The dCache Chemoreceptor TlpA of Helicobacter pylori Binds Multiple Attractant and Antagonistic Ligands via Distinct Sites

Johnson, Kevin S.; Elgamoudi, Bassam A.; Jen, Freda E.-C.; Day, Christopher J.; Sweeney, Emily Goers; Pryce, Megan L.; Guillemin, Karen; Haselhorst, Thomas; Korolik, Victoria; Ottemann, Karen M.

doi:10.1128/mbio.01819-21

Cited by 19 publications

(26 citation statements)

References 61 publications

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“…Our results reinforce the idea that dCache domains are able to bind a large diversity of ligands. Although many of them have been proved to bind amino acids, some dCache‐containing chemoreceptors have been shown to bind other kinds of molecules, such as lactate, fumarate, malate, polyamines, histamine and benzoate derivatives [29,35,48–50]. Surprisingly, SO_1056 dCache shares similarities with the PctA chemoreceptor described to bind amino acids, while S. oneidensis does not show any chemotactic behaviour towards amino acids [20].…”

Section: Discussionmentioning

confidence: 99%

Multiple detection of both attractants and repellents by the dCache‐chemoreceptor SO_1056 of Shewanella oneidensis

et al. 2022

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Chemoreceptors are usually transmembrane proteins dedicated to the detection of compound gradients or signals in the surroundings of a bacterium. After detection, they modulate the activation of CheA-CheY, the core of the chemotactic pathway, to allow cells to move upwards or downwards depending on whether the signal is an attractant or a repellent, respectively. Environmental bacteria such as Shewanella oneidensis harbour dozens of chemoreceptors or MCPs (methyl-accepting chemotaxis proteins). A recent study revealed that MCP SO_1056 of S. oneidensis binds chromate. Here, we show that this MCP also detects an additional attractant (L-malate) and two repellents (nickel and cobalt). The experiments were performed in vivo by the agarose-in-plug technique after overproducing MCP SO_1056 and in vitro, when possible, by submitting the purified ligand-binding domain (LBD) of SO_1056 to a thermal shift assay (TSA) coupled to isothermal titration calorimetry (ITC). ITC assays revealed a K D of 3.4 lM for L-malate and of 47.7 lM for nickel. We conclude that MCP SO_1056 binds attractants and repellents of unrelated composition. The LBD of SO_1056 belongs to the double Cache_1 family and is highly homologous to PctA, a chemoreceptor from Pseudomonas aeruginosa that detects several amino acids. Therefore, LBDs of the same family can bind diverse compounds, confirming that experimental approaches are required to define accurate LBD-binding molecules or signals.

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Section: Discussionmentioning

confidence: 99%

Multiple detection of both attractants and repellents by the dCache‐chemoreceptor SO_1056 of Shewanella oneidensis

et al. 2022

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“…Some of the primary cytokines include: 1) IL-17A, which promotes neutrophil recruitments through IL-8 and promotes the expression of antimicrobial peptides from epithelial cells; 2) IL-17F, which upregulates the expression of other pro-inflammatory cytokines and chemokines, inducing IL-2, TGF-β, IL-6, and GM-CSF; 3) IL-21, which promotes the proliferation of Th1 and Th17 cells, creating a positive feedback loop, and promote the proliferation of B-cells; and 4) IL-22, which acts on non-hematopoietic cells by upregulating antimicrobial peptide expression and promoting tissue repair (51). Interestingly, recent work has shown that arginine, a TlpA chemoattractant (25), and the polyamine pathway are critical for maintaining Th17 pathogenicity (54). Both of these factors drive Th17 cells toward a pro-inflammatory state.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it seems that loss of tlpA results in strains that are less able to thrive in the antrum and more able to thrive in the corpus. It is possible that TlpA’s signals—arginine, cysteine and fumarate (25)— are critical in the antral glands and therefore tlpA mutants cannot access these ligands efficiently and do not grow as well as WT.…”

Section: Discussionmentioning

confidence: 99%

“…Much work has been done to determine the sensing profile of these chemoreceptors and their roles in vivo. Multiple attractants are sensed that are beneficial for H. pylori growth, including arginine, fumarate, and cysteine by TlpA; urea by TlpB; and lactate by TlpC (21)(22)(23)(24)(25). Repellents, in contrast, are harmful to the bacteria and include acid sensed by multiple chemoreceptors, autoinducer-2 sensed by TlpB, and reactive oxygen species sensed by TlpD (26)(27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

