scholarly journals Copper intoxication in group B Streptococcus triggers transcriptional activation of the cop operon that contributes to enhanced virulence during acute infection

2021 ◽  
Author(s):  
Matthew J. Sullivan ◽  
Kelvin G. K. Goh ◽  
Dean Gosling ◽  
Lahiru Katupitiya ◽  
Glen C. Ulett
Keyword(s):  
Stress Responses ◽  
Transcriptional Activation ◽  
Acute Infection ◽  
Group B Streptococcus ◽  
Transcriptional Responses ◽  
Metal Transporters ◽  
Transcriptional Signature ◽  
Cu Stress ◽  
Cop Operon ◽  
Group B

AbstractBacteria require Copper (Cu) as an essential trace element to support cell processes; however, excess Cu can intoxicate bacteria. Here, we characterize the cop operon in group B Streptococcus (GBS), and establish its role in evasion of Cu intoxication and the response to Cu stress on virulence. Growth of GBS mutants deficient in either the copA Cu exporter, or the copY repressor, were severely compromised in Cu-stress conditions. GBS survival of Cu stress reflected a mechanism of CopY activation of the CopA efflux system. However, neither mutant was attenuated for intracellular survival in macrophages. Analysis of global transcriptional responses to Cu by RNA-sequencing revealed a stress signature encompassing homeostasis of multiple metals. Genes induced by Cu stress included putative metal transporters for manganese import, whereas a system for iron export was repressed. In addition, copA promoted the ability of GBS to colonize the blood, liver and spleen of mice following disseminated infection. Together, these findings show that GBS copA mediates resistance to Cu intoxication, via regulation by the Cu-sensing transcriptional repressor, copY. Cu stress responses in GBS reflect a transcriptional signature that heightens virulence and represents an important part of the bacteria’s ability to survive in different environments.

scholarly journals Copper intoxication in group B Streptococcus triggers transcriptional activation of the cop operon that contributes to enhanced virulence during acute infection

2021 ◽  
Author(s):  
Matthew J. Sullivan ◽  
Kelvin G. K. Goh ◽  
Dean Gosling ◽  
Lahiru Katupitiya ◽  
Glen C. Ulett
Keyword(s):  
Acute Infection ◽  
Group B Streptococcus ◽  
Mammalian Host ◽  
Transcriptional Responses ◽  
Metal Transporters ◽  
Disseminated Infection ◽  
Cu Stress ◽  
Cop Operon ◽  
Group B ◽  
Stressful Environments

Bacteria can utilize Copper (Cu) as a trace element to support cellular processes; however, excess Cu can intoxicate bacteria. Here, we characterize the cop operon in group B streptococcus (GBS), and establish its role in evasion of Cu intoxication and the response to Cu stress on virulence. Growth of GBS mutants deficient in either the copA Cu exporter, or the copY repressor, were severely compromised in Cu-stress conditions. GBS survival of Cu stress reflected a mechanism of CopY de-repression of the CopA efflux system. However, neither mutant was attenuated for intracellular survival in macrophages. Analysis of global transcriptional responses to Cu by RNA-sequencing revealed a stress signature encompassing homeostasis of multiple metals. Genes induced by Cu stress included putative metal transporters for manganese import, whereas a system for iron export was repressed. In addition, copA promoted the ability of GBS to colonize the blood, liver and spleen of mice following disseminated infection. Together, these findings show that GBS copA mediates resistance to Cu intoxication, via regulation by the Cu-sensing transcriptional repressor, copY . Cu stress responses in GBS reflect a transcriptional signature that heightens virulence and represents an important part of the bacteria’s ability to survive in different environments. Importance Understanding how bacteria manage cellular levels of metal ions, such as copper, helps to explain how microbial cells can survive in different stressful environments. We show how the opportunistic pathogen group B Streptococcus (GBS) achieves homeostasis of intracellular copper through the activities of the genes that comprise the cop operon, and describe how this helps GBS survive in stressful environments, including in the mammalian host during systemic disseminated infection.

scholarly journals Stenotrophomonas maltophiliaDifferential Gene Expression in Synthetic Cystic Fibrosis Sputum Reveals Shared and Cystic Fibrosis Strain-Specific Responses to the Sputum Environment

2019 ◽  
Vol 201 (15) ◽  
Author(s):  
Graham G. Willsey ◽  
Korin Eckstrom ◽  
Annette E. LaBauve ◽  
Lauren A. Hinkel ◽  
Kristin Schutz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Stress Responses ◽  
Metabolic Pathways ◽  
Stenotrophomonas Maltophilia ◽  
Acute Infection ◽  
Survival Strategies ◽  
Transcriptional Responses ◽  
Content Type ◽  
Insight Into

