{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T15:04:51Z","timestamp":1780499091375,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010997","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T00:00:00Z","timestamp":1670198400000}}],"reference-count":19,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T00:00:00Z","timestamp":1668988800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32 AI007281"],"award-info":[{"award-number":["T32 AI007281"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013017","name":"Vanderbilt University Medical Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013017","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI095755"],"award-info":[{"award-number":["AI095755"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["BX002943"],"award-info":[{"award-number":["BX002943"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30DK058404"],"award-info":[{"award-number":["P30DK058404"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Human infections caused by the toxin-producing, anaerobic and spore-forming bacterium <jats:italic>Paeniclostridium sordellii<\/jats:italic> are associated with a treatment-refractory toxic shock syndrome (TSS). Reproductive-age women are at increased risk for <jats:italic>P<\/jats:italic>. <jats:italic>sordellii<\/jats:italic> 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 <jats:italic>Clostridioides difficile<\/jats:italic> 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 <jats:italic>in vivo<\/jats:italic>, 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 <jats:italic>P<\/jats:italic>. <jats:italic>sordellii<\/jats:italic>, we observed highly reproducible intoxication and infection dynamics. PA41 showed efficacy in protecting against toxin in our transcervical <jats:italic>in vivo<\/jats:italic> model, but CDB1 did not. Furthermore, PA41 could provide protection following <jats:italic>P<\/jats:italic>. <jats:italic>sordellii<\/jats:italic> bacterial and spore infections, suggesting a path for further optimization and clinical translation in the effort to advance treatment options for PSI infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010997","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T18:52:56Z","timestamp":1669056776000},"page":"e1010997","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Paeniclostridium sordellii uterine infection is dependent on the estrous cycle"],"prefix":"10.1371","volume":"18","author":[{"given":"Sarah C.","family":"Bernard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Kay","family":"Washington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2273-8121","authenticated-orcid":true,"given":"D. Borden","family":"Lacy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"ppat.1010997.ref001","article-title":"Clostridium sordellii Infection: Epidemiology, Clinical Findings, and Current Perspectives on Diagnosis and Treatment","author":"MJ Aldape","year":"2006","journal-title":"Clin Infect Dis"},{"key":"ppat.1010997.ref002","article-title":"Lethal toxin is a critical determinant of rapid mortality in rodent models of Clostridium sordellii endometritis","author":"Y Hao","year":"2010","journal-title":"Anaerobe"},{"key":"ppat.1010997.ref003","article-title":"TcsL is an essential virulence factor in Clostridium sordellii ATCC 9714","author":"GP Carter","year":"2011","journal-title":"Infect Immun"},{"key":"ppat.1010997.ref004","article-title":"A neutralizing antibody that blocks delivery of the enzymatic cargo of clostridium difficile toxin TcdB into host cells","author":"HK Kroh","year":"2018","journal-title":"J Biol Chem"},{"key":"ppat.1010997.ref005","article-title":"Protection against clostridium difficile infection with broadly neutralizing antitoxin monoclonal antibodies","author":"AJ Marozsan","year":"2012","journal-title":"J Infect Dis"},{"key":"ppat.1010997.ref006","article-title":"Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography","author":"P Orth","year":"2014","journal-title":"J Biol Chem"},{"key":"ppat.1010997.ref007","article-title":"Bezlotoxumab for Preventing Recurrent Clostridium difficile Infections","author":"J Rounds","year":"2017","journal-title":"S D Med"},{"key":"ppat.1010997.ref008","article-title":"Purification and characterization of Clostridium sordellii lethal toxin and cross-reactivity with Clostridium difficile cytotoxin","author":"MR Popoff","year":"1987","journal-title":"Infect Immun"},{"key":"ppat.1010997.ref009","article-title":"Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability","author":"B Geny","year":"2007","journal-title":"Am J Pathol"},{"key":"ppat.1010997.ref010","article-title":"Misoprostol Impairs Female Reproductive Tract Innate Immunity against Clostridium sordellii","author":"DM Aronoff","year":"2008","journal-title":"J Immunol"},{"key":"ppat.1010997.ref011","article-title":"Use of a neutralizing antibody helps identify structural features critical for binding of Clostridium difficile toxin TcdA to the host cell surface","author":"HK Kroh","year":"2017","journal-title":"J Biol Chem"},{"key":"ppat.1010997.ref012","article-title":"Structural basis for CSPG4 as a receptor for TcdB and a therapeutic target in Clostridioides difficile infection","author":"P Chen","year":"2021","journal-title":"Nat Commun"},{"key":"ppat.1010997.ref013","article-title":"Genome-Wide CRISPR Screen Identifies Semaphorin 6A and 6B as Receptors for Paeniclostridium sordellii Toxin TcsL","author":"S Tian","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ppat.1010997.ref014","article-title":"Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins","author":"H Lee","year":"2020","journal-title":"Cell"},{"key":"ppat.1010997.ref015","article-title":"The reproductive cycle is a pathogenic determinant during gonococcal pelvic inflammatory disease in mice","author":"EA Islam","year":"2016","journal-title":"Mucosal Immunol"},{"key":"ppat.1010997.ref016","article-title":"Effects of estradiol and progesterone on susceptibility and early immune responses to Chlamydia trachomatis infection in the female reproductive tract","author":"C Kaushic","year":"2000","journal-title":"Infect Immun"},{"key":"ppat.1010997.ref017","article-title":"Progesterone Increases Susceptibility and Decreases Immune Responses to Genital Herpes Infection","author":"C Kaushic","year":"2003","journal-title":"J Virol"},{"key":"ppat.1010997.ref018","article-title":"Inositol hexakisphosphate-dependent processing of Clostridium sordellii lethal toxin and Clostridium novyi \u03b1-toxin","author":"G Guttenberg","year":"2011","journal-title":"J Biol Chem"},{"key":"ppat.1010997.ref019","article-title":"Mouse estrous cycle identification tool and images","author":"SL Byers","year":"2012","journal-title":"PLoS One"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1010997","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T00:00:00Z","timestamp":1670198400000}}],"container-title":["PLOS 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