Very long O-antigen chains of Salmonella Paratyphi A inhibit inflammasome activation and pyroptotic cell death

Area of Science:

• Immunology
• Microbiology
• Pathogenesis

Background:

• Salmonella Paratyphi A (SPtA) causes enteric fever, particularly in Asia.
• The precise pathogenesis of SPtA, especially its interaction with the host immune system, remains incompletely understood.
• Inflammasome activation is a critical component of the innate immune response to bacterial pathogens.

Purpose of the Study:

• To investigate the mechanisms of inflammasome activation and pyroptosis induction by SPtA in human macrophages.
• To elucidate the role of Salmonella pathogenicity island-1 (SPI-1) and LPS O-antigen length regulator FepE in SPtA-mediated immune evasion.

Main Methods:

• Infection of human macrophages with SPtA and Salmonella Typhimurium (STm) strains.
• Assessment of inflammasome activation (caspase-1, -4, -8) and pyroptosis (GSDMD-mediated cell death).
• Analysis of the role of SPI-1 injectisome and FepE in bacterial virulence and host immune response using genetic mutants.

Main Results:

• SPtA induces GSDMD-mediated pyroptosis via caspase activation.
• A functional SPI-1 injectisome is required for SPtA-induced cell death, while its overexpression enhances pyroptosis.
• SPtA's very long O-antigen chains, regulated by FepE, impair bacterial interaction with host cells and reduce inflammasome-mediated macrophage death.
• Compared to STm, SPtA exhibits lower FepE expression, leading to higher pyroptosis, while increased FepE in STm reduces pyroptosis.

Conclusions:

• SPtA employs distinct virulence strategies, including the modulation of inflammasome activation through long LPS O-polysaccharides.
• Differential FepE expression between SPtA and STm contributes to serovar-specific inflammasome responses.
• SPtA attenuates host immune detection by elaborating long LPS O-polysaccharides, contrasting with STm's pro-inflammatory approach.