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While Lpp activates Toll-like receptor 2, the MsbB acyltransferase modifies lipopolysaccharide. Here, we deleted the\n            <jats:italic>ail<\/jats:italic>\n            gene (encoding the\n            <jats:underline>a<\/jats:underline>\n            ttachment-\n            <jats:underline>i<\/jats:underline>\n            nvasion\n            <jats:underline>l<\/jats:underline>\n            ocus) from wild-type (WT) strain CO92 or its\n            <jats:italic>lpp<\/jats:italic>\n            single and \u0394\n            <jats:italic>lpp<\/jats:italic>\n            \u0394\n            <jats:italic>msbB<\/jats:italic>\n            double mutants. While the \u0394\n            <jats:italic>ail<\/jats:italic>\n            single mutant was minimally attenuated compared to the WT bacterium in a mouse model of pneumonic plague, the \u0394\n            <jats:italic>lpp<\/jats:italic>\n            \u0394\n            <jats:italic>ail<\/jats:italic>\n            double mutant and the \u0394\n            <jats:italic>lpp<\/jats:italic>\n            \u0394\n            <jats:italic>msbB<\/jats:italic>\n            \u0394\n            <jats:italic>ail<\/jats:italic>\n            triple mutant were increasingly attenuated, with the latter being unable to kill mice at a 50% lethal dose (LD\n            <jats:sub>50<\/jats:sub>\n            ) equivalent to 6,800 LD\n            <jats:sub>50<\/jats:sub>\n            s of WT CO92. The mutant-infected animals developed balanced T\n            <jats:sub>H<\/jats:sub>\n            1- and T\n            <jats:sub>H<\/jats:sub>\n            2-based immune responses based on antibody isotyping. The triple mutant was cleared from mouse organs rapidly, with concurrent decreases in the production of various cytokines and histopathological lesions. When surviving animals infected with increasing doses of the triple mutant were subsequently challenged on day 24 with the bioluminescent WT CO92 strain (20 to 28 LD\n            <jats:sub>50<\/jats:sub>\n            s), 40 to 70% of the mice survived, with efficient clearing of the invading pathogen, as visualized in real time by\n            <jats:italic>in vivo<\/jats:italic>\n            imaging. The rapid clearance of the triple mutant, compared to that of WT CO92, from animals was related to the decreased adherence and invasion of human-derived HeLa and A549 alveolar epithelial cells and to its inability to survive intracellularly in these cells as well as in MH-S murine alveolar and primary human macrophages. An early burst of cytokine production in macrophages elicited by the triple mutant compared to WT CO92 and the mutant's sensitivity to the bactericidal effect of human serum would further augment bacterial clearance. Together, deletion of the\n            <jats:italic>ail<\/jats:italic>\n            gene from the \u0394\n            <jats:italic>lpp<\/jats:italic>\n            \u0394\n            <jats:italic>msbB<\/jats:italic>\n            double mutant severely attenuated\n            <jats:named-content content-type=\"genus-species\">Y. pestis<\/jats:named-content>\n            CO92 to evoke pneumonic plague in a mouse model while retaining the required immunogenicity needed for subsequent protection against infection.\n          <\/jats:p>","DOI":"10.1128\/iai.02778-14","type":"journal-article","created":{"date-parts":[[2015,1,21]],"date-time":"2015-01-21T06:01:14Z","timestamp":1421820074000},"page":"1318-1338","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":26,"title":["Combinational Deletion of Three Membrane Protein-Encoding Genes Highly Attenuates Yersinia pestis while Retaining Immunogenicity in a Mouse Model of Pneumonic Plague"],"prefix":"10.1128","volume":"83","author":[{"given":"Bethany L.","family":"Tiner","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Sha","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Kirtley","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana E.","family":"Erova","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vsevolod L.","family":"Popov","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wallace B.","family":"Baze","sequence":"additional","affiliation":[{"name":"Department of Veterinary Sciences, University of Texas M. 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Anderson Cancer Center, Bastrop, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina J.","family":"van Lier","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duraisamy","family":"Ponnusamy","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jourdan A.","family":"Andersson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir L.","family":"Motin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadhana","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok K.","family":"Chopra","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/182051"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.10.1.35"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60566-2"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408026101"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.24.14043"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2000.01993.x"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2011.06.119"},{"key":"e_1_3_3_9_2","volume-title":"Protecting the American public by ensuring safe and secure possession, use, and transfer of select agents and toxins that pose a threat to public health","author":"Centers for Disease Control and Prevention","year":"2008","unstructured":"Centers for Disease Control and Prevention. 17 November 2008. 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