In Vivo Models to Evaluate Toxin Neutralizing Therapies to Protect Against Systemic Shiga Toxicosis
Dougherty, Morgan M.
2023
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Shiga toxin (Stx)-producing Escherichia coli (STEC) is involved in cases of foodborne illness across the world and can lead to serious complications such as hemolytic uremic syndrome (HUS). This can cause profound damage on the kidneys and gastrointestinal tract, is potentially fatal, and untreatable. The Tzipori and Shoemaker labs have developed a strategy using a camelid antibody heavy-chain-only ... read moreVH domain (VHH) to create a VHH tetramer that neutralizes Stx1 and Stx2 in mice and protects them from toxicosis. The VHH tetramer is encoded in replicon mRNA (mRNA 747) and delivered by lipid organic nanoparticles (LION). We previously found that when mRNA 747 is administered to mice 24 hours before lethal Stx2a challenge, it is protective against systemic toxicosis. Here instead of directly administering the toxin, we used Citrobacter rodentium (CR), a natural murine pathogen, engineered to express Stx2d to evaluate the efficacy of mRNA 747 against this variant. Intramuscular (IM) injection of mRNA 747 given 6 days after inoculation with CR-Stx protected against systemic intoxication in 4 of 5 male mice and 5 of 10 total mice demonstrating that the VHH tetramer was protective in male mice but not female mice when given at that timepoint. However, IM injection of mRNA 747 given 4 days after inoculation with CR-Stx protected against systemic intoxication in female mice as the probability of survival in the days post-inoculation with CR-Stx was significantly greater in female mice that were treated with mRNA 747 compared with the untreated female mice. In conclusion, the VHH tetramer is effective in protecting mice from fatal systemic intoxication after challenge with CR-producing Stx2d. Overall, the effectiveness of the VHH tetramer at neutralizing Stx2a and Stx2d open possibilities for it to eventually be a treatment option for patients with STEC-induced HUS.
Cummings School of Veterinary Medicine Student Summer Research 2023.read less - ID:
- n583z846b
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