Paeniclostridium sordellii NanS works synergistically with TcsL to increase cytotoxicity and the severity of pathogenesis in the murine uterus

Paeniclostridium sordellii , a pathogen capable of causing lethal uterine infections post-partum or post-abortion, produces a variety of potential virulence factors. Lethal toxin (TcsL) has been found to be essential for lethal P. sordellii infections, but the physiological role of NanS, a sialidase, remains elusive. Here, we purify enzymatically active P. sordellii NanS and report the crystal structure. We show that NanS works in a synergistic manner with TcsL to increase cytotoxicity and cell rounding of tissue culture cells. Using a mouse model of hormone-dependent uterine intoxication, we show that NanS augments TcsL-induced lethality in diestrus mice. In estrus mice, the combination of NanS and TcsL significantly increases uterine histologic damage compared to challenge with TcsL alone. This suggests that NanS enhancement of TcsL-induced uterine epithelial injury may potentiate TcsL access to the tissue when mucus is present. Author Summary P. sordellii produces several proteins predicted to contribute to lethal uterine infections following childbirth, stillbirth, or abortion. The role of lethal toxin (TcsL) in causing lethal outcomes, has been well documented, but little is known of how NanS, a sialidase, contributes to disease development. Previous reports have suggested a role for NanS in increasing the tissue culture cell toxicity from P. sordellii supernatants. In this study, we show in cell culture and using a uterine mouse model that TcsL and NanS work together to increase cell cytotoxicity and to worsen disease outcome. This finding suggests an accessory role for NanS to enhance P. sordellii pathogenesis when host environmental conditions reduce the influence of TcsL.