Animal Models Used to Study Superantigen-Mediated Diseases

Brosnahan, Amanda J.

doi:10.1007/978-1-4939-3344-0_1

Cited by 4 publications

(4 citation statements)

References 101 publications

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“…A variety of animal models have been used to investigate the efficacy of vaccine candidates targeting staphylococcal enterotoxin B (SEB) (Brosnahan, 2016; Fries and Varshney, 2013). The relative insensitivity of normal mice to this toxin has resulted in potentiation of its effects by co-administration of agents such as LPS (Stiles et al, 1993) or D-galactosamine (Miethke et al, 1992) to produce lethality.…”

Section: Introductionmentioning

confidence: 99%

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

Reichenberg

Garg

Fernalld

et al. 2017

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The cytokine storm induced by staphylococcal enterotoxin B (SEB) describes the rapid and dramatic induction of mediators which are likely responsible for the toxin’s deleterious effects. However despite the use of numerous animal models for investigating SEB related illness in humans, mechanisms of toxicity and correlates of protection remain unclear. In the present study, we used an LPS-potentiated model of SEB lethality to investigate the toxin-induced cytokine and chemokine responses in untreated and immunized mice. Of 30 separate mediators analyzed, serum levels for 28 or 27 of these cytokines and chemokines were elevated following administration of dosages of 3 or 30 LD50 of native SEB, respectively. Mice immunized with a non-toxic SEB vaccine candidate expressed in either E. coli or transgenic soy expression systems were protected from lethality when challenged with potentiated SEB. The majority of SEB-induced cytokines and chemokines (21 of 28 or 23 of 27 following challenge with dosages of 3 or 30 LD50 of native SEB, respectively) were significantly decreased in mice immunized with an SEB vaccine candidate when compared to control animals. Together, these studies provide the most comprehensive evaluation of the cytokine storm induced in this LPS-potentiated model of SEB lethality to date. As with other animal models, the identification of those mediators which are necessary and sufficient for SEB-induced toxicity remains unclear.

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Section: Introductionmentioning

confidence: 99%

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

Reichenberg

Garg

Fernalld

et al. 2017

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“…The route of infection, pathophysiology and severity must be similar. 24 In contrast with humans, there is not a strong binding of SAgs to murine MHC class II molecules. A possible solution to this is to develop transgenic mice to express human MHC class II (HLA-DR3) molecules.…”

Section: Covid-19mentioning

confidence: 99%

“…The animal disease should mimic the human disease. The route of infection, pathophysiology and severity must be similar 24 . In contrast with humans, there is not a strong binding of SAgs to murine MHC class II molecules.…”

Section: It Is Possible To Demonstrate This Hypothesis?mentioning

confidence: 99%

Are superantigens the cause of cytokine storm and viral sepsis in severe COVID‐19? Observations and hypothesis

Scaglioni

Soriano

2020

Scand J Immunol

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Right now the world is going through an unprecedented pandemic caused by a novel coronavirus. Recent papers pointed out the fatal outcome in most of the severe cases, in which a cytokine storm has been proven to be the cause of a systemic shock, acute respiratory syndrome, multiorgan failure and consequently death. Several explanations have been proposed trying to explain the pathophysiology of the cytokine storm, but viral proteins with a possible superantigen activity as a cause of immune dysregulation have not been addressed. If this hypothesis is proven, a different treatment approach might change the outcome in severe cases. How to cite this article: Scaglioni V, Soriano ER. Are superantigens the cause of cytokine storm and viral sepsis in severe COVID-19? Observations and hypothesis.

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“…Superantigens (SAgs) are a family of potent exotoxins produced by Staphylococcus aureus and Streptococcus pyogenes . SAgs are robust activators of T cells ( 10 , 11 ). SAgs bind directly to MHC class II molecules outside of the peptide-binding groove without undergoing any processing.…”

Section: Introductionmentioning

confidence: 99%

“Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor

et al. 2020

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Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.

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Animal Models Used to Study Superantigen-Mediated Diseases

Cited by 4 publications

References 101 publications

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

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

Are superantigens the cause of cytokine storm and viral sepsis in severe COVID‐19? Observations and hypothesis

“Small” Intestinal Immunopathology Plays a “Big” Role in Lethal Cytokine Release Syndrome, and Its Modulation by Interferon-γ, IL-17A, and a Janus Kinase Inhibitor

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