Research Article: Histamine release from intestinal mast cells induced by staphylococcal enterotoxin A (SEA) evokes vomiting reflex in common marmoset

Date Published: May 21, 2019

Publisher: Public Library of Science

Author(s): Hisaya K. Ono, Shouhei Hirose, Kouji Narita, Makoto Sugiyama, Krisana Asano, Dong-Liang Hu, Akio Nakane, Ambrose Cheung.


Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus are known as causative agents of emetic food poisoning. We previously demonstrated that SEA binds with submucosal mast cells and evokes mast cell degranulation in a small emetic house musk shrew model. Notably, primates have been recognized as the standard model for emetic assays and analysis of SE emetic activity. However, the mechanism involved in SEA-induced vomiting in primates has not yet been elucidated. In the present study, we established common marmosets as an emetic animal model. Common marmosets were administered classical SEs, including SEA, SEB and SEC, and exhibited multiple vomiting responses. However, a non-emetic staphylococcal superantigen, toxic shock syndrome toxin-1, did not induce emesis in these monkeys. These results indicated that the common marmoset is a useful animal model for assessing the emesis-inducing activity of SEs. Furthermore, histological analysis uncovered that SEA bound with submucosal mast cells and induced mast cell degranulation. Additionally, ex vivo and in vivo pharmacological results showed that SEA-induced histamine release plays a critical role in the vomiting response in common marmosets. The present results suggested that 5-hydroxytryptamine also plays an important role in the transmission of emetic stimulation on the afferent vagus nerve or central nervous system. We conclude that SEA induces histamine release from submucosal mast cells in the gastrointestinal tract and that histamine contributes to the SEA-induced vomiting reflex via the serotonergic nerve and/or other vagus nerve.

Partial Text

Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus (S. aureus) have emetic activity and are causative agents of bacterial food poisoning. The primary symptoms of staphylococcal food poisoning include nausea, abdominal cramping and vomiting, which develop up to 1–6 h after ingestion of the causative foods contaminated with S. aureus [1]. In 1930, Dack et al. showed that staphylococcal food poisoning is not due to S. aureus cells, but caused by intoxication with SEs in the contaminated foods [2]. These toxins are also superantigens, which have the ability to activate a large amount of T cells [3]. These emetic and superantigenic activities make SEs a public health concern. Five major serological types of SEs (SEA to SEE), so-called “classical SEs”, have been characterized [3]. Notably, new types of SEs and SE-like toxins (SEG to SElV, SElX and SElY) have also been reported [3–10]. Although the mechanism of superantigenic activity and the amino acid residues in the active site of SEs have been clarified, the exact molecular and cellular mechanisms of their emetic activity still remain unclear. We have previously elucidated the mechanism of SEA-induced emesis using a small emetic animal model, house musk shrew (Suncus murinus) model. This study has revealed shown that SEA binds with submucosal mast cells and evokes mast cell degranulation [11]. We also have demonstrated that 5-hydroxytryptamine (5-HT) is a key molecule in SEA-induced emesis in house musk shrews [12]. Notably, the primates have been recognized as the standard model for detecting the emetic activity of SEs [13, 14]. Therefore, it is necessary to conduct experiments in a primate model. However, the high cost and limited availability of primates have led to a reduction in the investigation of SE-induced emesis using this model.

The mechanism of SEA-induced vomiting has not been fully elucidated in primates [2]. To investigate this mechanism, we established the common marmoset as an emetic animal model. In the present study, we showed that vomiting was induced in the common marmosets by orogastric intubation of SEs, including classical SEs and recently identified SEs (Table 1). However, none of common marmosets administered with TSST-1 or PBS exhibited an emetic reaction (Table 1). Notably, PBMCs of common marmosets were susceptible to the superantigenic activity of SEs (Fig 1). These results are consistent with responses of human and other emetic animal models [6, 11–13, 18–21]. Although TSST-1 has the highest toxicity to humans among the superantigens, the present study showed that the superantigenic activity of TSST-1 against common marmosets was markedly lower than that against humans. The results suggest the possibility that major histocompatibility complex and/or T cell receptors of common marmosets have low binding affinity to TSST-1. Furthermore, our results indicated that SEI displayed weak emetic activity but was strongly superantigenic. These SEI properties provide information that there is no complete relationship between emetic activity and superantigenic activity. This observation correlates with the data from Harris et al. and Schlievert et al. which have shown the separation of emesis from superantigenic activity [22, 23]. Our previous report indicated that 5 out of 10 cynomolgus monkeys administered 10 μg/kg of SEA, and 6 out of 7 cynomolgus monkeys that had ingested 100 μg/kg of SEA exhibited vomiting responses [21]. We also reported that house musk shrews could be used as a small emetic animal model and that shrews were highly sensitive to SEA in the initial report (32 μg/kg, orogastric administration) [19]. However, our recent study showed that house musk shrews required a larger amount of SEA (1.4–2.0 mg/kg of body weight) to promote emesis, indicating a decreased susceptibility of shrews to SEA [24]. Therefore, it was assumed that the marmosets used in the present study showed almost the same sensitivity to SEA as cynomolgus monkeys. As the body weight of common marmosets was markedly low (approximately 0.3 kg), a lower amount of toxins was required compared with cynomolgus monkeys (1.4–2.0 kg). Furthermore, the complete genome sequences and transgenic marmosets have been reported [25, 26]. Hence, the common marmoset may be a useful animal model for detection and analysis of SEs.




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