Daily Sepsis Research Analysis

Sepsis in humans, as well as mouse models of infection, demonstrates sex-biased outcomes in which males tend to have a higher incidence, higher severity, and higher mortality compared to females. Despite this important sex-bias in sepsis outcomes, little is known about its mechanistic drivers nor therapeutic implications. Much of the foundational data on sepsis pathogenesis is derived from animal studies that included only male subjects, potentially contributing to the notable paucity of successful mouse-to-human translation of sepsis therapeutics. In this study, we demonstrate that male-biased illness severity and organ dysfunction in mouse models of bacterial sepsis are mediated by impaired disease tolerance in males, involving impaired tolerogenic shifts in mitochondrial oxidative metabolism compared to females. Microbiological and immunological analyses of sepsis between males and females revealed that sex-biased disease tolerance was independent of infection resistance mechanisms, as well as canonical immune/inflammatory dysregulation. Therapeutic potentiation of mitochondrial tolerance with doxycycline neutralized sexual dimorphism of illness severity and organ dysfunction through a male-predominant treatment effect. These data reveal that biological sex is a fundamental determinant of illness severity and treatment responsiveness in sepsis through modulation of disease tolerance, which may be

Sepsis research has long been constrained by limited labeled data and models designed for specific tasks that primarily rely on tabular inputs, overlooking the valuable insights contained in clinical text. To address these limitations, we propose the Sepsis Data Representation Model (SepsisDRM), an embedding model that jointly processes tabular and textual data to capture comprehensive patient representations. Trained on a dataset comprising 19,526 sepsis patients, SepsisDRM demonstrates strong generalization across diverse sepsis-related tasks without task-specific tuning. It effectively stratifies patients into four clinically interpretable phenotypes and achieves robust performance in predicting 28-day outcomes, with AUC scores of 0.92, 0.94, and 0.78 on retrospective, prospective, and external datasets, respectively. As the first embedding model developed specifically for sepsis, SepsisDRM establishes a novel paradigm for sepsis research and offers a promising approach for studies in other fields that involve the integration of both tabular and textual data.

Platelets are crucial to the development of thrombosis and coagulation abnormalities in sepsis, but the mechanisms by which they contribute to these pathological processes are not fully understood. Here, we identify a key role for platelet-released heat shock protein 90α (HSP90α) in driving neutrophil extracellular trap (NET) formation and supporting thromboinflammation during sepsis. Proteomic analysis of platelets from patients with sepsis showed a significant increase in HSP90α, which we traced back to trafficking pathways originating from megakaryocytes. When activated, platelets translocate HSP90α to their plasma membrane and release it into the extracellular space in both free and exosome-associated forms. Extracellular HSP90α acts as a damage-associated molecular pattern that binds to toll-like receptor 4 (TLR4) on neutrophils. This binding activates a downstream MyD88-Beclin 1 signaling pathway, triggering autophagy and leading to NET formation. Blocking extracellular HSP90α with a neutralizing monoclonal antibody significantly reduced NET formation both in vitro and in vivo, resulting in decreased sepsis-related thrombosis and inflammation. This platelet-HSP90α-TLR4-autophagy-NET pathway not only deepens our understanding of platelet-induced immunothrombosis but also suggests potential targets for therapies aimed at reducing coagulation problems and organ failure in septic patients.