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Medical Aspects of Biological Warfare Staphylococcal Enterotoxin B and Related Toxins Chapter 17 STAPHYLOCOCCAL ENTEROTOXIN B AND RELATED TOXINS PRODUCED BY STAPHYLOCOCCUS AUREUS AND STREPTOCOCCUS PYOGENES KAMAL U. SAIKH, PhD*; ROBERT G. ULRICH, PhD†; and TERESA KRAKAUER, PhD‡ INTRODUCTION CHARACTERIZATION OF TOXINS HOST RESPONSE AND ANIMAL MODELS CLINICAL DISEASE Fever Respiratory Symptoms Headache Nausea and Vomiting Other Signs and Symptoms DETECTION AND DIAGNOSIS MEDICAL MANAGEMENT VACCINES DEVELOPMENT OF THERAPEUTICS SUMMARY *Microbiologist, Department of Immunology, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Maryland 21702 †Microbiologist, Department of Immunology, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Maryland 21702 ‡Microbiologist, Department of Immunology, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Maryland 21702 403 244-949 DLA DS.indb 403 6/4/18 11:58 AM Medical Aspects of Biological Warfare INTRODUCTION Staphylococcus aureus and Streptococcus pyogenes are shock syndrome (TSS) may result from exposure to any ubiquitous, gram-positive cocci that play an important of the superantigens through a nonenteric route. High role in numerous human illnesses such as food poison- dose, microgram-level exposures to staphylococcal en- ing, pharyngitis, toxic shock, autoimmune diseases, terotoxin B (SEB) will result in fatalities, and inhalation and skin and soft tissue infections. These common bac- exposure to nanogram or lower levels may be severely teria readily colonize humans via numerous virulence incapacitating as well as fatal.3 In addition, the severe factors that facilitate their survival and dissemination. perturbation of the immune system caused by supe- Among these factors, staphylococcal enterotoxins rantigen exposure may lower the infectious or lethal (SEs), toxic shock syndrome toxin-1 (TSST-1), and dose of replicating agents, such as influenza virus.4 streptococcal pyrogenic exotoxins (SPEs) share a com- SEB is a prototype enterotoxin and potential biologi- mon three-dimensional protein fold characteristic of cal threat agent produced by many isolates of S aureus. these bacterial exotoxins called “superantigens” due During the 1960s, SEB was studied extensively as a to their potency in activating cells of the immune biological incapacitant in the US offensive program. system.1,2 Picomolar concentrations of these bacterial Recent studies on countermeasures and diagnostics superantigens activate specific Vβ-bearing T cells by have focused on SEB because of its effectiveness as binding to and cross-linking the major histocompat- a biological weapon, especially by inhalation. How- ibility complex (MHC) class II molecules on antigen- ever, SEB represents many related biologically active presenting cells (APC) and the T-cell receptor (TCR). superantigens that are readily isolated and manipu- Activated T cells proliferate and, together with APC, lated by recombinant DNA (deoxyribonucleic acid) produce proinflammatory mediators that, in elevated techniques. Moreover, the coadministration of SEB or quantities, can induce fever, hypotension, and lethal related toxins with replicating pathogens or pathogen- shock. Most strains of S aureus and S pyogenes exam- associated molecules can lower the lethal dose of toxin ined harbor genes for superantigens and are likely to by thousands fold. Pathogen-associated molecules produce at least one of these toxins. Strains that lack the such as endotoxins bind to toll-like receptors (TLRs) ability to produce superantigens are usually attenuated present on many cell types and activate similar intra- in virulence. The staphylococcal enterotoxins are most cellular signaling pathways as SEB, accounting for the frequently associated with food poisoning, yet not all synergy between these molecules and SEB in inducing superantigens are enterotoxins. Life-threatening toxic pathophysiological effects.5 CHARACTERIZATION OF TOXINS Genes encoding superantigens of S aureus and S The bacterial superantigens are 19- to 30-kD single- pyogenes arise from a common ancestral gene. Most of chain proteins with two major domains, containing the streptococcal superantigens are encoded by mobile β-sheet and α-helix structures, separated by a shallow genetic elements. SPE-A, SPE-C, SEA, and SEE are all groove.1,9 Based on amino acid sequences and struc- phage-borne, while SED is plasmid-encoded. A chro- tural homology, superantigens can be compiled into mosomal cluster of SE and SE-like genes are present in five different groups.10 TSST-1 is the most distantly strains of S aureus.6 Transcriptional control of TSST-1, related and lacks a “disulfide loop” commonly found SEB, SEC, and SED is mediated through