Evolving strategies of intracellular Hypervirulent Klebsiella pneumoniae during phage therapy: Reducing host autophagy and inflammation

Hypervirulent Klebsiella pneumoniae (hvKp) presents challenges in infection management due to antibiotic resistance associated with its intracellular persistence. This study investigates the efficacy of phage therapy against intracellular hvKp using a two-stage murine model. We assessed changes in virulence, host survival, and immune responses through phagocytosis assays, transmission electron microscopy, and Western blotting, complemented by transcriptomic and proteomic analyses. Results indicate that phage therapy reduces mortality and modulates bacterial virulence by downregulating capsule production. Following phage exposure, hvKp adapts by enhancing its oxidative stress resistance. Crucially, these adaptations weaken host inflammatory and autophagy responses, enabling better survival within host cells. These adaptations suggest that while phage therapy can mitigate infection severity, the capacity of hvKp to modulate host pathways underscores the complexity of treating intracellular infections and highlights the importance of targeting both bacterial and cellular responses. In this study, we investigated the use of phage therapy against intracellular infections caused by hypervirulent Klebsiella pneumoniae, a bacterium capable of evading antibiotics by residing within host cells. Using a mouse model, we demonstrated that phage therapy improves survival and reduces bacterial virulence. However, exposure to phages prompted the bacterium to enhance its oxidative stress defenses and adapt by suppressing host inflammatory and autophagy responses. These adaptations not only promote bacterial survival within host cells but also result in higher bacterial loads in tissues and organs, potentially leading to chronic infections. This poses a severe threat to immunocompromised individuals, underscoring the dual challenge of phage therapy: while it offers significant therapeutic potential, bacterial adaptations can undermine its efficacy. Our findings provide crucial insights into the host-pathogen dynamics during phage therapy, paving the way for more effective strategies to combat intracellular bacterial infections.