scholarly journals A monoclonal antibody against staphylococcal enterotoxin B superantigen inhibits SARS-CoV-2 entry in vitro

Structure ◽  
2021 ◽  
Author(s):  
Mary Hongying Cheng ◽  
Rebecca A. Porritt ◽  
Magali Noval Rivas ◽  
James M. Krieger ◽  
Asli Beyza Ozdemir ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Enterotoxin B

scholarly journals A monoclonal antibody against staphylococcal enterotoxin B superantigen inhibits SARS-CoV-2 entry in vitro

2020 ◽  
Author(s):  
Mary Hongying Cheng ◽  
Rebecca A. Porritt ◽  
Magali Noval Rivas ◽  
James M Krieger ◽  
Asli Beyza Ozdemir ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cleavage Site ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Furin Cleavage ◽  
Furin Cleavage Site ◽  
Enterotoxin B ◽  
Human Coronaviruses ◽  
Inflammatory Syndrome

AbstractWe recently discovered a superantigen-like motif, similar to Staphylococcal enterotoxin B (SEB), near the S1/S2 cleavage site of SARS-CoV-2 Spike protein, which might explain the multisystem-inflammatory syndrome (MIS-C) observed in children and cytokine storm in severe COVID-19 patients. We show here that an anti-SEB monoclonal antibody (mAb), 6D3, can bind this viral motif, and in particular its PRRA insert, to inhibit infection by blocking the access of host cell proteases, TMPRSS2 or furin, to the cleavage site. The high affinity of 6D3 for the furin-cleavage site originates from a poly-acidic segment at its heavy chain CDR2, a feature shared with SARS-CoV-2-neutralizing mAb 4A8. The affinity of 6D3 and 4A8 for this site points to their potential utility as therapeutics for treating COVID-19, MIS-C, or common cold caused by human coronaviruses (HCoVs) that possess a furin-like cleavage site.

scholarly journals Memory T cells are anergic to the superantigen staphylococcal enterotoxin B.

1992 ◽  
Vol 176 (2) ◽  
pp. 575-579 ◽  
Author(s):  
W T Lee ◽  
E S Vitetta
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Staphylococcal Enterotoxin ◽  
Peripheral Tolerance ◽  
Staphylococcal Enterotoxin B ◽  
Enterotoxin B

We have used staphylococcal enterotoxin B (SEB) to study the role of naive and memory T cells in the induction of peripheral tolerance. After administration of SEB to mice, the numbers of naive and memory T cells increase, as does the proportion of memory T cells, which are unresponsive to further stimulation with SEB in vitro. In addition, memory T cells generated in response to conventional antigen, which proliferate and provide help to B cells in the presence of the conventional antigen, fail to respond to superantigen. Hence, memory T cells, in general, are anergized by SEB. These results suggest that SEB-induced activation and anergy reflect the combined responses of naive and memory T cells. The differential activation vs. anergy of naive and memory T cells by superantigen may be related to cytokine production and may play an important role in the etiology of autoimmune diseases or immunodeficiency diseases such as acquired immune deficiency syndrome.

scholarly journals Induction of unresponsiveness and impaired T cell expansion by staphylococcal enterotoxin B in CD28-deficient mice.

1996 ◽  
Vol 183 (6) ◽  
pp. 2481-2488 ◽  
Author(s):  
H W Mittrücker ◽  
A Shahinian ◽  
D Bouchard ◽  
T M Kündig ◽  
T W Mak
Keyword(s):  
T Cells ◽  
T Cell ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Rapid Induction ◽  
Cd28 Costimulation ◽  
Enterotoxin B ◽  
Deficient Mice

We used CD28-deficient mice to analyze the importance of CD28 costimulation for the response against Staphylococcal enterotoxin B (SEB) in vivo. CD28 was necessary for the strong expansion of V beta 8+ T cells, but not for deletion. The lack of expansion was not due to a failure of SEB to activate V beta 8+ T cells, as V beta 8+ T cells from both CD28-/- and CD28+/+ mice showed similar phenotypic changes within the first 24 h after SEB injection and cell cycle analysis showed that an equal percentage of V beta 8+ T cells started to proliferate. However, the phenotype and the state of proliferation of V beta 8+ T cells was different at later time points. Furthermore, in CD28-/- mice injection with SEB led to rapid induction of unresponsiveness in SEB responsive T cells, indicated by a drastic reduction of proliferation after secondary SEB stimulation in vitro. Unresponsiveness could also be demonstrated in vivo, as CD28-/- mice produced only marginal amounts of TNF alpha after rechallenge with SEB. In addition CD28-/- mice were protected against a lethal toxic shock induced by a second injection with SEB. Our results indicate that CD28 costimulation is crucial for the T cell-mediated toxicity of SEB and demonstrate that T cell stimulation in the absence of CD28 costimulation induces unresponsiveness in vivo.

