrombotic metabolites in mice and humans with SARS-CoV-2 infection.

Methods: Sera of humanized ACE2 mice infected with live SARS-CoV-2 and of SARS-CoV-2 patients were probed with LC/MS-based targeted metabolomics and for enzymes involved in tryptophan metabolism. Tissue factor (TF), aryl hydrocarbon (AHR) activity, and indolamine-2-3-dioxygenase (IDO-1) activity assays were also performed.

Results: Humanized ACE2 mice under regular chow diet and infected with SARS-CoV-2 exhibited elevated sera levels of kynurenine (Kyn) and specific Kyn catabolites, compared to controls. SARS-CoV-2 infection led to increased expression of enzymes regulating Kyn biogenesis, IDO-1 and tryptophan 2,3-dioxygenase in kidneys and liver, respectively. In contrast, the Kyn catabolism enzymes, kynurenine monooxygenase and kynurinase were downregulated in kidney and lung. Endothelial cells (ECs) of microvessels of infected mice showed evidence of activation of the AHR-TF axis. AHR, a known upregulator of TF, is activated by Kyn. In accordance, COVID-19 patients sera showed significant increases in Kyn, kynurenic acid, anthranilic acid, and quinolinic acid. Compared to controls, IDO-1 activity was elevated in sera of COVID-19 patients, and these sera strongly upregulated AHR and TF activity in human ECs. Kyn levels correlated positively with the TF-inducing activity of sera. Treatment with selective preclinical IDO-1 or AHR inhibitors suppressed COVID-19 sera-induced TF activity.

Conclusion(s): This is the first report demonstrating changes in tryptophan metabolism in mice and humans infected with SARS-CoV-2, due to differential regulation of enzymes that control this pathway in various organs. Additionally, we show activation of the AHR-TF thrombosis axis in blood vessels of SARS-CoV-2-infected mice and patients, which can be targeted using a specific IDO-1 or AHR inhibitor.