Enhancement of pentylenetetrazole-induced seizures by Shigella dysenteriae in LPS-resistant C3H/HeJ mice: role of the host response.
Convulsions and encephalopathy are common complications of Shiga toxin (Stx)-producing Shigella and enterohemorrhagic Escherichia coli infections. In previous studies, we demonstrated that Stx and lipopolysaccharide (LPS) act in concert to enhance mice sensitivity to pentylenetetrazole (PTZ)-induced seizures via mechanisms involving tumor necrosis factor alpha (TNFalpha), interleukinl beta and nitric oxide. To further elucidate the role of the host response in Shigella-related seizures, we studied the ability of Shigella dysenteriae and its products to modulate seizures in C3H/HeJ (lps(d/d)) and in C3H/HeN (lps(n/n) mice. Injection of S. dysenteriae 60R sonicate elevated plasma TNFalpha and enhanced the convulsive response to PTZ in both mouse strains. Induced TNFalpha levels were markedly lower in LPS-hyporesponsive C3H/HeJ mice than in LPS- responsive C3H/HeN mice: 7.4 ng/ml vs 44 ng/ml (induced by 4LD50). Accordingly, a higher dose of S. dysenteriae sonicate was needed to sensitize the C3H/HeJ mice to seizures. Stx or LPS alone did not enhance seizures in either strain. Stx together with LPS enhanced seizures in LPS-responsive mice, but not in LPS-hyporesponsive mice in which they induced only a minor elevation in TNFalpha levels (1.5 ng/ml). As compared to LPS-responsive mice, the LPS-hyporesponsive mice were less susceptible to the lethal effects of Shigella sonicate and were resistant to the lethal effect of purified Stx with LPS. These results demonstrate the crucial role of the host response with regard to the sensitivity to to LPS, and specifically TNFalpha production, in Shigella lethality and Shigella-related seizures.
Yuhas
Yael
Y
Felsenstein Medical Research Center, Petah Tikva, Israel.
Nofech-Mozes
Yehuda
Y
Weizman
Abraham
A
Ashkenazi
Shai
S
D000818:Animals; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008809:Mice, Inbred C3H; D010433:Pentylenetetrazole; D012640:Seizures / Q000209:etiology*; D022621:Shiga Toxin / Q000633:toxicity; D012762:Shigella dysenteriae / Q000472:pathogenicity*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D022621:Shiga Toxin; D010433:Pentylenetetrazole