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Helicobacter chronic stage inflammation undergoes fluctuations that are altered in tlpA mutants

Johnson

Yang

Carter³

et al. 2022

Preprint

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Helicobacter pylori colonizes half of the world’s population and is responsible for a significant disease burden by causing gastritis, peptic ulcers, and gastric cancer. The development of host inflammation drives these diseases, but there are still open questions in the field about how H. pylori controls this process. We characterized H. pylori inflammation using an eight month mouse infection time course and comparison of wild type and a previously identified mutant lacking the TlpA chemoreceptor that causes elevated inflammation. Our work shows that H. pylori chronic stage corpus inflammation undergoes surprising fluctuations, with changes in Th17 and eosinophil numbers. The H. pylori tlpA mutant changed the inflammation temporal characteristics, resulting in different inflammation from wild type at some time points. tlpA mutants have equivalent total and gland colonization at late stage infections. During early infection, in contrast, they show elevated gland and total colonization compared to WT. Our results suggest the chronic inflammation setting is dynamic, and may be influenced by colonization properties of early infection.ImportanceHelicobacter pylori established chronic infection in half of the world’s population. This infection initiates during childhood, and leads to later life gastric diseases including gastritis, peptic ulcers, and gastric cancer. These diseases are driven by host inflammation, with more severe inflammation leading to more severe disease. It is not fully understood how H. pylori controls inflammation. In this work, we used an H. pylori mouse infection model and characterized inflammation and colonization of wild-type H. pylori and a mutant that was known to cause elevated inflammation. We found that inflammation in the chronic stage undergoes surprising fluctuations, with related changes in Th17 numbers. H. pylori tlpA mutants caused offset inflammation dynamics, suggesting that H. pylori infection underlies this dynamism. Although there were not colonization dynamics at the time of inflammation fluctuations, there were differences between WT and tlpA mutant colonization at early time points. Our results suggest the chronic inflammation setting is more dynamic than previously thought and may be influenced by colonization properties of early infection.

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“…There is now a significant body of evidence for the existence of naturally occurring signal antagonists (Busch et al ., 2007; Martin‐Mora et al ., 2018; Johnson et al ., 2021), which are compounds that bind to the same site as the signal molecules but fail to induce downstream signalling (Fig. 2) – a phenomenon likely due to different conformational changes induced by signal and signal antagonist binding (Koh et al ., 2016).…”

Section: Antagonists Targeting Signal Transduction Systems In Anti‐in...mentioning

confidence: 99%

Antimicrobial resistance: progress and challenges in antibiotic discovery and anti‐infective therapy

Krell

Matilla

2021

Microbial Biotechnology

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The alarming rise in the emergence of antimicrobial resistance in human, animal and plant pathogens is challenging global health and food production. Traditional strategies used for antibiotic discovery persistently result in the re-isolation of known compounds, calling for the need to develop more rational strategies to identify new antibiotics. Additionally, antiinfective therapy approaches targeting bacterial signalling pathways related to virulence is emerging as an alternative to the use of antibiotics. In this perspective article, we critically analyse approaches aimed at revitalizing the identification of new antibiotics and to advance antivirulence therapies. The development of high-throughput in vivo, in vitro and in silico platforms, together with the progress in chemical synthesis, analytical chemistry and structural biology, are reviving a research area that is of tremendous relevance for global health.

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The dCache Chemoreceptor TlpA of Helicobacter pylori Binds Multiple Attractant and Antagonistic Ligands via Distinct Sites

Abstract: Numerous chemotactic bacterial pathogens depend on the ability to sense a diverse array of signals through chemoreceptors to achieve successful colonization and virulence within their host. The signals sensed by chemoreceptors, however, are not always fully understood.

Cited by 19 publications

References 61 publications

Multiple detection of both attractants and repellents by the dCache‐chemoreceptor SO_1056 of Shewanella oneidensis

Multiple detection of both attractants and repellents by the dCache‐chemoreceptor SO_1056 of Shewanella oneidensis

Helicobacter chronic stage inflammation undergoes fluctuations that are altered in tlpA mutants

Antimicrobial resistance: progress and challenges in antibiotic discovery and anti‐infective therapy

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