A non-canonical role of caspase-1 in regulating bacterial physiology and antimicrobial resistance

Abstract

Abstract Caspase-1 is a key effector molecule involved in inflammasome activation and has a well-established role in restricting the growth of intracellular pathogens like Salmonella by triggering a form of cell death called pyroptosis. Here we reveal a non-canonical, cell death independent role for caspase-1 in controlling the transcriptional state and drug resistance of intracellular Salmonella. Using Pathogen-sequencing, a method for sensitive transcriptional profiling of miniscule numbers of intracellular bacteria from infected macrophages, we show that that caspase-1 regulates key processes involved in survival and antimicrobial susceptibility of intracellular Salmonella. Host caspase-1 increased susceptibility of Salmonella to endogenous cationic antimicrobial peptides, as well as to a cationic polypeptide antibiotic used as a last-line drug in Gram-negative bacterial infections. These effects of caspase-1 were independent of its enzymatic activity but dependent on its ability to repress activation of a two-component signal transduction system in intracellular bacteria. These effects were also independent of caspase-11. Our data suggest a “backup” role for caspase-1 in dampening antimicrobial resistance of intracellular Salmonella which evade initial innate immune detection and restriction by caspase-1. These findings also reveal the role of a key innate immune effector in altering pathogen physiology, broadening our view of host-pathogen crosstalk with possible implications for targeting caspase-1 in host-directed therapy to combat antimicrobial resistance. Supported by grant from NIH (R01 AI155685-A1 ) and AAI Careers in Immunology Fellowship (2018-2019)