Pp6-Pfkfb1 axis modulates intracellular bacterial proliferation by orchestrating host-pathogen metabolic crosstalk

Area of Science:

• Immunology
• Microbiology
• Metabolism

Background:

• Intracellular bacterial pathogens display varied replication rates within host macrophages.
• Mechanisms by which pathogens manipulate host factors for survival are not fully understood.

Purpose of the Study:

• To investigate the role of Protein Phosphatase 6 (Pp6) in host response to Salmonella Typhimurium infection.
• To identify host factors regulated by Pp6 that influence bacterial survival.

Main Methods:

• Utilized a fluorescence-dilution reporter system in Salmonella-infected macrophages.
• Employed conditional knockout models for Pp6 and microRNA-31 (miR-31).
• Performed yeast two-hybrid screening to identify Pp6 substrates.

Main Results:

• Pp6 was downregulated in macrophages with replicating Salmonella.
• Pp6 deficiency increased susceptibility to Salmonella, impairing antimicrobial defenses.
• miR-31 negatively regulated Pp6; its ablation enhanced bacterial clearance.
• Identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 (Pfkfb1) as a Pp6 substrate.
• Pp6 deficiency elevated Pfkfb1 expression, restricting Salmonella growth via nitric oxide (NO) production and suppressing arginase-1 (Arg-1).

Conclusions:

• The Pp6-Pfkfb1 axis is crucial for host metabolic adaptation during intracellular bacterial infections.
• This pathway modulates macrophage antimicrobial functions.
• The Pp6-Pfkfb1 axis represents a potential therapeutic target against multidrug-resistant pathogens.