A non-canonical role for caspase-1 in controlling antimicrobial resistance of intracellular Salmonella

---

Presentation Time: 02:00 PM - 02:15 PM
Abstract ID: 4505 - A

Presenting Author:
Ajay S Akhade , Senior Research Scientist at Inst. for Sys. Bio.

Abstract:

Caspase-1 is a key effector molecule involved in inflammasome activation and has a well-established role in restricting the growth of pathogens 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 an intracellular pathogen. Using Pathogen-sequencing, a method for sensitive transcriptional profiling of minuscule numbers of intracellular bacteria from infected macrophages, we show that host caspase-1 decreases the resistance of intracellular Salmonella to endogenous cationic antimicrobial peptides, and 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 the activation of a two-component signal transduction system in intracellular bacteria. These effects were also independent of caspase-11. Our data suggest an activity and inflammasome-independent role for caspase-1 later in infection in restricting intracellular Salmonella which evade initial inflammasome-dependent restriction by caspase-1. Our findings thus take host caspase-1 beyond the well-studied inflammasomes and tie it to signal transduction and drug resistance of an intracellular pathogen with possible implications for host-directed therapy to combat antimicrobial resistance.