scholarly journals The global redox-responsive transcriptional regulator Rex represses fermentative metabolism and is required for Listeria monocytogenes pathogenesis

2021 ◽  
Author(s):  
Cortney R. Halsey ◽  
Maureen K. Thomason ◽  
Rochelle C. Glover ◽  
Michelle L. Reniere
Keyword(s):  
Listeria Monocytogenes ◽  
Bacterial Infections ◽  
Transcriptional Regulator ◽  
Host Cells ◽  
Gi Tract ◽  
Fermentative Metabolism ◽  
Peripheral Organs ◽  
Redox Responsive ◽  
Redox Sensing

ABSTRACTThe Gram-positive bacterium Listeria monocytogenes is the causative agent of the foodborne disease listeriosis, one of the deadliest bacterial infections known. In order to cause disease, L. monocytogenes must properly coordinate its metabolic and virulence programs in response to rapidly changing environments within the host. However, the mechanisms by which L. monocytogenes senses and adapts to the many stressors encountered as it transits through the gastrointestinal (GI) tract and disseminates to peripheral organs are not well understood. In this study, we investigated the role of the redox-responsive transcriptional regulator Rex in L. monocytogenes growth and pathogenesis. Rex is a conserved canonical transcriptional repressor that monitors the intracellular redox state of the cell by sensing the ratio of reduced and oxidized nicotinamide adenine dinucleotides (NADH and NAD+, respectively). Here, we demonstrated that L. monocytogenes Rex represses fermentative metabolism and is therefore required for optimal growth in the presence of oxygen. We also show that Rex represses the production of virulence factors required for survival and invasion of the GI tract, as a strain lacking rex was more resistant to acidified bile and invaded host cells better than wt. Consistent with these results, Rex was dispensable for colonizing the GI tract and disseminating to peripheral organs in an oral listeriosis model of infection. However, Rex-dependent regulation was required for colonizing the spleen and liver, and L. monocytogenes lacking the Rex repressor were nearly sterilized from the gallbladder. Taken together, these results demonstrated that Rex functions as a repressor of fermentative metabolism and suggests a role for Rex-dependent regulation in L. monocytogenes pathogenesis. Importantly, the gallbladder is the bacterial reservoir during listeriosis, and our data suggest redox sensing and Rex-dependent regulation are necessary for bacterial survival and replication in this organ.AUTHOR SUMMARYListeriosis is a foodborne illness caused by Listeria monocytogenes and is one of the deadliest bacterial infections known, with a mortality rate of up to 30%. Following ingestion of contaminated food, L. monocytogenes disseminates from the gastrointestinal (GI) tract to peripheral organs, including the spleen, liver, and gallbladder. In this work, we investigated the role of the global redox-responsive regulator Rex in L. monocytogenes growth and pathogenesis. We demonstrated that Rex derepression coordinates expression of genes necessary in the GI tract during infection, including fermentative metabolism, bile resistance, and invasion of host cells. Accordingly, Rex was dispensable for colonizing the GI tract of mice during an oral listeriosis infection. Interestingly, Rex-dependent regulation was required for bacterial replication in the spleen, liver, and gallbladder. Taken together, our results demonstrate that Rex-mediated redox sensing and transcriptional regulation are important for L. monocytogenes metabolic adaptation and virulence.

scholarly journals The redox-responsive transcriptional regulator Rex represses fermentative metabolism and is required for Listeria monocytogenes pathogenesis

2021 ◽  
Vol 17 (8) ◽  
pp. e1009379
Author(s):  
Cortney R. Halsey ◽  
Rochelle C. Glover ◽  
Maureen K. Thomason ◽  
Michelle L. Reniere
Keyword(s):  
Listeria Monocytogenes ◽  
Bacterial Infections ◽  
Transcriptional Regulator ◽  
Host Cells ◽  
Bacterial Survival ◽  
Gi Tract ◽  
Fermentative Metabolism ◽  
Peripheral Organs ◽  
Redox Responsive

