Announcement
Thank you for attending THSNA 2026. The virtual meeting is now closed.
Thank you for attending THSNA 2026. The virtual meeting is now closed.
Presentation Details
| Pathogenesis of flu-induced pulmonary thrombosis in sickle cell disease mice.(THSNA �Travel Awardee) Tomasz Kaminski1, Nicholas Swendrowski1, Prithu Sundd1, 2. 1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI, USA.2Department of Medicine (Hematology and Oncology), Medical College of Wisconsin, Milwaukee, WI, USA |
Abstract
Background Sickle cell disease (SCD) is an inherited blood disorder affecting ~100,000 African Americans and over 8 million individuals worldwide. In SCD, polymerization of mutant hemoglobin drives erythrocyte sickling, vaso-occlusion, and hemolysis, leading to a chronic thrombo-inflammatory milieu. Although influenza A virus (IAV) infection typically causes a self-resolving upper airway inflammation in healthy humans, SCD patients exhibit a ~50-fold higher risk of ICU admission and mortality following flu. However, the mechanism linking mild viral infection to development of severe lung injury in SCD remains poorly understood. The current treatment for flu in SCD patients is limited to flu vaccine and antiviral therapy, however, these therapies need to be given prior to or at an early stage of infection. Understanding the mechanism driving flu severity in SCD will enable new therapies to halt development of respiratory failure in SCD patients with flu. Objectives To determine whether RIG-I/MAVS-signaling in platelets promotes flu-induced lung thrombo-inflammation in SCD. Methods A murine model of IAV-induced lung injury was developed in knock-in humanized Townes SCD (SS) or control (AS) mice inoculated intranasally with a mild dose of A/PR/8/34 (H1N1) IAV. Lung injury severity was assessed 14 days post-infection based on histological scoring. Oxygen saturation and body weight were measured every alternate day. Real-time multi-photon excitation-enabled real-time intravital lung microscopy was performed at days 10 and 14 to assess thrombo-inflammation, ischemia, vascular leakage, and neutrophil extracellular traps (NETs) generation in the pulmonary microcirculation. Platelets, neutrophils and plasma were collected for western blotting, co-immunoprecipitation, imaging flow cytometry, and assessment of circulating NETs and activation of type-I interferon signaling. Results At day 14 post flu infection, SCD mice manifested significant drop in oxygen saturation (<90%), body weight (³ 20%) and severe lung injury indicated by the presence of hemorrhage, vascular congestion and edema. Severe lung injury in SCD mice was associated with pulmonary thrombosis leading to microvasculature occlusion by neutrophil-platelet aggregates (NPAs), which resulted in pulmonary ischemia and loss of blood-air barrier. Unlike SCD mice, control mice developed only a mild pulmonary inflammation at day 10, which was completely resolved by day 14-post flu infection, leading to absence of lung injury and neutrophil-platelet aggregates in the pulmonary microcirculation. Pulmonary thrombosis in SCD mice was secondary to activation of the viral-RNA–sensing RIG-I–MAVS pathway in platelets, characterized by the K63-specific ubiquitination of RIG-I, elevated circulating IFN-α levels, and activation of downstream transcription factor IRF3. This platelet-driven antiviral response led to accumulation of NPAs, elevated type-I interferon signaling in neutrophils, and triggered NETs formation within the lung microcirculation, which contributed to lung injury. Conclusions These findings reveal for the first time that a mild flu infection (innocuous to control mice) triggers pulmonary thrombosis and severe lung injury in SCD mice, which is secondary to activation of anti-viral RIG-I/MAVS-signaling in platelets. Although traditional anti-platelet therapies have shown no benefit to flu patients, our new findings suggest that inhibition of platelet-RIG-I may offer a novel therapy for preventing respiratory failure in SCD patients with flu.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.