Methicillin-resistant Staphylococcus aureus (MRSA) remains a major human pathogen. Traditionally, MRSA infections occurred exclusively in hospitals and were limited to immunocompromised patients or individuals with predisposing risk factors. However, recently there has been an alarming epidemic caused by community-associated (CA)-MRSA strains, which can cause severe infections that can result in necrotizing fasciitis or even death in otherwise healthy adults outside of healthcare settings. In the US, CA-MRSA is now the cause of the majority of infections that result in trips to the emergency room. It is unclear what makes CA-MRSA strains more successful in causing human disease compared with their hospital-associated counterparts. Here we describe a class of secreted staphylococcal peptides that have a remarkable ability to recruit, activate and subsequently lyse human neutrophils, thus eliminating the main cellular defense against S. aureus infection. These peptides are produced at high concentrations by standard CA-MRSA strains and contribute significantly to the strains' ability to cause disease in animal models of infection. Our study reveals a previously uncharacterized set of S. aureus virulence factors that account at least in part for the enhanced virulence of CA-MRSA.
Methicillin-resistant Staphylococcus aureus (MRSA) is endemic in hospitals worldwide and a significant cause of morbidity and mortality. Healthcare-associated MRSA infections occur in individuals with predisposing risk factors for disease, such as surgery or presence of an indwelling medical device. By contrast, community-associated MRSA (CA-MRSA) infections often occur in otherwise healthy individuals who lack such risk factors. In addition, CA-MRSA infections are epidemic in some countries. These observations suggest that CA-MRSA strains are more virulent and transmissible than traditional hospital-associated MRSA strains. Relatively limited treatment options for CA-MRSA infections compound the problem of enhanced virulence and transmission. Although progress has been made toward understanding emergence of CA-MRSA, virulence, and treatment of infections, our knowledge in these areas remains incomplete. Here were review the most current knowledge in these areas and provide perspective on future outlook for prophylaxis and/or new therapies for CA-MRSA infections.
Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features.
Many human pathogens produce phenotypic variants as a means to circumvent the host immune system and enhance survival and, as a potential consequence, exhibit increased virulence. For example, it has been known for almost 90 y that clinical isolates of the human bacterial pathogen group A streptococci (GAS) have extensive phenotypic heterogeneity linked to variation in virulence. However, the complete underlying molecular mechanism(s) have not been defined. Expression microarray analysis of nine clinical isolates identified two fundamentally different transcriptomes, designated pharyngeal transcriptome profile (PTP) and invasive transcriptome profile (ITP). PTP and ITP GAS differed in approximately 10% of the transcriptome, including at least 23 proven or putative virulence factor genes. ITP organisms were recovered from skin lesions of mice infected subcutaneously with PTP GAS and were significantly more able to survive phagocytosis and killing by human polymorphonuclear leukocytes. Complete genome resequencing of a mouse-derived ITP GAS revealed that the organism differed from its precursor by only a 7-bp frameshift mutation in the gene (covS) encoding the sensor kinase component of a two-component signal transduction system implicated in virulence. Genetic complementation, and sequence analysis of covR/S in 42 GAS isolates confirmed the central role of covR/S in transcriptome, exoproteome, and virulence modulation. Genome-wide analysis provides a heretofore unattained understanding of phenotypic variation and disease specificity in microbial pathogens, resulting in new avenues for vaccine and therapeutics research.
Methicillin-resistant Staphylococcus aureus (MRSA) remains a major problem in hospitals, and it is now spreading in the community. A single toxin, Panton-Valentine leukocidin (PVL), has been linked by epidemiological studies to community-associated MRSA (CA-MRSA) disease. However, the role that PVL plays in the pathogenesis of CA-MRSA has not been tested directly. To that end, we used mouse infection models to compare the virulence of PVL-positive with that of PVL-negative CA-MRSA representing the leading disease-causing strains. Unexpectedly, strains lacking PVL were as virulent in mouse sepsis and abscess models as those containing the leukotoxin. Isogenic PVL-negative (lukS/F-PV knockout) strains of USA300 and USA400 were as lethal as wild-type strains in a sepsis model, and they caused comparable skin disease. Moreover, lysis of human neutrophils and pathogen survival after phagocytosis were similar between wild-type and mutant strains. Although the toxin may be a highly linked epidemiological marker for CA-MRSA strains, we conclude that PVL is not the major virulence determinant of CA-MRSA.
Biofilms play an important role in many chronic bacterial infections. Production of an extracellular mixture of sugar polymers called exopolysaccharide is characteristic and critical for biofilm formation. However, there is limited information about the mechanisms involved in the biosynthesis and modification of exopolysaccharide components and how these processes influence bacterial pathogenesis. Staphylococcus epidermidis is an important human pathogen that frequently causes persistent infections by biofilm formation on indwelling medical devices. It produces a poly-N-acetylglucosamine molecule that emerges as an exopolysaccharide component of many bacterial pathogens. Using a novel method based on size exclusion chromatography-mass spectrometry, we demonstrate that the surface-attached protein IcaB is responsible for deacetylation of the poly-N-acetylglucosamine molecule. Most likely due to the loss of its cationic character, non-deacetylated poly-acetylglucosamine in an isogenic icaB mutant strain was devoid of the ability to attach to the bacterial cell surface. Importantly, deacetylation of the polymer was essential for key virulence mechanisms of S. epidermidis, namely biofilm formation, colonization, and resistance to neutrophil phagocytosis and human antibacterial peptides. Furthermore, persistence of the icaB mutant strain was significantly impaired in a murine model of device-related infection. This is the first study to describe a mechanism of exopolysaccharide modification that is indispensable for the development of biofilm-associated human disease. Notably, this general virulence mechanism is likely similar for other pathogenic bacteria and constitutes an excellent target for therapeutic maneuvers aimed at combating biofilmassociated infection.
Exopolysaccharide (EPS)1 is a key component of the biofilm matrix in many biofilm-forming bacteria and may be composed of various sugar polymers (1). It has an important role in immune evasion and tolerance toward antibacterial agents. By far most known EPS molecules are neutral or polyanionic (2). Enzymatic alteration of EPS is believed to significantly change its physicochemical properties and, thus, biofilm structure. However, particularly in Gram-positive bacteria, EPS-modifying enzymes and the relationship between the composition of EPS and its biological function have remained poorly characterized.The Gram-positive bacterium Staphylococcus epidermidis is the most prevalent pathogen involved in hospital-acquired infections (3). The costs related to infections caused by S. epidermidis in the hospital setting are enormous and represent a major health care burden. Most infections caused by S. epidermidis occur after the insertion of indwelling devices such as catheters or prosthetic heart valves. In these cases, the ability of S. epidermidis to form biofilms represents the most important virulence determinant (3). In a biofilm, the bacteria are dramatically less susceptible to antibiotic treatment and attacks by innate host defense. For these reasons, S. ...
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