The Gram-positive bacterium Listeria monocytogenes is the causative agent of the foodborne disease listeriosis, one of the deadliest bacterial infections known. In order to cause disease, L. monocytogenes must properly coordinate its metabolic and virulence programs in response to rapidly changing environments within the host. However, the mechanisms by which L. monocytogenes senses and adapts to the many stressors encountered as it transits through the gastrointestinal (GI) tract and disseminates to peripheral organs are not well understood. In this study, we investigated the role of the redox-responsive transcriptional regulator Rex in L. monocytogenes growth and pathogenesis. Rex is a conserved canonical transcriptional repressor that monitors the intracellular redox state of the cell by sensing the ratio of reduced and oxidized nicotinamide adenine dinucleotides (NADH and NAD+, respectively). Here, we demonstrated that L. monocytogenes Rex represses fermentative metabolism and is therefore required for optimal growth in the presence of oxygen. We also show that in vitro, Rex represses the production of virulence factors required for survival and invasion of the GI tract, as a strain lacking rex was more resistant to acidified bile and invaded host cells better than wt. Consistent with these results, Rex was dispensable for colonizing the GI tract and disseminating to peripheral organs in an oral listeriosis model of infection. However, Rex-dependent regulation was required for colonizing the spleen and liver, and L. monocytogenes lacking the Rex repressor were nearly sterilized from the gallbladder. Taken together, these results demonstrated that Rex functions as a repressor of fermentative metabolism and suggests a role for Rex-dependent regulation in L. monocytogenes pathogenesis. Importantly, the gallbladder is the bacterial reservoir during listeriosis, and our data suggest redox sensing and Rex-dependent regulation are necessary for bacterial survival and replication in this organ.

scholarly journals Stabilin-1 plays a protective role against Listeria monocytogenes infection through the regulation of cytokine and chemokine production and immune cell recruitment

2021 ◽  
Author(s):  
Rita Pombinho ◽  
Jorge Pinheiro ◽  
Mariana Resende ◽  
Diana Meireles ◽  
Sirpa Jalkanen ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Immune Cell ◽  
Scavenger Receptor ◽  
Protective Role ◽  
Host Cells ◽  
Cell Trafficking ◽  
Host Cell Membrane ◽  
Chemokine Production

ABSTRACTScavenger receptors are part of a complex surveillance system expressed by host cells to efficiently orchestrate innate immune response against bacterial infections. Stabilin-1 (STAB-1) is a scavenger receptor involved in cell trafficking, inflammation and cancer, however its role in infection remains to be elucidated. Listeria monocytogenes (Lm) is a major intracellular human food-borne pathogen causing severe infections in susceptible hosts. Using a mouse model of infection, we demonstrate here that STAB-1 controls Lm-induced cytokine and chemokine production and immune cell accumulation in Lm-infected organs. We show that STAB-1 also regulates the recruitment of myeloid cells in response to Lm infection and contributes to clear circulating bacteria. In addition, whereas STAB-1 appears to promote bacterial uptake by macrophages, infection by pathogenic Listeria induces the down regulation of STAB-1 expression and its delocalization from the host cell membrane.We propose STAB-1 as a new SR involved in the control of Lm infection through the regulation of host defense mechanisms, a process that would be targeted by bacterial virulence factors to promote infection.

scholarly journals Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

2020 ◽  
Author(s):  
Daisy X. Ji ◽  
Kristen C. Witt ◽  
Dmitri I. Kotov ◽  
Shally R. Margolis ◽  
Alexander Louie ◽  
...  
Keyword(s):  
Immune Responses ◽  
Legionella Pneumophila ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Transcriptional Regulator ◽  
Type I Interferons ◽  
Type I ◽  
Viral Immunity ◽  
Type I Ifns

AbstractType I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. How type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections, remains poorly understood. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to many bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that functions to repress the expression of type I IFNs during bacterial infections. We generated Sp140−/− mice and find they are susceptible to infection by diverse bacteria, including Listeria monocytogenes, Legionella pneumophila, and Mycobacterium tuberculosis. Susceptibility of Sp140−/− mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar−/−). Our results implicate Sp140 as an important repressor of type I IFNs that is essential for resistance to bacterial infections.

