scholarly journals Effects of the twin-arginine translocase on secretion of virulence factors, stress response, and pathogenesis

2002 ◽  
Vol 99 (12) ◽  
pp. 8312-8317 ◽  
Author(s):  
U. A. Ochsner ◽  
A. Snyder ◽  
A. I. Vasil ◽  
M. L. Vasil
Keyword(s):  
Stress Response ◽  
Virulence Factors ◽  
Twin Arginine Translocase

scholarly journals Genome-Wide Identification of Acinetobacter baumannii Genes Necessary for Persistence in the Lung

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Nengding Wang ◽  
Egon A. Ozer ◽  
Mark J. Mandel ◽  
Alan R. Hauser
Keyword(s):  
Amino Acid ◽  
Stress Response ◽  
Acinetobacter Baumannii ◽  
Virulence Factors ◽  
Efflux Pumps ◽  
Integration Host Factor ◽  
Nucleotide Metabolism ◽  
Massively Parallel ◽  
Rich Medium ◽  
Content Type

ABSTRACTAcinetobacter baumanniiis a Gram-negative bacterium that causes diseases such as pneumonia, bacteremia, and soft tissue infections in hospitalized patients. Relatively little is known about howA. baumanniicauses these infections. Thus, we used insertion sequencing (INSeq), a combination of transposon mutagenesis and massively parallel next-generation sequencing, to identify novel virulence factors ofA. baumannii. To this end, we generated a random transposon mutant library containing 150,000 unique insertions inA. baumanniistrain ATCC 17978. The INSeq analysis identified 453 genes required for growth in rich medium. The library was then used in a murine pneumonia model, and the relative levels of abundance of mutants before and after selection in the mouse were compared. When genes required for growth in rich medium were removed from the analysis, 157 genes were identified as necessary for persistence in the mouse lung. Several of these encode known virulence factors ofA. baumannii, such as OmpA and ZnuB, which validated our approach. A large number of the genes identified were predicted to be involved in amino acid and nucleotide metabolism and transport. Other genes were predicted to encode an integration host factor, a transmembrane lipoprotein, and proteins involved in stress response and efflux pumps. Very few genes, when disrupted, resulted in an increase inA. baumanniinumbers during host infection. The INSeq approach identified a number of novel virulence determinants ofA. baumannii, which are candidate targets for therapeutic interventions.IMPORTANCEA. baumanniihas emerged as a frequent cause of serious infections in hospitals and community settings. Due to increasing antibiotic resistance, alternative approaches, such as antivirulence strategies, are desperately needed to fightA. baumanniiinfections. Thorough knowledge ofA. baumanniipathogenicity is essential for such approaches but is currently lacking. With the increasingly widespread use of massively parallel sequencing, a class of techniques known as transposon insertion sequencing has been developed to perform comprehensive virulence screens of bacterial genomesin vivo. We have applied one of these approaches (INSeq) to uncover novel virulence factors inA. baumannii. We identified several such factors, including those predicted to encode amino acid and nucleotide metabolism proteins, an integration host factor protein, stress response factors, and efflux pumps. These results greatly expand the number ofA. baumanniivirulence factors and uncover potential targets for antivirulence treatments.

scholarly journals The Cpx Envelope Stress Response Is Controlled by Amplification and Feedback Inhibition

1999 ◽  
Vol 181 (17) ◽  
pp. 5263-5272 ◽  
Author(s):  
Tracy L. Raivio ◽  
Daniel L. Popkin ◽  
Thomas J. Silhavy
Keyword(s):  
Escherichia Coli ◽  
Stress Response ◽  
Virulence Factors ◽  
Histidine Kinase ◽  
Feedback Inhibition ◽  
Response Regulator ◽  
Regulatory System ◽  
Concomitant Increase ◽  
Envelope Stress ◽  
Two Component