ABSTRACTStenotrophomonas maltophiliais a Gram-negative opportunistic pathogen that can infect the lungs of people with cystic fibrosis (CF). The highly viscous mucus in the CF lung, expectorated as sputum, serves as the primary nutrient source for microbes colonizing this site and induces virulence-associated phenotypes and gene expression in several CF pathogens. Here, we characterized the transcriptional responses of threeS. maltophiliastrains during exposure to synthetic CF sputum medium (SCFM2) to gain insight into how this organism interacts with the host in the CF lung. These efforts led to the identification of 881 transcripts differentially expressed by all three strains, many of which reflect the metabolic pathways used byS. maltophiliain sputum, as well as altered stress responses. The latter correlated with increased resistance to peroxide exposure after pregrowth in SCFM2 for two of the strains. We also compared the SCFM2 transcriptomes of twoS. maltophiliaCF isolates to that of the acute infection strain,S. maltophiliaK279a, allowing us to identify CF isolate-specific signatures in differential gene expression. The expression of genes from the accessory genomes was also differentially altered in response to SCFM2. Finally, a number of biofilm-associated genes were differentially induced in SCFM2, particularly in K279a, which corresponded to increased aggregation and biofilm formation in this strain relative to both CF strains. Collectively, this work details the response ofS. maltophiliato an environment that mimics important aspects of the CF lung, identifying potential survival strategies and metabolic pathways used byS. maltophiliaduring infections.IMPORTANCEStenotrophomonas maltophiliais an important infecting bacterium in the airways of people with cystic fibrosis (CF). However, compared to the other CF pathogens,S. maltophiliahas been relatively understudied. The significance of our research is to provide insight into the global transcriptomic changes ofS. maltophiliain response to a medium that was designed to mimic important aspects of the CF lung. This study elucidates the overall metabolic changes that occur whenS. maltophiliaencounters the CF lung and generates a road map of candidate genes to test usingin vitroandin vivomodels of CF.

scholarly journals The two-component response regulator LiaR regulates cell wall stress responses, pili expression and virulence in group B Streptococcus

Microbiology ◽  
2013 ◽  
Vol 159 (Pt_7) ◽  
pp. 1521-1534 ◽  
Author(s):  
David C. Klinzing ◽  
Nadeeza Ishmael ◽  
Julie C. Dunning Hotopp ◽  
Hervé Tettelin ◽  
Kelly R. Shields ◽  
...  
Keyword(s):  
Cell Wall ◽  
Stress Responses ◽  
Response Regulator ◽  
Group B Streptococcus ◽  
Wall Stress ◽  
Cell Wall Stress ◽  
Two Component ◽  
Group B

scholarly journals The copper resistome of group B Streptococcus reveals insight into the genetic basis of cellular survival during metal ion stress

2021 ◽  
Author(s):  
Kelvin GK Goh ◽  
Matthew J Sullivan ◽  
Glen C Ulett
Keyword(s):  
Metal Ion ◽  
Cell Damage ◽  
Bacterial Genome ◽  
Group B Streptococcus ◽  
Cellular Survival ◽  
Cu Stress ◽  
Targeted Mutation ◽  
Genetic Systems ◽  
Group B

In bacteria, copper (Cu) can support metabolic processes as an enzymatic cofactor but can also cause cell damage if present in excess, leading to intoxication. In group B Streptococcus (GBS) a system for control of Cu efflux based on the canonical cop operon supports survival during Cu stress. In some other bacteria, genetic systems additional to the cop operon are engaged during Cu stress and also contribute to Cu management. Here, we examined genetic systems beyond the cop operon in GBS for regions that contribute to survival of GBS in Cu stress using a forward genetic screen and probe of the entire bacterial genome. A high-density mutant library, generated using pGh9-ISS1, was used to expose GBS to Cu stress and compared to non-exposed controls en masse. Nine genes were identified as essential for GBS survival in Cu stress, whereas five genes constrained GBS growth in Cu stress. The genes encode varied factors including enzymes for metabolism, cell wall synthesis, transporters and global transcriptional regulators. Targeted mutation of the genes validated their roles in GBS resistance to Cu stress. Notably, several genes, including stp1, yceG, plyB and rfaB were also essential for resistance to Zn stress. Excepting copA, the genes identified are new to the area of bacterial metal ion intoxication. We conclude that a discrete and limited suite of genes beyond the cop operon in GBS contribute to a repertoire of mechanisms used to survive Cu stress in vitro and achieve cellular homeostasis.

scholarly journals Role of p38 and Early Growth Response Factor 1 in the Macrophage Response to Group B Streptococcus

2009 ◽  
Vol 77 (6) ◽  
pp. 2474-2481 ◽  
Author(s):  
Sybille Kenzel ◽  
Sandra Santos-Sierra ◽  
Sachin D. Deshmukh ◽  
Inga Moeller ◽  
Bilge Ergin ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Growth Response ◽  
Group B Streptococcus ◽  
Early Growth ◽  
Mitogen Activated Protein Kinase ◽  
Response Factor ◽  
Macrophage Response ◽  
Early Growth Response ◽  
Group B

ABSTRACT Group B streptococcus (GBS), the most frequent single isolate in neonatal sepsis and meningitis, potently activates inflammatory macrophage genes via myeloid differentiation antigen 88 (MyD88). However, events parallel to and downstream of MyD88 that instruct the macrophage response are incompletely understood. In this study, we found that only MyD88, not the Toll-like receptor (TLR) adapter proteins MAL/TIRAP, TRIF, and TRAM, essentially mediates the cytokine (tumor necrosis factor [TNF] and interleukin-6) and chemokine (RANTES) responses to whole GBS organisms, although MAL, TRIF, and TRAM have been shown to mediate the responses to substructures in other gram-positive and gram-negative bacteria. GBS-induced, MyD88-dependent phosphorylation of the mitogen-activated protein kinase p38 activated the transcription factor AP-1 and early growth response factor 1 (Egr-1) but not NF-κB. Furthermore, phosphorylation of Ets-like molecule 1 (Elk-1) was mediated by p38. However, in contrast to Egr-1 and AP-1, Elk-1 was dispensable for transcriptional activation of TNF by GBS organisms. Studies of macrophages from Elk-1-deficient mice revealed that Elk-1 was furthermore nonessential for the TNF responses to purified TLR2 and TLR4 agonists, which was in notable contrast to what was revealed in studies employing in vitro expression systems. In conclusion, MyD88, p38, and Egr-1, but not Elk-1, essentially mediate the inflammatory cytokine response to GBS organisms.

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