Sickly Sweet – How Sugar Utilization Impacts Pneumococcal Disease Progression

Minhas, Vikrant; Paton, James C.; Trappetti, Claudia

doi:10.1016/j.tim.2021.01.016

Cited by 10 publications

(11 citation statements)

References 20 publications

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“…Interestingly, HOCl stress also caused the induction of several regulons involved in the uptake and utilization of alternative carbohydrates, which serve as energy and carbon sources in the absence of glucose and are important for virulence in S. pneumoniae (Minhas et al, 2021). The induction of these sugar catabolic regulons was accompanied by the derepression of 76 genes of the CcpA regulon (2–50.5‐fold), indicating that CcpA is partially inactivated after HOCl exposure in the pneumococcus (Figure 1; Tables S1 and S2).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, HOCl caused derepression of the CcpA regulon in S. pneumoniae , accompanied by induction of many regulons for the uptake and utilization of alternative carbohydrates, including the ScrR, FcsR, RafR, MalR, RegR, AgaR, XylR, BguR, GalR and LacR regulons (Minhas et al, 2021). While the basis for the CcpA derepression under HOCl in the pneumococcus is unknown, this study provides insights into the usage of alternative carbon sources under the growth conditions in supplemented RPMI medium.…”

Section: Discussionmentioning

confidence: 99%

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The MerR‐family regulator NmlR is involved in the defense against oxidative stress in Streptococcus pneumoniae

Fritsch

Linzner

Busche

et al. 2022

Molecular Microbiology

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Streptococcus pneumoniae has to cope with the strong oxidant hypochlorous acid (HOCl), during host–pathogen interactions. Thus, we analyzed the global gene expression profile of S. pneumoniae D39 towards HOCl stress. In the RNA‐seq transcriptome, the NmlR, SifR, CtsR, HrcA, SczA and CopY regulons and the etrx1‐ccdA1‐msrAB2 operon were most strongly induced under HOCl stress, which participate in the oxidative, electrophile and metal stress response in S. pneumoniae. The MerR‐family regulator NmlR harbors a conserved Cys52 and controls the alcohol dehydrogenase‐encoding adhC gene under carbonyl and NO stress. We demonstrated that NmlR senses also HOCl stress to activate transcription of the nmlR‐adhC operon. HOCl‐induced transcription of adhC required Cys52 of NmlR in vivo. Using mass spectrometry, NmlR was shown to be oxidized to intersubunit disulfides or S‐glutathionylated under oxidative stress in vitro. A broccoli‐FLAP‐based assay further showed that both NmlR disulfides significantly increased transcription initiation at the nmlR promoter by RNAP in vitro, which depends on Cys52. Phenotype analyses revealed that NmlR functions in the defense against oxidative stress and promotes survival of S. pneumoniae during macrophage infections. In conclusion, NmlR was characterized as HOCl‐sensing transcriptional regulator, which activates transcription of adhC under oxidative stress by thiol switches in S. pneumoniae.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The MerR‐family regulator NmlR is involved in the defense against oxidative stress in Streptococcus pneumoniae

Fritsch

Linzner

Busche

et al. 2022

Molecular Microbiology

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“…Due to a low availability of glucose in the airways, Spn in the nasopharynx and ME relies on the galactose and mannose derived from the airway mucosal glycan lining, as a main carbon source for energy metabolism and virulence (Paixao et al, 2015a;Paixao et al, 2015b). Several recent studies have unveiled the impact of carbohydrate utilization and metabolic processes in Spn virulence, persistence, and infection at nasopharynx, which involves a series of regulators (galK, galR, hyl, ugl, lacD, nanA, eng, rafK, estA, and auto-inducer AI-2) (Afzal et al, 2015;Mclean et al, 2020;Minhas et al, 2021). Sensing of the host carbohydrates for environmental adaptation is mainly carried out by pneumococcal short hydrophobic peptide (SHP) and phosphatase regulator (Phr) that interact with RRNPP superfamily of transcription regulator, regulator gene of glycosyltrasferase (Rgg) and transcription factor regulated by Phr peptide (Tpr), respectively.…”

Section: Mechanism In Gene Regulation: Pheromone Peptide Signalingmentioning

confidence: 99%

Gene Expression Regulation in Airway Pathogens: Importance for Otitis Media

Janouková

Straw

et al. 2022

Front. Cell. Infect. Microbiol.

