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While some individuals are asymptomatic\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    carriers, symptomatic disease ranges from mild diarrhea to potentially lethal toxic megacolon. The wide disease spectrum has been attributed to the infected host\u2019s age, underlying diseases, immune status, and microbiome composition. However, strain-specific differences in\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    virulence have also been implicated in determining colitis severity. Because patients infected with\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    are unique in terms of medical history, microbiome composition, and immune competence, determining the relative contribution of\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    virulence to disease severity has been challenging, and conclusions regarding the virulence of specific strains have been inconsistent. To address this, we used a mouse model to test 33 clinical\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    strains isolated from patients with disease severities ranging from asymptomatic carriage to severe colitis, and we determined their relative\n                    <jats:italic>in vivo<\/jats:italic>\n                    virulence in genetically identical, antibiotic-pretreated mice. We found that murine infections with\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    clade 2 strains (including multilocus sequence type 1\/ribotype 027) were associated with higher lethality and that\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    strains associated with greater human disease severity caused more severe disease in mice. While toxin production was not strongly correlated with\n                    <jats:italic>in vivo<\/jats:italic>\n                    colonic pathology, the ability of\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    strains to grow in the presence of secondary bile acids was associated with greater disease severity. Whole-genome sequencing and identification of core and accessory genes identified a subset of accessory genes that distinguish high-virulence from lower-virulence\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    strains.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    <jats:italic>Clostridium difficile<\/jats:italic>\n                    is an important cause of hospital-associated intestinal infections, and recent years have seen an increase in the number and severity of cases in the United States. A patient\u2019s antibiotic history, immune status, and medical comorbidities determine, in part, the severity of\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    infection. The relative virulence of different clinical\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    strains, although postulated to determine disease severity in patients, has been more difficult to consistently associate with mild versus severe colitis. We tested 33 distinct clinical\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    isolates for their ability to cause disease in genetically identical mice and found that\n                    <jats:italic>C.\u00a0difficile<\/jats:italic>\n                    strains belonging to clade 2 were associated with higher mortality. Differences in survival were not attributed to differences in toxin production but likely resulted from the distinct gene content in the various clinical isolates.\n                  <\/jats:p>","DOI":"10.1128\/mbio.00885-17","type":"journal-article","created":{"date-parts":[[2017,8,8]],"date-time":"2017-08-08T20:10:14Z","timestamp":1502223014000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":62,"title":["Pathogenicity Locus, Core Genome, and Accessory Gene Contributions to\n                    <i>Clostridium difficile<\/i>\n                    Virulence"],"prefix":"10.1128","volume":"8","author":[{"given":"Brittany B.","family":"Lewis","sequence":"first","affiliation":[{"name":"Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA"},{"name":"Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Carter","sequence":"additional","affiliation":[{"name":"Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilan","family":"Ling","sequence":"additional","affiliation":[{"name":"Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Leiner","sequence":"additional","affiliation":[{"name":"Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Taur","sequence":"additional","affiliation":[{"name":"Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA"},{"name":"Weill Cornell Medical College, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mini","family":"Kamboj","sequence":"additional","affiliation":[{"name":"Infection Control, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik R.","family":"Dubberke","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao","family":"Xavier","sequence":"additional","affiliation":[{"name":"Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric G.","family":"Pamer","sequence":"additional","affiliation":[{"name":"Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA"},{"name":"Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York, USA"},{"name":"Weill Cornell Medical College, New York, New York, USA"},{"name":"Immunology Program, Sloan-Kettering Institute, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408913"},{"key":"e_1_3_2_3_2","volume-title":"Antibiotic resistance threats in the United States, 2013","author":"CDC","year":"2013","unstructured":"CDC . 2013. 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