scholarly journals Pirfenidone Blocks the In Vitro and In Vivo Effects of Staphylococcal Enterotoxin B

2002 ◽  
Vol 70 (6) ◽  
pp. 2989-2994 ◽  
Author(s):  
Martha L. Hale ◽  
Solomon B. Margolin ◽  
Teresa Krakauer ◽  
Chad J. Roy ◽  
Bradley G. Stiles
Keyword(s):  
Human Peripheral Blood ◽  
Biological Effects ◽  
Interleukin 1 ◽  
Staphylococcal Enterotoxin ◽  
Sublethal Dose ◽  
Staphylococcal Enterotoxin B ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Enterotoxin B

ABSTRACT Pirfenidone [5-methyl-1-phenyl-2-(1H)-pyridone] down-regulates expression of cytokines and other mediators involved in the onset and development of pulmonary fibrosis. Pirfenidone also inhibits production of tumor necrosis factor alpha (TNF-α) from macrophages incubated with endotoxin and protects mice against endotoxin shock. Pirfenidone's ability to reduce cytokine expression in these disorders led us to investigate the drug's effect on another cytokine anomaly, superantigen-induced shock. BALB/c mice were exposed to staphylococcal enterotoxin B (SEB) either systemically or by aerosol and subsequently potentiated with a sublethal dose of lipopolysaccharide. In these experiments, pirfenidone given 2 to 4.25 h after SEB resulted in 80 to 100% survival versus only 0 to 10% survival among untreated control animals. Relative to serum cytokine levels from controls given toxin but no drug, there was a 35 to 80% decrease in TNF-α, interleukin 1, and other proinflammatory cytokines. In vitro experiments with human peripheral blood lymphocytes revealed that pirfenidone reduced SEB-induced cytokine levels 50 to 80% and inhibited 95% of SEB-induced T-cell proliferation. Overall, these studies demonstrated the potential utility of pirfenidone as a therapeutic against septic shock and the biological effects of SEB.

scholarly journals Sublethal Staphylococcal Enterotoxin B Challenge Model in Pigs To Evaluate Protection following Immunization with a Soybean-Derived Vaccine

2012 ◽  
Vol 20 (1) ◽  
pp. 24-32 ◽  
Author(s):  
Laura C. Hudson ◽  
Brynn S. Seabolt ◽  
Jack Odle ◽  
Kenneth L. Bost ◽  
Chad H. Stahl ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Staphylococcal Enterotoxin ◽  
Sublethal Dose ◽  
Staphylococcal Enterotoxin B ◽  
Triple Mutant ◽  
Content Type ◽  
Vaccine Candidates ◽  
E Coli ◽  
Enterotoxin B

ABSTRACTIn an effort to develop a sustainable platform for manufacturing protein-based vaccine candidates, we expressed a triple mutant of staphylococcal enterotoxin B carrying the L45R, Y89A, and Y94A modifications in transgenic soybean seeds (soy-mSEB). Soy-mSEB possessed no detectable superantigen activityin vitro. We found that this soybean-derived, nontoxic mutant of SEB could be stably expressed, stored in seeds for extended periods at room temperature without degradation, and easily purified from contaminating soy proteins. Vaccination of pigs with purified soy-mSEB, or the identical triple mutant expressed inEscherichia coli(E. coli-mSEB), resulted in high antibody titers against the native toxin in immunized animals. In fact, titers were indistinguishable regardless of the immunogen used, demonstrating the equivalence of soy-mSEB andE. coli-mSEB vaccinations. Antisera from either immunized group were able to block native SEB superantigen activity in anin vitroneutralization assay. Similar results were obtained when immunized animals were challenged with a sublethal dose of native toxin. Significant reductions in toxin-induced serum cytokine levels were observed in soy-mSEB- andE. coli-mSEB-immunized pigs compared to control animals. The reductions in SEB-induced cytokine responses were similar regardless of the immunogen used for vaccination. Surprisingly, however, some clinical symptoms, such as prostration, lethargy, emesis, and/or diarrhea, were still observed in all immunized animals. These studies demonstrate the potential for soybean-derived proteins as a platform technology for sustainable vaccine manufacturing and the usefulness of a sublethal challenge model in pigs for evaluating the efficacy of potential SEB vaccine candidates.