Rv0494 Mediates Tolerance to Antibiotics in Mycobacterium Tuberculosis

2021 ◽  
Author(s):  
Lei Ji ◽  
Damin Cai ◽  
Kouzhen Hua ◽  
Peng Du ◽  
Yuanyuan Chen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Fatty Acid ◽  
Bacterial Infections ◽  
Deletion Mutant ◽  
Acid Metabolism ◽  
Transcriptional Regulator ◽  
Good Target ◽  
New Antibiotics ◽  
Increased Susceptibility

Abstract Background: Fatty acid metabolism plays an important role in the survival and pathogenesis of Mycobacterium tuberculosis. During dormancy, lipids are considered to be the main source of energy. The previous studies find that Rv0494 is a starvation-inducible, lipid-responsive transcriptional regulator. However, the role of Rv0494 in bacterial persister survival has not been studied.Methods: We constructed Rv0494 deletion mutant and assessed the susceptibility of the mutant to various antibiotics conditions in persister assays.Results: We found that mutations in Rv0494 caused a defect in persister survival as shown by their increased susceptibility to Isoniazid.Conclusions: We conclude that Rv0494 is important for persister survival and may serve as a good target for developing new antibiotics that kill persister bacteria for improved treatment of persistent bacterial infections.

scholarly journals A Redox-Responsive Transcription Factor Is Critical for Pathogenesis and Aerobic Growth of Listeria monocytogenes

2017 ◽  
Vol 85 (5) ◽  
Author(s):  
Aaron T. Whiteley ◽  
Brittany R. Ruhland ◽  
Mauna B. Edrozo ◽  
Michelle L. Reniere
Keyword(s):  
Oxidative Stress ◽  
Listeria Monocytogenes ◽  
Aerobic Growth ◽  
Redox Stress ◽  
Content Type ◽  
Redox Responsive ◽  
Cell Cytosol ◽  
Redox Sensing ◽  
Anaerobic Environment

ABSTRACT Bacterial pathogens have evolved sophisticated mechanisms to sense and adapt to redox stress in nature and within the host. However, deciphering the redox environment encountered by intracellular pathogens in the mammalian cytosol is challenging, and that environment remains poorly understood. In this study, we assessed the contributions of the two redox-responsive, Spx-family transcriptional regulators to the virulence of Listeria monocytogenes, a Gram-positive facultative intracellular pathogen. Spx-family proteins are highly conserved in Firmicutes, and the L. monocytogenes genome contains two paralogues, spxA1 and spxA2. Here, we demonstrate that spxA1, but not spxA2, is required for the oxidative stress response and pathogenesis. SpxA1 function appeared to be conserved with the Bacillus subtilis homologue, and resistance to oxidative stress required the canonical CXXC redox-sensing motif. Remarkably, spxA1 was essential for aerobic growth, demonstrating that L. monocytogenes SpxA1 likely regulates a distinct set of genes. Although the ΔspxA1 mutant did not grow in the presence of oxygen in the laboratory, it was able to replicate in macrophages and colonize the spleens, but not the livers, of infected mice. These data suggest that the redox state of bacteria during infection differs significantly from that of bacteria growing in vitro. Further, the host cell cytosol may resemble an anaerobic environment, with tissue-specific variations in redox stress and oxygen concentration.

scholarly journals Role of lipid rafts in E-cadherin– and HGF-R/Met–mediated entry of Listeria monocytogenes into host cells

2004 ◽  
Vol 166 (5) ◽  
pp. 743-753 ◽  
Author(s):  
Stéphanie Seveau ◽  
Hélène Bierne ◽  
Stéphanie Giroux ◽  
Marie-Christine Prévost ◽  
Pascale Cossart
Keyword(s):  
Listeria Monocytogenes ◽  
Lipid Rafts ◽  
Host Cells ◽  
Bacterial Invasion ◽  
Membrane Cholesterol ◽  
Cholesterol Depletion ◽  
Lipid Domains ◽  
Initial Interaction ◽  
E Cadherin

Listeria monocytogenes uptake by nonphagocytic cells is promoted by the bacterial invasion proteins internalin and InlB, which bind to their host receptors E-cadherin and hepatocyte growth factor receptor (HGF-R)/Met, respectively. Here, we present evidence that plasma membrane organization in lipid domains is critical for Listeria uptake. Cholesterol depletion by methyl-β-cyclodextrin reversibly inhibited Listeria entry. Lipid raft markers, such as glycosylphosphatidylinositol-linked proteins, a myristoylated and palmitoylated peptide and the ganglioside GM1 were recruited at the bacterial entry site. We analyzed which molecular events require membrane cholesterol and found that the presence of E-cadherin in lipid domains was necessary for initial interaction with internalin to promote bacterial entry. In contrast, the initial interaction of InlB with HGF-R did not require membrane cholesterol, whereas downstream signaling leading to F-actin polymerization was cholesterol dependent. Our work, in addition to documenting for the first time the role of lipid rafts in Listeria entry, provides the first evidence that E-cadherin and HGF-R require lipid domain integrity for their full activity.

