Staphylococcal Superantigens Spark Host-Mediated Danger Signals

Abstract

Staphylococcal enterotoxin B (SEB) of Staphylococcus aureus, and related superantigenic toxins produced by myriad microbes, are potent stimulators of the immune system causing a variety of human diseases from transient food poisoning to lethal toxic shock. These protein toxins bind directly to specific Vβ regions of T-cell receptors (TCR) and major histocompatibility complex (MHC) class II on antigen-presenting cells, resulting in hyperactivation of T lymphocytes and monocytes/macrophages. Activated host cells produce excessive amounts of proinflammatory cytokines and chemokines, especially tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 causing clinical symptoms of fever, hypotension, and shock. Because of superantigen-induced T cells skewed toward TH1 helper cells, and the induction of proinflammatory cytokines, superantigens can exacerbate autoimmune diseases. Upon TCR/MHC ligation, pathways induced by superantigens include the mitogen-activated protein kinase cascades and cytokine receptor signaling, resulting in activation of NFκB and the phosphoinositide 3-kinase/mammalian target of rapamycin pathways. Various mouse models exist to study SEB-induced shock including those with potentiating agents, transgenic mice and an “SEB-only” model. However, therapeutics to treat toxic shock remain elusive as host response genes central to pathogenesis of superantigens have only been identified recently. Gene profiling of a murine model for SEB-induced shock reveals novel molecules upregulated in multiple organs not previously associated with SEB-induced responses. The pivotal genes include intracellular DNA/RNA sensors, apoptosis/DNA damage-related molecules, immunoproteasome components, as well as antiviral and IFN-stimulated genes. The host-wide induction of these, and other, antimicrobial defense genes provide evidence that SEB elicits danger signals resulting in multi-organ damage and toxic shock. Ultimately, these discoveries might lead to novel therapeutics for various superantigen-based diseases.

Systemic cytokine and chemokine responses in immunized mice challenged with staphylococcal enterotoxin B

“…Alternatively, transgenic mice which express human major histocompatibility class II molecules have been engineered resulting in a more robust response to SEB (Faulkner et al, 2005; Rajagopalan et al, 2009). Larger animal models respond systemically to SEB as a superantigen (Krakauer et al, 2016), including swine (Bost et al, 2016; Hudson et al, 2013) and non-human primates (He et al, 2014; Komisar et al, 2001; Weng et al, 1997). These models have also been used to suggest efficacy of various SEB vaccination formulations (Boles et al, 2003; Hudson et al, 2013; Tseng et al, 1995).…”

“…These models have also been used to suggest efficacy of various SEB vaccination formulations (Boles et al, 2003; Hudson et al, 2013; Tseng et al, 1995). Despite such a diversity of studies using a variety of animal models, the immune parameters central for mediating SEB toxicity in humans remain unclear (Fries and Varshney, 2013; Krakauer et al, 2016). An SEB-induced cytokine storm is universally described as being deleterious (Tisoncik et al, 2012).…”

Розвиток Імунної Відповіді При Стафілококовій Пневмонії (Частина 1)

“…Сигнал 1 обусловлен взаимодействием су-перантигена с TCR, которое обусловливает ак-тивацию протеинтирозинкиназы (protein tyrosine kinases -PTK), которая, в свою очередь, фосфори-лирует тирозиновые активирующие мотивы интра-доменов TCR, что приводит к фосфорилированию фосфолипазы γ (phospholipase C gamma -PLC-γ) [33,38]. Функционирование фосфолипазы γ акти-вирует протеинкиназу С (protein kinase C -PKC), которая возбуждает фактор транскрипции NF-κB и способствует увеличению внутриклеточной концентрации кальция, который активирует че-рез кальциневрин фактор транскрипции NF-AT.…”

“…Цитокины IL-1β и TNF-α могут ак-тивировать фибробласты, эпителиальные и эндо-телиальные клетки, обеспечивая воспалительную среду для активации Т-клеток. Влияние провос-палительных цитокинов на гепатоциты приводит к продукции острофазовых белков [33,34].…”

Agents to reduce cytokine storm

“…If these systems are disturbed, extreme hyperinflammation may occur: this is typical for toxic shock syndrome, where bacterial “superantigens” (for example, Staphylococcal enterotoxin B) are able to “fool” the MHC-II–TCR system ( Figure 1B, upper part). The inhibitory downstream pathways are bypassed, and specific kinase systems within the T cells are activated, thus inducing a fast and overwhelming cytokine storm 20 . A similar effect is initiated in humans by the application of an agonistic anti-CD28 antibody, which was previously tested in macaques without side effects 2 .…”