Enterotoxin-producing staphylococci cause intestinal inflammation by a combination of direct epithelial cytopathy and superantigen-mediated T-cell activation

Edwards, Lindsey; O’Neill, Colette; Furman, M; Hicks, Susan; Torrente, Franco; Perez‐Machado, Miguel; Wellington, Elizabeth M. H.; Phillips, Alan D.; Murch, Simon

doi:10.1002/ibd.21852

Cited by 29 publications

(21 citation statements)

References 60 publications

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“…It has also been suggested that SAgs liberated in the gastrointestinal tract by food-borne pathogens may cross the perturbed gut mucosa either directly or with the assistance of other bacterial toxins [57,58] and consequently access the liver via the portal vein [12]. The abundance of MAIT cells in the intestine and in the liver inevitably puts them in a unique position to respond to SAgs with deleterious outcomes.…”

Section: Discussionmentioning

confidence: 99%

MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression

et al. 2017

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Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a “cytokine storm” with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm’s initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host’s ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT) cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or γδ T cells, and is characterized by production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vβ–specific manner but are largely contributed by IL-12 and IL-18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg-associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses.

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Section: Discussionmentioning

confidence: 99%

MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression

et al. 2017

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“…Strains of S. aureus can produce enterotoxins, capable of functioning as superantigens that activate large numbers of non-specific T-cells in the gut [14]. In vitro stimulation of peripheral blood mononuclear cells (PBMC) with superantigenic S. aureus and/or other toxins from staphylococci induces IL-17 production by T-cells [15,16], a cytokine highly associated with both allergy and autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Lactobacilli Regulate Staphylococcus aureus 161:2-Induced Pro-Inflammatory T-Cell Responses In Vitro

et al. 2013

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There seems to be a correlation between early gut microbiota composition and postnatal immune development. Alteration in the microbial composition early in life has been associated with immune mediated diseases, such as autoimmunity and allergy. We have previously observed associations between the presence of lactobacilli and Staphylococcus (S.) aureus in the early-life gut microbiota, cytokine responses and allergy development in children. Consistent with the objective to understand how bacteria modulate the cytokine response of intestinal epithelial cell (IEC) lines and immune cells, we exposed IEC lines (HT29, SW480) to UV-killed bacteria and/or culture supernatants (-sn) from seven Lactobacillus strains and three S. aureus strains, while peripheral blood mononuclear cells (PBMC) and cord blood mononuclear cells (CBMC) from healthy donors were stimulated by bacteria-sn or with bacteria conditioned IEC-sn. Although the overall IEC response to bacterial exposure was characterized by limited sets of cytokine and chemokine production, S. aureus 161:2-sn induced an inflammatory response in the IEC, characterized by CXCL1/GROα and CXCL8/IL-8 production, partly in a MyD88-dependent manner. UV-killed bacteria did not induce a response in the IEC line, and a combination of both UV-killed bacteria and the bacteria-sn had no additive effect to that of the supernatant alone. In PBMC, most of the Lactobacillus-sn and S. aureus-sn strains were able to induce a wide array of cytokines, but only S. aureus-sn induced the T-cell associated cytokines IL-2, IL-17 and IFN-γ, independently of IEC-produced factors, and induced up regulation of CTLA-4 expression and IL-10 production by T-regulatory cells. Notably, S. aureus-sn-induced T-cell production of IFN- γ and IL-17 was down regulated by the simultaneous presence of any of the different Lactobacillus strains, while the IEC CXCL8/IL-8 response was unaltered. Thus these studies present a possible role for lactobacilli in induction of immune cell regulation, although the mechanisms need to be further elucidated.

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“…In more recent years, experts in both Europe and the USA have rekindled their interests in S. aureus as a potential cause for AAE [62,86-88]. It is also important to note that other pathogens such as Klebsiella oxytoca have also been found to cause AAE [15].…”

Section: Discussionmentioning

confidence: 99%

A systematic review for pursuing the presence of antibiotic associated enterocolitis caused by methicillin resistant Staphylococcus aureus

et al. 2014

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BackgroundAlthough it has received a degree of notoriety as a cause for antibiotic-associated enterocolitis (AAE), the role of methicillin resistant Staphylococcus aureus (MRSA) in the pathogenesis of this disease remains enigmatic despite a multitude of efforts, and previous studies have failed to conclude whether MRSA can cause AAE. Numerous cases of AAE caused by MRSA have been reported from Japan; however, due to the fact that these reports were written in the Japanese language and a good portion lacked scientific rigor, many of these reports went unnoticed.MethodsWe conducted a systematic review of pertinent literatures to verify the existence of AAE caused by MRSA. We modified and applied methods in common use today and used a total of 9 criteria to prove the existence of AAE caused by Klebsiella oxytoca. MEDLINE/Pubmed, Excerpta Medica Database (EMBASE), the Cochrane Database of Systematic Reviews, and the Japan Medical Abstract Society database were searched for studies published prior to March 2013.ResultsA total of 1,999 articles were retrieved for evaluation. Forty-five case reports/series and 9 basic studies were reviewed in detail. We successfully identified articles reporting AAE with pathological and microscopic findings supporting MRSA as the etiological agent. We also found comparative studies involving the use of healthy subjects, and studies detecting probable toxins. In addition, we found animal models in which enteritis was induced by introducing MRSA from patients. Although we were unable to identify a single study that encompasses all of the defined criteria, we were able to fulfill all 9 elements of the criteria by collectively analyzing multiple studies.ConclusionsAAE caused by MRSA—although likely to be rarer than previous Japanese literatures have suggested—most likely does exist.

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Enterotoxin-producing staphylococci cause intestinal inflammation by a combination of direct epithelial cytopathy and superantigen-mediated T-cell activation

Cited by 29 publications

References 60 publications

MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression

MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression

Lactobacilli Regulate Staphylococcus aureus 161:2-Induced Pro-Inflammatory T-Cell Responses In Vitro

A systematic review for pursuing the presence of antibiotic associated enterocolitis caused by methicillin resistant Staphylococcus aureus

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