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Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins

Tor C Savidge1, Petri Urvil, Numan Oezguen

  • 1Department of Gastroenterology & Hepatology, University of Texas Medical Branch, Galveston, Texas, USA. tcsavidg@utmb.edu

Nature Medicine
|August 23, 2011
PubMed

Insights

Host nitric oxide (NO) protects against Clostridium difficile toxins by S-nitrosylation, inhibiting toxin activity. Inositol hexakisphosphate (InsP6) enhances this innate immunity, offering new therapeutic strategies for C. difficile infection.

Area of Science:

  • Microbiology
  • Immunology
  • Biochemistry

Background:

  • Severe Clostridium difficile infection is a significant global health concern, driven by potent glucosylating toxins.
  • Toxin virulence relies on autoactivation of a cysteine protease, facilitated by inositol hexakisphosphate (InsP6).
  • Host defense mechanisms against bacterial exotoxins are not fully understood, though nitric oxide (NO) plays a role in immunity via S-nitrosylation.

Purpose of the Study:

  • To investigate host mechanisms for combating C. difficile toxins.
  • To explore the role of nitric oxide (NO) and S-nitrosylation in C. difficile toxin regulation.
  • To assess the therapeutic potential of S-nitrosothiols and InsP6 in C. difficile infection models.

Main Methods:

  • Analysis of C. difficile toxin S-nitrosylation in infected hosts.
  • Investigating the impact of S-nitrosylation on toxin self-cleavage and cell entry.
  • Utilizing mouse models to evaluate the efficacy of exogenous InsP6 and S-nitrosothiols as treatments.

Main Results:

  • C. difficile toxins are S-nitrosylated by the host, which inhibits their virulence.
  • InsP6 and inositol pyrophosphate (InsP7) facilitate host S-nitrosothiols to modify the toxin's catalytic cysteine.
  • Exogenous InsP6 amplified the therapeutic effect of oral S-nitrosothiols in mouse models of C. difficile infection.

Conclusions:

  • Host S-nitrosylation serves as an innate immune defense against C. difficile toxins.
  • Exploiting allosteric regulation of bacterial proteins, like C. difficile toxins, can lead to novel therapeutic strategies.
  • Nitrosothiol-based therapies, potentially enhanced by InsP6, show promise for treating C. difficile infections.

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