Abstract
The general stress response (GSR) in Listeria monocytogenes plays a critical role in the survival of this pathogen in the host gastrointestinal tract. The GSR is regulated by the alternative sigma factor B (σB), whose role in protection against acid stress is well established. Here, we investigated the involvement of the stressosome, a sensory hub, in transducing low pH signals to induce the GSR. Mild acid shock (15 min at pH 5.0) activated σB and conferred protection against a subsequent lethal pH challenge. A mutant strain where the stressosome subunit RsbR1 was solely present retained the ability to induce σB activity at pH 5.0. The role of stressosome phosphorylation in signal transduction was investigated by mutating the putative phosphorylation sites in the core stressosome proteins RsbR1 (rsbR1-T175A, -T209A, -T241A) and RsbS (rsbS-S56A), or the stressosome kinase RsbT (rsbT-N49A). The rsbS S56A and rsbT N49A mutations abolished the response to low pH. The rsbR1-T209A and rsbR1-T241A mutants displayed constitutive σB activity. Mild acid shock upregulates invasion genes inlAB and stimulates epithelial cell invasion, effects that were abolished in mutants with an inactive or overactive stressosome. Overall, the results show that the stressosome is required for acid-induced activation of σB in L. monocytogenes. Furthermore, they show that RsbR1 can function independently of its paralogues and signal transduction requires RsbT-mediated phosphorylation of RsbS on S56 and RsbR1 on T209 but not T175. These insights shed light on the mechanisms of signal transduction that activate the GSR in L. monocytogenes in response to acidic environments, and highlight the role this sensory process in the early stages of the infectious cycle.
Highlights
The firmicute Listeria monocytogenes is a stress-tolerant Gram-positive bacterium that causes listeriosis, a food-borne infection that poses a particular risk for immunocompromised individuals and for pregnant women that is often associated with a high mortality rates [1]
The stress sensing hub known as the stressosome, found in many bacterial and archaeal lineages, plays a crucial role in both stress tolerance and virulence in the food-borne pathogen Listeria monocytogenes
We examined the signal transduction mechanisms that operate in the stressosome in response to acid stress
Summary
The firmicute Listeria monocytogenes is a stress-tolerant Gram-positive bacterium that causes listeriosis, a food-borne infection that poses a particular risk for immunocompromised individuals and for pregnant women that is often associated with a high mortality rates (ranging from 20 to 30%) [1]. L. monocytogenes employs the alternative sigma factor B (σB) to upregulate a regulon of approximately 300 genes, which collectively confer an array of homeostatic and protective mechanisms that allow survival under severe stress conditions A ΔsigB mutant exhibits attenuated virulence [10–12] This has been partly attributed to the σB-dependent expression of the internalins A and B, encoded by inlA and inlB, respectively. Important for L. monocytogenes acid tolerance, ΔsigB mutants are still able to develop further resistance towards lethal acid pH when pre-exposed to mild acidic stress (pH 5.0) for one hour [25–27]. This phenomenon is known as the adaptive acid tolerance response (ATR) [28,29]. Genes known to be involved in acid tolerance are upregulated in a σB-dependent manner following a mild acid treatment [23,30–32] but the mechanisms of signal transduction involved have not been described yet
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