Of note, this excludes an impact of TSST-1 on ST59 pathogenesis

Of note, this excludes an impact of TSST-1 on ST59 pathogenesis. value of including SEB as a target in multipronged antistaphylococcal drug development strategies. Furthermore, they indicate that contributes to fatal exacerbation of community-associated methicillin-resistant contamination. is usually a producer of many toxins that collectively contribute to its virulence potential [1]. The staphylococcal enterotoxins (SEs) are a subset of the staphylococcal superantigen family, which also includes toxic shock syndrome (TSS) toxin 1 (TSST-1) and enterotoxinlike serotypes [2]. All superantigen A419259 toxins are powerful nonspecific stimulators of T cells [2]. They bypass the normal antigen-specific restrictions of immune A419259 cell activation by forming a bridge between the major histocompatibility class (MHC) II receptors on antigen-presenting cells with V chains on T-cell receptors [3]. This nonconventional mechanism of immune cell activation results in rapid T-cell growth and is accompanied by a massive proinflammatory cytokine release, which is the principal mediator of a number of diseases, such as immunoglobulin ECassociated inflammatory diseases, pulmonary, and, most notably, TSS [2]. TSS is usually a systemic disease characterized by the fast onset of fever, organ failure, and death [4]. There are about 20 different SEs, which are encoded on different staphylococcal pathogenicity islands [5]. Staphylococcal enterotoxin B (SEB), which is usually encoded together with SEs K, L, and Q around the pathogenicity island SaPI3, has received most attention. It is considered a biological weapon and classified as a select agent in the United States. Therefore, considerable efforts have been dedicated to creating SEB-neutralizing strategies [6]. It has been reported early that there is an epidemiological association MYO7A of TSS not only with TSST-1 but also with SEB [7]. Furthermore, manifestations of TSS disease have been exhibited in multiple studies in different animal species that received purified SEB toxin [6] and in animals that were infected with SEB-producing strains [8]. Moreover, plasmid-based expression of SEB in a laboratory strain devoid of other superantigens resulted in increased fatality in a mouse pneumonia model [9] and anti-SEB antibodies decreased morbidity and mortality rates in several mouse infection models [10]. However, while it has frequently been speculated that SEB may contribute to disease in a natural strain background, this cannot be concluded from these study findings and has never been directly investigated, which can be done only by comparing an mutant with an isogenic parental clinical strain in an appropriate animal model. Because the gene is usually encoded around the mobile genetic element SaPI3, SEB production is limited to specific genetic lineages [11C15]. Among clinically important lineages, it has been reported to occur frequently in the predominant Asian community-associated methicillin-resistant (CA-MRSA) lineage of sequence type (ST) 59 [16, 17]. Similar to other CA-MRSA lineages such as USA300, ST59 isolates exhibit exceptional virulence that is believed to underlie epidemiological success and an ability to infect otherwise healthy individuals [18]. In the current study, we therefore selected a representative ST59 CA-MRSA strain as a host to create an isogenic mutant and investigate the contribution of SEB to pathogenesis. We compared the virulence characteristics of this mutant with A419259 its wild-type (WT) parent in local and systemic disease, using the HLA transgenic mouse model. This is an established model to determine SEB-induced lethal shock and is based on MHC class II knockout mice that express human MHC class II HLA-DR3 [19C21]. Our data provide previously unavailable direct evidence for a contribution of SEB to pathogenesis and indicate that SEB plays a significant role in the observed hypervirulence of a clinically A419259 important, widespread CA-MRSA lineage. METHODS Study Approval The Animal Care and Use Community at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, reviewed and approved the animal protocol used (Animal Study Protocol LB-1E), according to the animal.