ABSTRACT In Escherichia coli, the Cpx two-component regulatory system activates expression of protein folding and degrading factors in response to misfolded proteins in the bacterial envelope (inner membrane, periplasm, and outer membrane). It is comprised of the histidine kinase CpxA and the response regulator CpxR. This response plays a role in protection from stresses, such as elevated pH, as well as in the biogenesis of virulence factors. Here, we show that the Cpx periplasmic stress response is subject to amplification and repression through positive and negative autofeedback mechanisms. Western blot and operon fusion analyses demonstrated that the cpxRA operon is autoactivated. Conditions that lead to elevated levels of phosphorylated CpxR cause a concomitant increase in transcription ofcpxRA. Conversely, overproduction of CpxP, a small, Cpx-regulated protein of previously unknown function, represses the regulon and can block activation of the pathway. This repression is dependent on an intact CpxA sensing domain. The ability to autoactivate and then subsequently repress allows for a temporary amplification of the Cpx response that may be important in rescuing cells from transitory stresses and cueing the appropriately timed elaboration of virulence factors.

scholarly journals Understanding GroEL and DnaK Stress Response Proteins as Antigens for Bacterial Diseases

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 773
Author(s):  
Kezia R. Fourie ◽  
Heather L. Wilson
Keyword(s):  
Immune System ◽  
Stress Response ◽  
Cell Surface ◽  
Virulence Factors ◽  
Cellular Localization ◽  
Vaccine Development ◽  
Host Immune System ◽  
A Cell ◽  
Stress Response Proteins ◽  
Shock Proteins

Bacteria do not simply express a constitutive panel of proteins but they instead undergo dynamic changes in their protein repertoire in response to changes in nutritional status and when exposed to different environments. These differentially expressed proteins may be suitable to use for vaccine antigens if they are virulence factors. Immediately upon entry into the host organism, bacteria are exposed to a different environment, which includes changes in temperature, osmotic pressure, pH, etc. Even when an organism has already penetrated the blood or lymphatics and it then enters another organ or a cell, it can respond to these new conditions by increasing the expression of virulence factors to aid in bacterial adherence, invasion, or immune evasion. Stress response proteins such as heat shock proteins and chaperones are some of the proteins that undergo changes in levels of expression and/or changes in cellular localization from the cytosol to the cell surface or the secretome, making them potential immunogens for vaccine development. Herein we highlight literature showing that intracellular chaperone proteins GroEL and DnaK, which were originally identified as playing a role in protein folding, are relocated to the cell surface or are secreted during invasion and therefore may be recognized by the host immune system as antigens. In addition, we highlight literature showcasing the immunomodulation effects these proteins can have on the immune system, also making them potential adjuvants or immunotherapeutics.

scholarly journals Role of RpoS in Virulence of Pathogens

2009 ◽  
Vol 78 (3) ◽  
pp. 887-897 ◽  
Author(s):  
Tao Dong ◽  
Herb E. Schellhorn
Keyword(s):  
Stress Response ◽  
Virulence Factors ◽  
Metabolic Flux ◽  
Response Regulator ◽  
Infectious Disease Control ◽  
Global Regulators ◽  
Defense Systems ◽  
Physiological Processes ◽  
As Stress

ABSTRACT Understanding mechanisms of bacterial pathogenesis is critical for infectious disease control and treatment. Infection is a sophisticated process that requires the participation of global regulators to coordinate expression of not only genes coding for virulence factors but also those involved in other physiological processes, such as stress response and metabolic flux, to adapt to host environments. RpoS is a key response regulator to stress conditions in E scherichia coli and many other proteobacteria. In contrast to its conserved well-understood role in stress response, effects of RpoS on pathogenesis are highly variable and dependent on species. RpoS contributes to virulence through either enhancing survival against host defense systems or directly regulating expression of virulence factors in some pathogens, while RpoS is dispensable, or even inhibitory, to virulence in others. In this review, we focus on the distinct and niche-dependent role of RpoS in virulence by surveying recent findings in many pathogens.

scholarly journals The Histoplasma capsulatum DDR48 Gene Is Required For Survival Within Macrophages, Response To Oxidative Stress, And Resistance to Antifungal Drugs

2020 ◽  
Author(s):  
Logan T. Blancett ◽  
Kauri A. Runge ◽  
Gabriella M. Reyes ◽  
Lauren A. Kennedy ◽  
Sydney C. Jackson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Drug Resistance ◽  
Stress Response ◽  
Virulence Factors ◽  
Histoplasma Capsulatum ◽  
The United States ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Antifungal Drug Resistance

