An orally applicable Shiga toxin neutralizer functions in the intestine to inhibit the intracellular transport of the toxin.
Shiga toxin 2 (Stx2) is a major virulence factor in infections with Stx-producing Escherichia coli (STEC), which causes gastrointestinal diseases and sometimes fatal systemic complications. Recently, we developed an oral Stx2 inhibitor known as Ac-PPP-tet that exhibits remarkable therapeutic potency in an STEC infection model. However, the precise mechanism underlying the in vivo therapeutic effects of Ac-PPP-tet is unknown. Here, we found that Ac-PPP-tet completely inhibited fluid accumulation in the rabbit ileum caused by the direct injection of Stx2. Interestingly, Ac-PPP-tet accumulated in the ileal epithelial cells only through its formation of a complex with Stx2. The formation of Ac-PPP-tet-Stx2 complexes in cultured epithelial cells blocked the intracellular transport of Stx2 from the Golgi apparatus to the endoplasmic reticulum, a process that is essential for Stx2 cytotoxicity. Thus, Ac-PPP-tet is the first Stx neutralizer that functions in the intestine by altering the intracellular transport of Stx2 in epithelial cells.
Watanabe-Takahashi
Miho
M
Department of Molecular Life Sciences, Doshisha University, Tatara, Kyotanabe, Kyoto 610-0321, Japan.
Sato
Toshio
T
Dohi
Taeko
T
Noguchi
Noriko
N
Kano
Fumi
F
Murata
Masayuki
M
Hamabata
Takashi
T
Natori
Yasuhiro
Y
Nishikawa
Kiyotaka
K
D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D006801:Humans; D007082:Ileum / Q000378:metabolism* / Q000382:microbiology*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D046509:Tissue Culture Techniques
C546398:Ac-PPP-tet; D010455:Peptides; D022641:Shiga Toxin 2