scholarly journals Oral Vaccine Formulations Stimulate Mucosal and Systemic Antibody Responses against Staphylococcal Enterotoxin B in a Piglet Model

2010 ◽  
Vol 17 (8) ◽  
pp. 1163-1169 ◽  
Author(s):  
Tiffany K. Inskeep ◽  
Chad Stahl ◽  
Jack Odle ◽  
Judy Oakes ◽  
Laura Hudson ◽  
...  
Keyword(s):  
Subunit Vaccine ◽  
Human Subjects ◽  
Oral Vaccine ◽  
Staphylococcal Enterotoxin ◽  
Antibody Responses ◽  
Staphylococcal Enterotoxin B ◽  
Triple Mutant ◽  
Relevant Animal Model ◽  
Enterotoxin B

ABSTRACT Despite the potential for its use as an agent of biowarfare or bioterrorism, no approved vaccine against staphylococcal enterotoxin B (SEB) exists. Nontoxic, mutant forms of SEB have been developed; however, it has been difficult to determine the efficacy of such subunit vaccine candidates due to the lack of superantigen activity of native SEB in rodents and due to the limitations of primate models. Since pigs respond to SEB in a manner similar to that of human subjects, we utilized this relevant animal model to investigate the safety and immunogenicity of a triple mutant of SEB carrying the amino acid changes L45R, Y89A, and Y94A. This recombinant mutant SEB (rmSEB) did not possess superantigen activity in pig lymphocyte cultures. Furthermore, rmSEB was unable to compete with native SEB for binding to pig leukocytes. These in vitro studies suggested that rmSEB could be a safe subunit vaccine. To test this possibility, piglets immunized orally with rmSEB formulations experienced no significant decrease in food consumption and no weight loss during the vaccination regimen. Oral vaccination with 1-mg doses of rmSEB on days 0, 7, 14, and 24 resulted in serum IgG and fecal IgA levels by day 36 that cross-reacted with native SEB. Surprisingly, the inclusion of cholera toxin adjuvant in vaccine formulations containing rmSEB did not result in increased antibody responses compared to formulations using the immunogen alone. Taken together, these studies provide additional evidence for the potential use of nontoxic forms of SEB as vaccines.

scholarly journals Mycobacterium bovis BCG-Infected Mice Are More Susceptible to Staphylococcal Enterotoxin B-Mediated Toxic Shock than Uninfected Mice despite Reduced In Vitro Splenocyte Responses to Superantigens

2002 ◽  
Vol 70 (8) ◽  
pp. 4148-4157 ◽  
Author(s):  
João A. Pedras-Vasconcelos ◽  
Yvan Chapdelaine ◽  
Renu Dudani ◽  
Henk van Faassen ◽  
Dean K. Smith ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Strong Type ◽  
Ifn Γ ◽  
Enterotoxin B

ABSTRACT Type 1 T-cell responses against intracellular pathogens play a crucial role in mediating protection. We examined whether the induction of a strong type 1 T-cell response during a chronic bacterial infection influences responses to superantigens capable of inducing acute shock. Intravenous infection of mice with Mycobacterium bovis BCG appeared to induce a progressive anergy towards staphylococcal enterotoxin B (SEB) and towards antigen preparation of BCG (BCG-Ag) itself, based on diminished gamma interferon (IFN-γ) production by SEB- and BCG-Ag-stimulated splenocytes from infected mice. In contrast to these in vitro results, injection of SEB into BCG-infected mice led to a dramatic increase in the serum IFN-γ levels and the death of infected but not of control mice. In vitro hyporesponsiveness towards SEB and BCG-Ag occurred only with unfractionated splenocyte cultures, as purified T cells from infected mice produced higher levels of IFN-γ. Hyporesponsiveness towards SEB and BCG-Ag in unfractionated splenocyte cultures was not due to suppressive antigen-presenting cells (APCs), as APCs from infected mice stimulated higher levels of IFN-γ from purified T cells. The diminished IFN-γ levels observed with bulk splenocytes appear to be due to changes in the T-cell-to-APC ratio that result in a decreased proportion of T cells, coupled to reduced proliferative responses and an increased susceptibility of effector T cells to activation-induced cell death in vitro. Our results indicate that the reported phenomena of T-cell anergy during mycobacterial infection may be an in vitro consequence of the development of a strong type 1 response in vivo.

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