Takehiko Uchiyama

Emetic Potentials of Newly Identified Staphylococcal Enterotoxin-Like Toxins

ABSTRACT Staphylococcal enterotoxins (SEs) are a common causative agent of food poisoning. Recently, many new SE-like (SEl) toxins have been reported, although the role of SEls in food poisoning remains unclear. In this study, the emetic potentials of SElK, SElL, SElM, SElN, SElO, SElP, and SElQ were assessed using a monkey-feeding assay. All the SEls that were tested induced emetic reactions in monkeys at a dose of 100 μg/kg, although the numbers of affected monkeys were significantly smaller than the numbers that were affected after consuming SEA or SEB. This result suggests that these new SEs may play some role in staphylococcal food poisoning.

Long-term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation

Bacterial infection has become a focus of attention in the pathogenesis of primary biliary cirrhosis (PBC). We earlier reported that the bacterial lipoteichoic acid was detected at the sites of inflammation around damaged bile ducts in the livers of PBC, and PBC patients sera showed high titers against streptococcal histone-like protein. Here, we investigated whether chronic bacterial exposure could trigger PBC-like epithelial cell damage in normal mouse. BALB/c mice were repeatedly inoculated with various bacteria for 8 weeks. At 1 week (Group 1) and 3, 4, or 20 months (long term; Group 2) after the final inoculation, mice were killed to obtain samples. In the livers of the Streptococcus intermedius (S.i.)-inoculated mice in Group 1, cellular infiltration was predominantly observed around the bile ducts over the hepatic parenchyma. In the S.i.-inoculated mice in Group 2, portal but not parenchymal inflammation was observed in the livers, and periductal cellular infiltrates were detected in the salivary glands. Both S.i.-inoculated Groups 1 and 2 BALB/c mice sera had antibodies against HuCCT1 biliary epithelial cells, anti-nuclear antibodies, and anti-gp210 antibodies, but not anti-mitochondrial antibodies. Immunoreactivity to histone-like DNA-binding protein of S.i. (S.i.-HLP) was detectable around the sites of chronic nonsuppurative destructive cholangitis in the portal area in the livers of both S.i.-inoculated Groups 1 and 2 BALB/c mice. Furthermore, anti-S.i.-HLP antibody bound to synthetic gp210 peptide, as well. Bacteria triggered PBC-like cholangitis, multifocal epithelial inflammation, and autoantibody production. Bacteria are likely involved in the pathogenesis of PBC and of associated multifocal epithelial inflammation.

CHAPTER 50 – Staphylococcal superantigens and the diseases they cause

Seventeen years have passed since the superantigen (SAG) concept was proposed for several exotoxins from Staphylococcus aureus (S. aureus), such as toxic shock syndrome (TSS) toxin-1 (TSST-1) and enterotoxin A (SEA) and B (SEB). Recently, staphylococcal and streptococcal species other than S. aureus and S. pyogenes were also reported to produce SAGs. To date, approximately 30 bacterial SAGs have been identified. A remarkable biological feature of SAGs is their capacity to stimulate T cells in vast numbers in a T cell receptor (TCR) Vβ element-specific manner in direct association with MHC class II molecules on antigen-presenting cells (APCs). This chapter reviews the progress in research into newstaphylococcal SAGs and the infectious diseases they cause, focusing on pathogenic mechanisms and early definitive disease diagnosis. Some staphylococcal enterotoxins were originally identified as enterotoxins because of their emetic activity. The international nomenclature committee on staphylococcal SAGs has proposed that only toxins exhibiting emetic activity after oral administration in a primate model be designated staphylococcal enterotoxins. Other related toxins lacking emetic activity or as yet untested for this activity were recommended to be designated staphylococcal enterotoxin-like toxin type X (SEIX). Staphylococcal SAGs exhibit potent T cell-stimulating activities that are closely related to the pathogenic mechanisms of TSS and NTED.

Possible role of LECT2 as an intrinsic regulatory factor in SEA-induced toxicity in d-galactosamine-sensitized mice.

To elucidate whether leukocyte cell-derived chemotaxin 2 (LECT2) controls the progression of staphylococcal enterotoxin A (SEA)-induced toxicity, we examined the role of LECT2 in a mouse model. Almost all the C57BL/6J (B6) mice survived for 72 h after the injection of 0.1 μg of SEA and 20 mg of d-galactosamine (d-GalN). However, the same treatment protocol in LECT2(-/-) mice produced a high lethality (~90%), severe hepatic apoptosis, and massive hepatic and pulmonary hemorrhage, similar to the situation observed in B6 mice treated with 1.0 μg SEA/d-GalN. The plasma LECT2 levels in B6 mice treated with 1.0 μg SEA/d-GalN were inversely correlated with the plasma cytokine levels and were associated with prognosis. LECT2 administration increased the survival of B6 mice and down-regulated TNF-α and IL-6. These results suggest the involvement of LECT2 in the regulation of fatal SEA-induced toxicity in d-GalN-sensitized mice.