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Otitis media (OM) is an inflammatory disorder in the middle ear. It is mainly caused by viruses or bacteria associated with the airways. Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are the three main pathogens in infection-related OM, especially in younger children. In this review, we will focus upon the multifaceted gene regulation mechanisms that are well-orchestrated in S. pneumoniae, H. influenzae, and M. catarrhalis during the course of infection in the middle ear either in experimental OM or in clinical settings. The sophisticated findings from the past 10 years on how the othopathogens govern their virulence phenotypes for survival and host adaptation via phase variation- and quorum sensing-dependent gene regulation, will be systematically discussed. Comprehensive understanding of gene expression regulation mechanisms employed by pathogens during the onset of OM may provide new insights for the design of a new generation of antimicrobial agents in the fight against bacterial pathogens while combating the serious emergence of antimicrobial resistance.

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“…Commonly observed galactosidase-containing GH families include GH110, members of which have been implicated in group B blood antigen hydrolysis. Both fucosidase GH families with members active on host glycans, GH29 and GH95, were frequently detected, as were L-fucose Mann et al, 13 degradation I pathway constituents. The Tanerellaceae genomes were notably devoid of fucosemetabolizing genes, though they encoded GH29 and GH95, suggesting that these organisms might release fucose into the environment to the benefit of crossfeeders.…”

Section: N-acetyl-d-glucosamine/n-acetyl-d-galactosamine-6-phosphate ...mentioning

confidence: 99%

“…Collectively, N-and O-glycans on host proteins play myriad roles, notably in cell-to-cell signalling, host-microbe interactions and immune system regulation (11) and the enzymes that contribute to their destruction are recognized virulence factors (12)(13)(14)(15). The colonic epithelium is protected from direct assault by a glycocalyx overlaid by a carbohydrate-rich mucous bilayer embedded with antimicrobial proteins (16).…”

Section: Introductionmentioning

confidence: 99%

Human gut metagenomes encode diverse GH156 sialidases

Mann

Shekarriz

Surette

2022

Preprint

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The intestinal lining is protected by a mucous barrier composed predominantly of complex carbohydrates. Gut microbes employ an array of glycoside hydrolases (GHs) to liberate mucosal sugars as a nutrient source to facilitate host colonization. Intensive catabolism of mucosal glycans, however, may contribute to barrier erosion, pathogen encroachment and inflammation.Sialic acid is an acidic sugar featured at terminal positions of host glycans. Characterized sialidases from the microbiome belong to the GH33 family, according to CAZy (Carbohydrate Active enZyme) database classification. A 2018 functional metagenomics screen using thermal spring DNA uncovered the founding member of the GH156 sialidase family, which lacks homology to GH33 sialidases and could not be taxonomically assigned. Subsequent structural analysis revealed critical active site residues. We sought to determine if GH156 sialidases are present in the human gut microbiome where they might contribute to mucous erosion.A subset of GH156 sequences from the CAZy database containing key sialidase residues was used to build a Hidden Markov Model. HMMsearch against public databases revealed ∼10X more putative GH156 sialidases than currently recognized by CAZy. Represented phyla include Bacteroidota, Verrucomicrobiota and Firmicutes_A from human microbiomes, all of which play notable roles in carbohydrate fermentation. Genomic analyses suggested that taxa containing GH156-encoding genes may utilize host-glycans. Analyses of metagenomic datasets revealed that GH156s are frequently encoded in metagenomes, with a greater variety and abundance of GH156 genes observed in traditional hunter-gatherer or agriculturalist societies than in industrialized societies, particularly relative to individuals with IBD. A GH156 gene frequently detected in traditional populations was cloned from stool sample DNA and the recombinant protein exhibited sialidase activity with a fluorogenic substrate.ImportanceSialic acids occupy terminal positions of human glycans where they act as receptors for microbes, toxins and immune signaling molecules. Microbial enzymes that remove sialic acids, sialidases, are abundant in the human microbiome where they may contribute to shaping the microbiota community structure or contribute to pathology. Furthermore, sialidases have proven to hold therapeutic potential for cancer therapy. Here we examined the sequence space of a sialidase family of enzymes, GH156, previously unknown to the human gut environment. Our analyses suggest that human populations with disparate dietary practices harbour distinct varieties and abundances of GH156-encoding genes. Furthermore, we demonstrate the sialidase activity of a gut derived GH156. These results expand the diversity of sialidases that may contribute to host glycan degradation and these sequences may have biotechnological or clinical utility.

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Sickly Sweet – How Sugar Utilization Impacts Pneumococcal Disease Progression

Cited by 10 publications

References 20 publications

The MerR‐family regulator NmlR is involved in the defense against oxidative stress in Streptococcus pneumoniae

The MerR‐family regulator NmlR is involved in the defense against oxidative stress in Streptococcus pneumoniae

Gene Expression Regulation in Airway Pathogens: Importance for Otitis Media

Human gut metagenomes encode diverse GH156 sialidases

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