PGRN promotes host defense against B. thailandensis-induced sepsis by augmenting macrophage antibacterial capacity...

Burkholderia thailandensis (B. thailandensis) is an emerging pathogen. Although it has not yet caused large-scale outbreaks, severe infections can lead to sepsis. Currently, there are no effective treatment strategies available, highlighting the urgent need to develop novel therapies. Progranulin (PGRN) is a multifunctional protein with complex roles in regulating infectious processes. Our study investigated the role and mechanism of PGRN in host defense against lethal B. thailandensis infection. We found that PGRN expression was significantly upregulated during B. thailandensis infection. Compared with wild-type (WT) mice, PGRN knockout (PGRN-/-) mice exhibited significantly higher mortality, increased bacterial burdens in tissues, and more severe liver injury. Further analysis revealed that the heightened susceptibility of PGRN-/- mice was closely associated with impaired phagocytic and bactericidal activities of macrophages. Mechanistically, RNA sequencing and Western blot analysis demonstrated that PGRN deficiency attenuated the activation of the JAK1-STAT3 signaling pathway in macrophages. Importantly, pharmacological activation of STAT3 rescued antimicrobial defects in PGRN-/- macrophages and significantly improved the survival rate of PGRN-/- mice infected with B. thailandensis. Collectively, our findings identify PGRN as a critical host defense factor that enhances macrophage antibacterial function via JAK1-STAT3 pathway, thereby protecting against lethal B. thailandensis sepsis. These results highlight the potential of PGRN as a promising therapeutic target for the treatment of B. thailandensis-induced sepsis.