the accessory in SEs, whereas SEs with emetic properties such as gene regulator (agr) locus,7 whereas SEA expression SEA, SEB, SEC, SED, and SEE all possess this loop appears to be independent of agr. Strains that are agr- structure. Despite significant sequence divergence, negative generally produce less toxin; however, there with similarities as low as 14%, overall protein folds are also considerable differences in production levels are similar among staphylococcal and streptococcal among agr-positive isolates. These toxins are synthe- superantigens. Cross-reactivities of polyclonal and sized during the late logarithmic to stationary phases monoclonal antibodies to SEs, TSST-1, and SPEs indi- of growth, and production of many SEs is dependent cate common epitopes among these superantigens.11 on glucose concentration and environmental pH. The The toxin genes have evolved by strong selective great diversity of superantigens and the highly mobile pressures to maintain receptor-binding surfaces by nature of their genetic elements suggest an accelerated preserving three-dimensional protein structure. The rate of evolution. Staphylococcal and streptococcal contact surfaces with MHC class II molecules involve strains that colonize domestic animals are potential ge- variations of conserved structural elements,12,13 which netic reservoirs for new toxin genes,8 and the transfer of include a ubiquitous hydrophobic surface loop, a these sequences may contribute to hybrid polypeptides. polar-binding pocket present in most superantigens, 404 244-949 DLA DS.indb 404 6/4/18 11:58 AM Staphylococcal Enterotoxin B and Related Toxins and one or more zinc-binding sites found in some toxins. Comparison of antibody recognition among superantigens11 suggests that antigenic variation is maximized while three-dimensional structures, and hence receptor-binding surfaces, are conserved. From a practical standpoint, this observation indicates that a large panel of antibody probes will be required for proper sample identification. Molecular details of the receptor interaction and biological actions of bacterial superantigens are well established. Superantigens target cells that mediate innate and adaptive immunity, resulting in an intense activation and subsequent pathology associated with aberrant host-immune responses. In contrast to “conventional” antigens, bacterial supe- rantigens bind on the outside of the peptide-binding groove of MHC class II molecules and exert their biological effects without being “processed.” Most superantigens share a common mode for binding MHC class II molecules, with additional stabiliz- ing interactions that are unique to each toxin.14 A second, zinc-dependent molecular binding mode for some superantigens increases T cell signaling and may impart greater toxicities in some cases. Figure 17-1. Molecular model of receptor binding. Staphy- In normal T-cell responses to peptide antigens, the lococcal enterotoxins and other bacterial superantigens CD4 molecule stabilizes interactions between TCR target the multireceptor communication between T cells and MHC class II molecules on APC (Figure 17-1). and antigen-presenting cells that is fundamental to initiat- Superantigens also cross-link TCR and MHC class ing pathogen-specific immune clearance. The superantigen II molecules, mimicking the CD4 molecule,15 and inserts itself between the antigen receptor of T cells and the hence stimulate large numbers of T cells. Recogni- major histocompatibility complex class II molecule display- ing peptides from potential pathogens. Toxin exposure tion of a superantigen by TCR is dependent on the results in hyperactivation of the immune system, and the pa- variable region of the β chain (Vβ) of the TCR. Each thology is mediated by tumor necrosis factor-α, interferon-γ, toxin binds to a distinct repertoire of TCR Vβ, thus and other cytokines. revealing the unique Vβ specificities of an individual HLA-DR: Human Leukocyte Antigen DR; SEB: staphylococ- superantigen.16 An intense and rapid release of cy- cal enterotoxin B; TCR: T-cell receptor tokines, such as interferon-g, interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) is responsible for the sys- transcytosis of toxin.20 Other studies suggest various temic effects of the toxins.17–19 Although SEB has en- binding regions of SEB to epithelial cell membrane terotoxic effects, the interaction of toxin with specific proteins.21,22 The release of histamine and cysteinyl cells and receptors of the gastrointestinal tract is less leukotriene from mast cells likely accounts for the well-defined. A specific region in SEB is involved in emetic effects of staphylococcal enterotoxins.23 HOST RESPONSE AND ANIMAL MODELS
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