Journal Article

Cytokine-driven PANoptosis of alveolar macrophages mediated by STAT1 underlies acute lung injury in hypervirulent Klebsiella pneumoniae infection

Peng, Mingxiu, Liu, Xiaoxuan, Yang, Guan, Heng, Heng, Xu, Qi, Chen, Sheng, Chan, Edward Wai-Chi, Zhao, Wenxing, Wang, Han, Luo, Mei

2026

Overview

Klebsiella pneumoniae , particularly hypervirulent strains (hv Kp ), poses a critical public health threat due to its capacity to cause severe, rapidly progressing infections such as pneumonia and sepsis, often leading to acute lung injury (ALI) and high mortality. Despite the recognized role of excessive inflammation and cytokine storms in hv Kp pathogenesis, the precise mechanisms linking immune hyperactivation to fatal tissue damage remain poorly defined. This study reveals that hv Kp infection triggers a coordinated form of inflammatory cell death, PANoptosis, in AMs, the frontline immune defenders in the lungs. We identify the transcription factor STAT1 as a central regulator of this process, driven by a synergistic cytokine milieu, especially involving IFN-γ. Our findings establish a direct mechanistic pathway from hv Kp -induced cytokine release to STAT1-mediated PANoptosis, macrophage depletion, and subsequent lung failure. This work not only advances the understanding of hv Kp virulence but also highlights host signaling pathways and specific cytokines as potential therapeutic targets to modulate immunopathology and improve outcomes in severe Klebsiella infections.

• Publisher: American Society for Microbiology,American Society for Microbiology (ASM)
• Subject: Acute Lung Injury - immunology / Acute Lung Injury - microbiology / Acute Lung Injury - pathology / alveolar macrophage / Animal Infection Models / Animals / cytokine / Cytokines - immunology / Cytokines - metabolism / Disease Models, Animal / Host-Microbial Interactions / Host-Pathogen Interactions / Innate Immunity / Interferon-gamma - immunology / Interferon-gamma - metabolism / Klebsiella Infections - immunology / Klebsiella Infections - microbiology / Klebsiella Infections - pathology / Klebsiella pneumoniae / Klebsiella pneumoniae - immunology / Klebsiella pneumoniae - pathogenicity / Lung - immunology / Lung - microbiology / Lung - pathology / Macrophage Activation and Deactivation / Macrophage Biology / Macrophage Cell Death Mechanisms / Macrophage Function in Innate Immunity / Macrophage Infection and Intracellular Survival / Macrophage-Mediated Pathogen Clearance / Macrophage-Pathogen Interactions / Macrophages, Alveolar - immunology / Macrophages, Alveolar - microbiology / Mice / Mice, Inbred C57BL / Mice, Knockout / Microbial Pathogenesis and Immunology / Mouse Lung Infection Models / Murine Pneumonia Models / PANoptosis / Pulmonary Innate Immunity / Research Article / Signal Transduction / STAT1 / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - immunology / STAT1 Transcription Factor - metabolism / Virulence