| dc.description.abstract | This dissertation describes research aimed at understanding the role of two key virulence factors, TcsL and NanS, in Paeniclostridium sordellii infection (PSI). P. sordellii is a bacterium capable of causing uterine infections in post-partum women. While PSI in humans is rare, it is typically fatal. Once identified, antibiotics can be used to eradicate the bacteria, but these are not effective at neutralizing the secreted TcsL lethal toxin that can cause a treatment-refractory toxic shock syndrome. Since TcsL shares 76% sequence identity with Clostridioides difficile toxin B (TcdB), we reasoned that a neutralizing monoclonal antibody (mAB) against TcdB might also provide protection against TcsL and the severe outcomes of PSI. To determine the efficacy of two C. difficile TcdB mABs, PA41 and CDB1, we first established a non-surgical, uterine infection model in mice and made the discovery that disease symptoms varied with the reproductive cycle of the animals. In this model, PA41 showed efficacy in protecting against TcsL, but CDB1 did not. Furthermore, PA41 could provide protection following P. sordellii spore infections, suggesting a path for further optimization and clinical translation in the effort to advance treatment options for PSI. Although TcsL is the essential virulence factor for lethal PSI, the physiological role of NanS, a sialidase, remained elusive. We show in vitro that NanS works in a synergistic manner with TcsL to increase cytotoxicity and cell rounding of tissue culture cells. Using our uterine mouse model, we show that the co-presence of purified NanS results in significant TcsL-induced lethality in mice, suggesting NanS can work synergistically with TcsL to exacerbate P. sordellii-mediated disease. | |
