This article reviews the literature regarding the structure and function of two types of exotoxins expressed by Staphylococcus aureus, pyrogenic toxin superantigens (PTSAgs) and hemolysins. The molecular basis of PTSAg toxicity is presented in the context of two diseases known to be caused by these exotoxins: toxic shock syndrome and staphylococcal food poisoning. The family of staphylococcal PTSAgs presently includes toxic shock syndrome toxin-1 (TSST-1) and most of the staphylococcal enterotoxins (SEs) (SEA, SEB, SEC, SED, SEE, SEG, and SEH). As the name implies, the PTSAgs are multifunctional proteins that invariably exhibit lethal activity, pyrogenicity, superantigenicity, and the capacity to induce lethal hypersensitivity to endotoxin. Other properties exhibited by one or more staphylococcal PTSAgs include emetic activity (SEs) and penetration across mucosal barriers (TSST-1). A detailed review of the molecular mechanisms underlying the toxicity of the staphylococcal hemolysins is also presented.

Exotoxins of Staphylococcus aureus

The cell wall envelope of gram-positive bacteria is a macromolecular, exoskeletal organelle that is assembled and turned over at designated sites. The cell wall also functions as a surface organelle that allows gram-positive pathogens to interact with their environment, in particular the tissues of the infected host. All of these functions require that surface proteins and enzymes be properly targeted to the cell wall envelope. Two basic mechanisms, cell wall sorting and targeting, have been identified. Cell well sorting is the covalent attachment of surface proteins to the peptidoglycan via a C-terminal sorting signal that contains a consensus LPXTG sequence. More than 100 proteins that possess cell wall-sorting signals, including the M proteins of Streptococcus pyogenes, protein A of Staphylococcus aureus, and several internalins of Listeria monocytogenes, have been identified. Cell wall targeting involves the noncovalent attachment of proteins to the cell surface via specialized binding domains. Several of these wall-binding domains appear to interact with secondary wall polymers that are associated with the peptidoglycan, for example teichoic acids and polysaccharides. Proteins that are targeted to the cell surface include muralytic enzymes such as autolysins, lysostaphin, and phage lytic enzymes. Other examples for targeted proteins are the surface S-layer proteins of bacilli and clostridia, as well as virulence factors required for the pathogenesis of L. monocytogenes (internalin B) and Streptococcus pneumoniae (PspA) infections. In this review we describe the mechanisms for both sorting and targeting of proteins to the envelope of gram-positive bacteria and review the functions of known surface proteins.

Surface Proteins of Gram-Positive Bacteria and Mechanisms of Their Targeting to the Cell Wall Envelope

The accessory genes of Staphylococcus aureus, including those involved in pathogenesis, are controlled by a complex regulatory network that includes at least four two-component systems, one of which, agr, is a quorum sensor, an alternative sigma factor and a large set of transcription factors, including at least two of the superantigen genes, tst and seb. These regulatory genes are hypothesized to act in a time- and population density-dependent manner to integrate signals received from the external environment with the internal metabolic machinery of the cell, in order to achieve the production of particular subsets of accessory/virulence factors at the time and in quantities that are appropriate to the needs of the organism at any given location. From the standpoint of pathogenesis, the regulatory agenda is presumably tuned to particular sites in the host organism. To address this hypothesis, it will be necessary to understand in considerable detail the regulatory interactions among the organism's numerous controlling systems. This review is an attempt to integrate a large body of data into the beginnings of a model that will hopefully help to guide research towards a full-scale test.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2958.2003.03526.x

Autoinduction and signal transduction in the regulation of staphylococcal virulence

Bacteria were for a long time believed to exist as individual cells that sought primarily to find nutrients and multiply The discovery of intercellular communication among bacteria has led to the realization that bacteria are capable of coordinated activity that was once believed to be restricted to multicellular organisms The capacity to behave collectively as a group has obvious advantages, for example, the ability to migrate to a more suitable environment/better nutrient supply and to adopt new modes of growth, such as sporulation or biofilm formation, which may afford protection from deleterious environments The “language” used for this intercellular communication is based on small, self-generated signal molecules called autoinducers Through the use of autoinducers, bacteria can regulate their behavior according to population density The phenomenon of quorum sensing, or cell-to-cell communication, relies on the principle that when a single bacterium releases autoinducers (AIs) into the environment, their concentration is too low to be detected However, when sufficient bacteria are present, autoinducer concentrations reach a threshold level that allows the bacteria to sense a critical cell mass and, in response, to activate or repress target genes Most of the bacteria thus far identified that utilize quorum-sensing systems are associated in some way with plants or animals The nature of these relationships can be either amicable, as characterized by symbiotic bacteria, or adversarial, as seen with pathogenic bacteria There are numerous bacteria that have components of a quorum-sensing system for which the phenotype regulated remains an enigma Similarly, there are bacteria known to regulate a specific phenotype via quorum sensing for which one or more of the regulatory components have thus far eluded identification In this review we give examples of pathogenic relationships, focusing on organisms for which many of the facets of their quorum-sensing systems have been elucidated

Bacterial Quorum Sensing in Pathogenic Relationships

The staphylococcal agr locus encodes a quorum sensing (QS) system that controls the expression of virulence and other accessory genes by a classical two-component signaling module. Like QS modalities in other Gram-positive bacteria, agr encodes an autoactivating peptide (AIP) that is the inducing ligand for AgrC, the agr signal receptor. Unlike other such systems, agr variants have arisen that show strong cross-inhibition in heterologous combinations, with important evolutionary implications. Also unlike other systems, the effector of global gene regulation in the agr system is a major regulatory RNA, RNAIII. In this review, we describe the functions of the agr system's elements, show how they interact to bring about the regulatory response, and discuss the role of QS in staphylococcal pathobiology. We conclude with the suggestion that agr autoactivation, unlike classical enzyme induction, can occur under suboptimal conditions and can distinguish self from non-self by inducing an exclusive and coordinated...

Quorum Sensing in Staphylococci

Insertion of the erythromycin-resistance transposon Tn551 into the Staphylococcus aureus chromosome at a site which maps between the purB and ilv loci has a pleiotrophic effect on the production of a number of extracellular proteins. Production of alpha, beta and delta hemolysin, toxic shock syndrome toxin (TSST-1) and staphylokinase was depressed about fifty-fold while protein A production was elevated twenty-fold. Hybridization analysis showed that the defect in expression of TSST-1 and alpha hemolysin was at the transcriptional level. Inability of the mutant strain to express either a cloned TSST-1 gene or the chromosomal gene indicates that the transposon has inactivated a trans-active positive control element. This element has been designated agr for accessory gene regulator.

P. Recsei

Papers

Regulation of exoprotein gene expression in Staphylococcus aureus by agr