AbstractHistoplasma capsulatum (Hc) is a systemic, dimorphic fungal pathogen that affects upwards of 500,000 individuals in the United States annually. Hc grows as a multicellular mold at environmental temperatures; whereas, upon inhalation into a human or other mammalian host, it transforms into a unicellular, pathogenic yeast. This manuscript is focused on characterizing the DNA damage-responsive gene HcDDR48. HcDDR48 was originally isolated via a subtractive DNA library enriched for transcripts enriched in the mold-phase of Hc growth. Upon further analysis we found that HcDDR48 is not just expressed in the mold morphotype, but both growth programs dependent upon the environment. We found that HcDDR48 is involved in oxidative stress response, antifungal drug resistance, and survival within resting and activated macrophages. Growth of ddr48Δ yeasts was severely decreased when exposed to the reactive oxygen species generator paraquat, as compared to wildtype controls. We also found that ddr48Δ yeasts were 2-times more sensitive to the antifungal drugs amphotericin b and ketoconazole. To test HcDDR48’s involvement in vivo, we infected resting and activated RAW 264.7 murine macrophages with Hc yeasts and measured yeast survival 24-hours post-infection. We observed a significant decrease in yeast recovery in the ddr48Δ strain compared to wildtype Hc levels. Herein, we demonstrate the importance of maintaining a functional copy of HcDDR48 in order for Hc yeasts to sense and respond to numerous environmental and host-associated stressors.ImportanceHistoplasma capsulatum is an intracellular pathogen of phagocytes, where it subverts immune recognition and avoids killing by the innate immune system. Macrophages provide a permissive environment for Hc replication and killing only occurs upon the onset of the T-cell driven adaptive immune response. Hc has evolved numerous virulence factors that aid in its survival against host-derived ROS and RNS in vivo. While these virulence factors have been described in past years, only a few reports describing the regulation of these genes and how this intricate system leads to fungal survival. In this study, we characterized the stress response gene DDR48 and determined it to be indispensable for Hc survival within macrophages. HcDDR48 regulates transcript levels of superoxide dismutases and catalases responsible for detoxification of ROS and contributes to antifungal drug resistance. Our studies highlight DDR48 as a potential target to control Hc infection and decrease the severity of the disease process.

CarR, a MarR-family regulator from Corynebacterium glutamicum, modulated antibiotic and aromatic compound resistance

2019 ◽  
Vol 476 (21) ◽  
pp. 3141-3159 ◽  
Author(s):  
Meiru Si ◽  
Can Chen ◽  
Zengfan Wei ◽  
Zhijin Gong ◽  
GuiZhi Li ◽  
...  
Keyword(s):  
Stress Response ◽  
Ligand Binding ◽  
Corynebacterium Glutamicum ◽  
Conformational Changes ◽  
Cysteine Oxidation ◽  
Transcriptional Regulatory ◽  
Ligand Free ◽  
Redox Sensing

Abstract MarR (multiple antibiotic resistance regulator) proteins are a family of transcriptional regulators that is prevalent in Corynebacterium glutamicum. Understanding the physiological and biochemical function of MarR homologs in C. glutamicum has focused on cysteine oxidation-based redox-sensing and substrate metabolism-involving regulators. In this study, we characterized the stress-related ligand-binding functions of the C. glutamicum MarR-type regulator CarR (C. glutamicum antibiotic-responding regulator). We demonstrate that CarR negatively regulates the expression of the carR (ncgl2886)–uspA (ncgl2887) operon and the adjacent, oppositely oriented gene ncgl2885, encoding the hypothetical deacylase DecE. We also show that CarR directly activates transcription of the ncgl2882–ncgl2884 operon, encoding the peptidoglycan synthesis operon (PSO) located upstream of carR in the opposite orientation. The addition of stress-associated ligands such as penicillin and streptomycin induced carR, uspA, decE, and PSO expression in vivo, as well as attenuated binding of CarR to operator DNA in vitro. Importantly, stress response-induced up-regulation of carR, uspA, and PSO gene expression correlated with cell resistance to β-lactam antibiotics and aromatic compounds. Six highly conserved residues in CarR were found to strongly influence its ligand binding and transcriptional regulatory properties. Collectively, the results indicate that the ligand binding of CarR induces its dissociation from the carR–uspA promoter to derepress carR and uspA transcription. Ligand-free CarR also activates PSO expression, which in turn contributes to C. glutamicum stress resistance. The outcomes indicate that the stress response mechanism of CarR in C. glutamicum occurs via ligand-induced conformational changes to the protein, not via cysteine oxidation-based thiol modifications.

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