Staphylococcus aureus produces many virulence factors, including toxins, immune-modulatory factors, and exoenzymes. Previous studies involving the analysis of virulence expression were mainly performed by in vitro experiments using bacterial medium. However, when S. aureus infects a host, the bacterial growth conditions are quite different from those in a medium, which may be related to the different expression of virulence factors in the host. In this study, we investigated the expression of virulence factors in S. aureus grown in calf serum. The expression of many virulence factors, including hemolysins, enterotoxins, proteases, and iron acquisition factors, was significantly increased compared with that in bacterial medium. In addition, the expression of RNA III, a global regulon for virulence expression, was significantly increased. This effect was partially restored by the addition of 300 M FeCl 3 into serum, suggesting that iron depletion is associated with the increased expression of virulence factors in serum. In chemically defined medium without iron, a similar effect was observed. In a mutant with agr inactivated grown in serum, the expression of RNA III, psm, and sec4 was not increased, while other factors were still induced in the mutant, suggesting that another regulatory factor(s) is involved. In addition, we found that serum albumin is a major factor for the capture of free iron to prevent the supply of iron to bacteria grown in serum. These results indicate that S. aureus expresses virulence factors in adaptation to the host environment.Staphylococcus aureus is one of the major pathogens of humans; it causes various suppurative diseases, food poisoning, pneumonia, and toxic shock syndrome (11,20). In addition, S. aureus, especially methicillin-resistant S. aureus (MRSA), often causes serious problems via nosocomial infection in hospitals (10, 16). Furthermore, community-acquired MRSA has recently emerged and has been reported to cause serious infectious diseases, sepsis, and pneumonia (3, 9).It is well known that S. aureus produces many virulence factors, such as hemolysins, leukocidins, proteases, enterotoxins, exfoliative toxins, and immune-modulatory factors (11,12,21,31). The expression of these factors is tightly regulated during growth. The agr system, known as the quorum-sensing system, is known to play a central role in the regulation of virulence factors (5,26,27). AgrAC is a two-component system (TCS) that consists of a histidine kinase and a response regulator. The Agr system regulates the expression of the gene coding for small RNA, known as RNA III, which is localized divergently at the agr operon and regulates the expression of many virulence factors, such as hemolysins, leukocidins, and protein A (26, 27). In addition, RNA III, known as hld, encodes delta-hemolysin. The mechanisms of RNA III regulation for the expression of several virulence factors and regulatory factors, including alpha-hemolysin, coagulase, protein A, Map, and Rot, have been demonstrated to occur at the posttran...
Staphylococcus aureus uses two-component systems (TCSs) to adapt to stressful environmental conditions. To colonize a host, S. aureus must resist bacteriocins produced by commensal bacteria. In a comprehensive analysis using individual TCS inactivation mutants, the inactivation of two TCSs, graRS and braRS, significantly increased the susceptibility to the class I bacteriocins, nukacin ISK-1 and nisin A, and inactivation of vraSR slightly increased the susceptibility to nukacin ISK-1. In addition, two ABC transporters (BraAB and VraDE) regulated by BraRS and one transporter (VraFG) regulated by GraRS were associated with resistance to nukacin ISK-1 and nisin A. We investigated the role of these three TCSs of S. aureus in co-culture with S. warneri, which produces nukacin ISK-1, and Lactococcus lactis, which produces nisin A. When co-cultured with S. warneri or L. lactis, the braRS mutant showed a significant decrease in its population compared with the wild-type, whereas the graRS and vraSR mutants showed slight decreases. Expression of vraDE was elevated significantly in S. aureus co-cultured with nisin A/nukacin ISK-1-producing strains. These results suggest that three distinct TCSs are involved in the resistance to nisin A and nukacin ISK-1. Additionally, braRS and its related transporters played a central role in S. aureus survival in co-culture with the strains producing nisin A and nukacin ISK-1.
Streptococcus mutans is a cariogenic pathogen that produces an extracellular polysaccharide (glucan) from dietary sugars, which allows it to establish a reproductive niche and secrete acids that degrade tooth enamel. While two enzymes (GlmS and NagB) are known to be key factors affecting the entrance of amino sugars into glycolysis and cell wall synthesis in several other bacteria, their roles in S. mutans remain unclear. Therefore, we investigated the roles of GlmS and NagB in S. mutans sugar metabolism and determined whether they have an effect on virulence. NagB expression increased in the presence of GlcNAc while GlmS expression decreased, suggesting that the regulation of these enzymes, which functionally oppose one another, is dependent on the concentration of environmental GlcNAc. A glmS -inactivated mutant could not grow in the absence of GlcNAc, while nagB -inactivated mutant growth was decreased in the presence of GlcNAc. Also, nagB inactivation was found to decrease the expression of virulence factors, including cell-surface protein antigen and glucosyltransferase, and to decrease biofilm formation and saliva-induced S. mutans aggregation, while glmS inactivation had the opposite effects on virulence factor expression and bacterial aggregation. Our results suggest that GlmS and NagB function in sugar metabolism in opposing directions, increasing and decreasing S. mutans virulence, respectively.
