Paeniclostridium sordellii uterine infection is dependent on the estrous cycle

Abstract

Human infections caused by the toxin-producing, anaerobic and spore-forming bacterium Paeniclostridium sordellii are associated with a treatment-refractory toxic shock syndrome (TSS). Reproductive-age women are at increased risk for P. sordellii infection (PSI) because this organism can cause intrauterine infection following childbirth, stillbirth, or abortion. PSI-induced TSS in this setting is nearly 100% fatal, and there are no effective treatments. TcsL, or lethal toxin, is the primary virulence factor in PSI and shares 70% sequence identity with Clostridioides difficile toxin B (TcdB). We therefore reasoned that a neutralizing monoclonal antibody (mAB) against TcdB might also provide protection against TcsL and PSI. We characterized two anti-TcdB mABs: PA41, which binds and prevents translocation of the TcdB glucosyltransferase domain into the cell, and CDB1, a biosimilar of bezlotoxumab, which prevents TcdB binding to a cell surface receptor. Both mABs could neutralize the cytotoxic activity of recombinant TcsL on Vero cells. To determine the efficacy of PA41 and CDB1 in vivo, we developed a transcervical inoculation method for modeling uterine PSI in mice. In the process, we discovered that the stage of the mouse reproductive cycle was a key variable in establishing symptoms of disease. By synchronizing the mice in diestrus with progesterone prior to transcervical inoculation with TcsL or vegetative P. sordellii, we observed highly reproducible intoxication and infection dynamics. PA41 showed efficacy in protecting against toxin in our transcervical in vivo model, but CDB1 did not. Furthermore, PA41 could provide protection following P. sordellii bacterial and spore infections, suggesting a path for further optimization and clinical translation in the effort to advance treatment options for PSI infection.