Serratia marcescens ShlA pore-forming toxin is responsible for early induction of autophagy in host cells and is transcriptionally regulated by RcsB

DI VENANZIO, G.; STEPANENKO, T.; GARCÍA VÉSCOVI, E.

INFECTION AND IMMUNITY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2014 vol. 82 p. 3542 - 3554

0019-9567

Serratia marcescens is a gram-negative bacterium that thrives in a wide variety of ambient niches and interacts with an ample range of hosts. As an opportunistic human pathogen, it has increased its clinical incidence in recent years, being responsible for life-threatening nosocomial infections. S. marcescens produces numerous exoproteins with toxic effects, including ShlA pore-forming toxin that has been catalogued as its most potent cytotoxin. However, the regulatory mechanisms that govern ShlA expression as well as its action towards the host have remained unclear. We have shown that Serratia marcescens elicits an autophagic response in host non-phagocytic cells. In this work, we determine that the expression of ShlA is responsible for the autophagic response that is promoted previous to the bacterial internalization in epithelial cells. We show that a strain unable to express ShlA is no longer able to induce this autophagic mechanism while heterologous expression of ShlA/ShlB suffices to confer non-invasive E. coli the capacity to trigger autophagy. We also demonstrate that shlBA harbors a binding motif for the RcsB regulator in its promoter region. RcsB-dependent control of shlBA constitutes a feed-forward regulatory mechanism that allows interplay with the flagellar biogenesis regulation. At the top of the circuit, activated RcsB down-regulates expression of flagella by binding to flhDC promoter region, preventing FliA-activated transcription of shlBA. Simultaneously, RcsB interaction within shlBA promoter represses ShlA expression. This circuit offers multiple access points to finely tune ShlA production. These findings also strengthen RcsB role in orchestrating the expression of Serratia virulence factors.