Bacterial cell surface charge is responsible for susceptibility to cationic antimicrobial peptides. Previously, Staphylococcus aureus dlt and mprF were identified as factors conferring a positive charge upon cell surfaces. In this study, we investigated the regulation of cell surface charge during growth. Using a group of S. aureus MW2 mutants, which are gene-inactivated in 15 types of two-component systems (TCSs), we tested dltC and mprF expression and found that two TCSs, aps and agr, were associated with dltC and mprF expression in a growth phase-dependent manner. The first of these, aps, which had already been identified as a sensor of antimicrobial peptides and a positive regulator of dlt and mprF expression, was expressed strongly in the exponential phase, while its expression was significantly suppressed by agr in the stationary phase, resulting in higher expression of dltC and mprF in the exponential phase and lower expression in the stationary phase. Since both types of expression affected the cell surface charge, the susceptibility to antimicrobial peptides and cationic antibiotics was changed during growth. Furthermore, we found that the ability to sense antimicrobial peptides only functioned in the exponential phase. These results suggest that cell surface charge is tightly regulated during growth in S. aureus. INTRODUCTIONStaphylococcus aureus is a well-known major pathogen in humans. S. aureus produces many toxins and exoenzymes to cause various suppurative diseases, food poisoning and toxic shock syndrome (Foster, 2004;Lowy, 1998;Manders, 1998). Furthermore, strains isolated clinically, especially meticillin-resistant S. aureus (MRSA), exhibit multiple antibiotic resistance (Deurenberg et al., 2007;Grundmann et al., 2006), resulting in serious problems with regard to therapy of S. aureus infectious disease. Recently, besides these virulence factors, S. aureus has also been found to possess the ability to produce several factors that protect against host-derived innate immune factors, such as complement, antibodies and neutrophils, as well as recently recognized innate immune antimicrobial peptides, such as LL-37 and defensins (Foster, 2005;Rooijakkers et al., 2005).Human antimicrobial peptides are one of the innate immune factors and are produced in various tissues and organs, such as the skin, lung and intestines (Ganz et al., 1985;Ganz & Lehrer, 1995;Lehrer & Ganz, 1999;Selsted & Ouellette, 2005;Zaiou & Gallo, 2002). The most wellknown antimicrobial peptides are the defensins. Defensins are classified into two types: alpha-defensins from neutrophils and Paneth cells, and beta-defensins from epithelial cells (Cunliffe, 2003;Ganz et al., 1985;Ganz & Lehrer, 1995). Another major peptide is CAP18/LL37, which is found in neutrophils and epithelial cells (Larrick et al., 1995;Ramanathan et al., 2002;Zaiou & Gallo, 2002). These cationic peptides are electrostatically attracted to bacterial cell surfaces. Then, the peptides interact with membrane lipids, causing membrane permeabilization and leading to ...
Large numbers of bacteria coexist in the oral cavity. Streptococcus sanguinis, one of the major bacteria in dental plaque, produces hydrogen peroxide (H 2 O 2 ), which interferes with the growth of other bacteria. Streptococcus mutans, a cariogenic bacterium, can coexist with S. sanguinis in dental plaque, but to do so, it needs a means of detoxifying the H 2 O 2 produced by S. sanguinis. In this study, we investigated the association of three oxidative stress factors, Dpr, superoxide dismutase (SOD), and AhpCF, with the resistance of S. sanguinis to H 2 O 2 . The knockout of dpr and sod significantly increased susceptibility to H 2 O 2 , while the knockout of ahpCF had no apparent effect on susceptibility. In particular, dpr inactivation resulted in hypersensitivity to H 2 O 2 . Next, we sought to identify the factor(s) involved in the regulation of these oxidative stress genes and found that PerR negatively regulated dpr expression. The knockout of perR caused increased dpr expression levels, resulting in low-level susceptibility to H 2 O 2 compared with the wild type. Furthermore, we evaluated the roles of perR, dpr, and sod when S. mutans was cocultured with S. sanguinis. Culturing of the dpr or sod mutant with S. sanguinis showed a significant decrease in the S. mutans population ratio compared with the wild type, while the perR mutant increased the ratio. Our results suggest that dpr and sod in S. mutans are involved in coexistence with S. sanguinis, and PerR is associated with resistance to H 2 O 2 in regulating the expression of Dpr.
Bacterial two-component systems (TCSs) have been demonstrated to be associated with not only the expression of virulence factors, but also the susceptibility to antibacterial agents. In Staphylococcus aureus, 16 types of TCSs have been identified. We previously found that the inactivation of one uncharacterized TCS (designated as BceRS, MW gene ID: MW2545-2544) resulted in an increase in susceptibility to bacitracin. In this study, we focused on this TCS and tried to identify the TCS-controlled factors affecting the susceptibility to bacitracin. We found that two ABC transporters were associated with the susceptibility to bacitracin. One transporter designated as BceAB (MW2543-2542) is downstream of this TCS, while another (formerly designated as VraDE: MW2620-2621) is separate from this TCS. Both transporters showed homology with several bacitracin-resistance factors in Gram-positive bacteria. Inactivation of each of these two transporters increased the susceptibility to bacitracin. Expressions of these transporters were significantly increased by the addition of bacitracin, while this induction was not observed in the TCS-inactivated mutant. These results indicate that this TCS senses bacitracin, and also positively regulates the expression of two ABC transporters.
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