Affiliation:
1. Bacterial Stress Response Group, Microbiology, Ryan Institute, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland
2. Department of Food Biosciences, Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland
3. School of Biological Sciences, Queen’s University Belfast, Belfast, Northern Ireland
Abstract
ABSTRACT
Stomach acid provides a significant innate barrier to the entry of the food-borne pathogen
Listeria monocytogenes
into the human gastrointestinal tract. A key determinant of acid resistance in this bacterium is the conserved glutamate decarboxylase system, GadD2 (encoded by the
gadT2D2
operon), which helps to maintain the intracellular pH during exposure to gastric acid. In this study, we identified a premature stop codon in a gene located immediately downstream of the
gadT2D2
operon that was highly linked to an acid-sensitive phenotype. When this open reading frame was restored through homologous recombination, an acid-resistant phenotype was restored. Through a series of genetic, transcriptomic, and survival experiments, we established that this gene, which we designated
gadR
, encodes a transcriptional regulator of the
gadT2D2
operon. GadR belongs to the RofA family of regulators, primarily found in streptococci, where they are involved in regulating virulence. The data further showed that
gadR
plays a critical role in the development of acid resistance in response to mild acid exposure, a response that is known as the adaptive acid tolerance response (ATR). A deletion analysis of the
gadT2D2
promoter region identified two 18-bp palindromic sequences that are required for the GadR-mediated induction of
gadT2D2
, suggesting that they act as binding sites for GadR. Overall, this study uncovers a new RofA-like regulator of acid resistance in
L. monocytogenes
, which plays a significant role in both growth phase-dependent acid resistance and ATR and accounts for previously observed strain-to-strain differences in survival at low pH.
IMPORTANCE
The ability to survive the acidic conditions found in the stomach is crucial for the food-borne pathogen
Listeria monocytogenes
to gain access to the mammalian gastrointestinal tract. Little is currently known about how acid resistance is regulated in this pathogen and why this trait is highly variable between strains. Here, we used comparative genomics to identify a novel RofA-family transcriptional regulator, GadR, that controls the development of acid resistance. The RofA family of regulators was previously found only in a small group of bacterial pathogens, including streptococci, where they regulate virulence properties. We show that
gadR
encodes the dominant regulator of acid resistance in
L. monocytogenes
and that its sequence variability accounts for previously observed differences between strains in this trait. Together, these findings significantly advance our understanding of how this important pathogen copes with acid stress and suggest a potential molecular target to aid its control in the food chain.
Funder
Department of Agriculture, Food and the Marine, Ireland
Science Foundation Ireland
Publisher
American Society for Microbiology
Cited by
3 articles.
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