scholarly journals Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sangsu Bang ◽  
Christopher R. Donnelly ◽  
Xin Luo ◽  
Maria Toro-Moreno ◽  
Xueshu Tao ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Bacterial Infections ◽  
Protective Role ◽  
Host Cells ◽  
Biological Functions ◽  
Wild Type ◽  
Neuroprotectin D1 ◽  
Protective Actions ◽  
Protection Against Infection

AbstractGPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia following challenge by lipopolysaccharide (LPS), Listeria bacteria, and the mouse malaria parasite Plasmodium berghei. Sepsis induced by LPS and Listeria in wild-type mice is protected by artesunate (ARU) and neuroprotectin D1 (NPD1), but the protective actions of these agents are lost in Gpr37−/− mice. Notably, we found that ARU binds to GPR37 in macrophages and promotes phagocytosis and clearance of pathogens. Moreover, ablation of macrophages potentiated infection, sepsis, and their sequelae, whereas adoptive transfer of NPD1- or ARU-primed macrophages reduced infection, sepsis, and pain-like behaviors. Our findings reveal physiological actions of ARU in host cells by activating macrophages and suggest that GPR37 agonists may help to treat sepsis, bacterial infections, and malaria.

An alternative role of C1q in bacterial infections: Facilitating Streptococcus pneumoniae adherence and invasion of host cells

Immunobiology ◽  
2012 ◽  
Vol 217 (11) ◽  
pp. 1137
Author(s):  
Vaibhav Agarwal ◽  
Jonas Ahl ◽  
Kristian Riesbeck ◽  
Anna M. Blom
Keyword(s):  
Streptococcus Pneumoniae ◽  
Bacterial Infections ◽  
Host Cells

scholarly journals Essential Role of CCL2 in Clustering of Splenic ERTR-9+ Macrophages during Infection of BALB/c Mice by Listeria monocytogenes

2006 ◽  
Vol 75 (1) ◽  
pp. 462-470 ◽  
Author(s):  
Jadwiga Jablonska ◽  
Kurt E. Dittmar ◽  
Tanja Kleinke ◽  
Jan Buer ◽  
Siegfried Weiss
Keyword(s):  
Listeria Monocytogenes ◽  
Marginal Zone ◽  
Early Time ◽  
Cell Types ◽  
Host Cells ◽  
Early Time Point ◽  
Infected Cells ◽  
Different Cell Types ◽  
Time Point

ABSTRACT Early interactions between pathogens and host cells are often decisive for the subsequent course of infection. Here we investigated early events during infection by Listeria monocytogenes, a ubiquitously occurring facultative intracellular microorganism that exhibits severe pathogenicity, mainly in immunocompromised individuals. We show that the inflammatory chemokine CCL2 is highly up-regulated early after Listeria infection in spleens of BALB/c mice. ERTR-9+ macrophages of the marginal zone were identified as the only infected cells and exclusive producers of CCL2 at the early time point. Consequently, clusters of different cell types were formed around infected ERTR-9+ cells. Metallophilic MOMA-1+ marginal zone macrophages were, however, excluded from the clusters and migrated into the B-cell follicles. Depletion of CCL2 during infection resulted in a different composition of cell clusters in the spleen and increased the mortality rate of treated mice. Interestingly, ERTR-9+ macrophages no longer were part of clusters in such mice but remained at their original location in the marginal zone.

scholarly journals An Alternative Role of C1q in Bacterial Infections: FacilitatingStreptococcus pneumoniaeAdherence and Invasion of Host Cells

2013 ◽  
Vol 191 (8) ◽  
pp. 4235-4245 ◽  
Author(s):  
Vaibhav Agarwal ◽  
Jonas Ahl ◽  
Kristian Riesbeck ◽  
Anna M. Blom
Keyword(s):  
Bacterial Infections ◽  
Host Cells
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