Induction of the pneumococcal vncRS operon by lactoferrin is essential for pneumonia.

Streptococcus pneumoniae (pneumococcus), the major pathogen for pneumonia, commonly colonizes the lung, but the mechanism underlying the coordination of virulence factors during invasion via the host protein remains poorly understood. Bacterial lysis releases the components of the cell wall, and triggers innate immunity and the subsequent secretion of pro-inflammatory cytokines. Previously, the virulence of the pep27 mutant was shown to be attenuated as a feasible candidate for vaccine development.

Panax ginseng aqueous extract prevents pneumococcal sepsis in vivo by potentiating cell survival and diminishing inflammation.

Background: More than 50% of sepsis cases are caused by Streptococcus pneumoniae, and hospital mortality related to sepsis comprises 52% of all hospital deaths. Therefore, sepsis is a medical emergency, and any treatment against the agent that produces it, is welcome.

Purpose: The role of Panax ginseng C.

ClpL is a chaperone without auxiliary factors.

Caseinolytic protease L (ClpL) is a member of the heat shock protein (Hsp) 100 family, which is found mostly in Gram-positive bacteria. Here, ClpL, a major HSP in Streptococcus pneumoniae (pneumococcus), was biochemically characterized in vitro. Recombinant ClpL shows nucleotide hydrolase, refolding, holdase and disaggregation activity using either Mg(2+) or Mn(2+) and does not require the DnaK system for chaperone activity.

Heat-shock protein ClpL/HSP100 increases penicillin tolerance in Streptococcus pneumoniae.

Penicillin resistance and tolerance has been an increasing threat to the treatment of pneumococcal pneumoniae. However, no penicillin tolerance-related genes have been claimed. Here we show that a major heat shock protein ClpL/HSP100 could modulate the expression of a cell wall synthesis enzyme PBP2x, and subsequently increase cell wall thickness and penicillin tolerance in Streptococus pneumoniae.

Decrease in penicillin susceptibility due to heat shock protein ClpL in Streptococcus pneumoniae.

Antibiotic resistance and tolerance are increasing threats to global health as antibiotic-resistant bacteria can cause severe morbidity and mortality and can increase treatment cost 10-fold. Although several genes contributing to antibiotic tolerance among pneumococci have been identified, we report here that ClpL, a major heat shock protein, could modulate cell wall biosynthetic enzymes and lead to decreased penicillin susceptibility. On capsular type 1, 2, and 19 genetic backgrounds, mutants lacking ClpL were more susceptible to penicillin and had thinner cell walls than the parental strains, whereas a ClpL-overexpressing strain showed a higher resistance to penicillin and a thicker cell wall.

Reduction-sensitive and cysteine residue-mediated Streptococcus pneumoniae HrcA oligomerization in vitro.

In both gram-positive and several gram-negative bacteria, the transcription of dnaK and groE operons is negatively regulated by HrcA; however, the mechanism modulating HrcA protein activity upon thermal stress remains elusive. Here, we demonstrate that HrcA is modulated via reduction and oligomerization in vitro. Native-PAGE analysis was used to reveal the oligomeric structure of HrcA.

Selective toxicity of ginsenoside Rg3 on multidrug resistant cells by membrane fluidity modulation.

Multidrug resistance (MDR) is a major problem in cancer chemotherapy. It was previously reported that a red ginseng saponin, 20(S)-ginsenoside Rg3 could modulate MDR in vitro and extend the survival of mice implanted with ADR-resistant murine leukemia P388 cells. This study examined the cytotoxicity of Rg3 on normal and transformed cells, along with its effect on the membrane fluidity.

Modulation of adherence, invasion, and tumor necrosis factor alpha secretion during the early stages of infection by Streptococcus pneumoniae ClpL.

Heat shock proteins (HSPs) play a pivotal role as chaperones in the folding of native and denatured proteins and can help pathogens penetrate host defenses. However, the underlying mechanism(s) of modulation of virulence by HSPs has not been fully determined. In this study, the role of the chaperone ClpL in the pathogenicity of Streptococcus pneumoniae was assessed.

Analyses of single nucleotide polymorphisms and haplotype linkage of the human ABCB1 (MDR1) gene in Korean.

Single nucleotide polymorphisms (SNPs) in the MDR1 gene that are responsible for drug efflux can cause toxicity. Therefore, this study determined the SNPs of the Korean MDR1 gene, and analyzed the haplotypes and a linkage disequilibrium (LD) of the SNPs determined. The frequency of 9 SNPs from the MDR1 gene was determined by PCR-RFLP analyses of 100 to 500 healthy individuals.

Ca2+-dependent expression of the CIRCE regulon in Streptococcus pneumoniae.

DnaK and GroEL play a pivotal role in protein folding, and promote cell proliferation and survival. In Gram-positive and several Gram-negative bacteria, HrcA represses the transcription of dnaK and groE operons by binding to the highly conserved CIRCE (controlling inverted repeat of chaperone expression) operator sequence in the presence of GroEL. HrcA may respond to environmental stress and various other factors that modulate the transcription of the dnaK and groE operons.

The ClpP protease of Streptococcus pneumoniae modulates virulence gene expression and protects against fatal pneumococcal challenge.

Streptococcus pneumoniae usually colonizes the nasopharynx of humans asymptomatically but occasionally translocates from this niche to the lungs, the brain, and the blood, causing potentially fatal infections. Spread to other host tissues requires a significant morphological change and the expression of virulence factors, such as capsular polysaccharide, and virulence proteins, such as pneumolysin (Ply), PspA, and CbpA. Modulation of the expression of pneumococcal virulence genes by heat shock and by heat shock proteins ClpL and ClpP, as well as the attenuation of virulence of a clpP mutant in a murine intraperitoneal infection model, was demonstrated previously.

Effect of heat shock and mutations in ClpL and ClpP on virulence gene expression in Streptococcus pneumoniae.

Spread of Streptococcus pneumoniae from the nasopharynx to other host tissues would require the organism to adapt to a variety of environmental conditions. Since heat shock proteins are induced by environmental stresses, we investigated the effect of heat shock on ClpL and ClpP synthesis and the effect of clpL and clpP mutations on the expression of key pneumococcal virulence genes. Pulse labeling with [(35)S]methionine and chase experiments as well as immunoblot analysis demonstrated that ClpL, DnaK, and GroEL were stable.

Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg(3).

Multidrug resistance has been a major problem in cancer chemotherapy. In this study, in vitro and in vivo modulations of MDR by ginsenoside Rg(3), a red ginseng saponin, were investigated. In flow cytometric analysis using rhodamine 123 as an artificial substrate, Rg(3) promoted accumulation of rhodamine 123 in drug-resistant KBV20C cells in a dose-dependent manner, but it had no effect on parental KB cells.