{"id":{"repo_id":"utmb","oai_identifier":"oai:utmb-ir.tdl.org:2152.3/11155"},"canonical_url":"https://search.dev.ndltd.org/etd/utmb/oai:utmb-ir.tdl.org:2152.3/11155","repository":{"repo_id":"utmb","name":"University of Texas Medical Branch","base_url":"https://utmb-ir.tdl.org/server/oai/request"},"display":{"title":"Novel Virulence Factors in the Pathogenesis of Yersinia pestis Infection, the Causative Agent of Plague","abstract":"Identification of new virulence factors in Yersinia pestis, the causative agent of plague, and understanding their molecular mechanisms during an infection process are necessary in designing a better vaccine or to formulate an appropriate therapeutic intervention. By using a high-throughput, signature-tagged mutagenic approach, we screened 5,088 mutants of Y. pestis CO92. From this screen, 118 clones showing impairment in disseminating to spleen were obtained. In a subsequent screen, 20/118 mutants exhibited attenuation when tested individually in a mouse model of bubonic plague, with 10/20 aforementioned mutants providing 40% or higher survival rates at an infectious dose of 40 LD50. Upon sequencing, six of the attenuated mutants carried interruptions in genes encoding hypothetical proteins or proteins with putative functions. In-frame deletion mutation of two of the genes identified from the screen were also found to exhibit some attenuation at 11-12 LD50 in a mouse model of pneumonic plague. Likewise, among the remaining 18 signature-tagged mutants, 9 were also attenuated (40-100%) at 12 LD50 in a pneumonic plague mouse model. Combinatorial deletions including the newly identified genes, rbsA and vasK, were significantly attenuated in pneumonic plague models. Interestingly, rbsA gene products have been associated with a highly conserved inter-bacterial signaling system mediated by autoinducer-2 (AI-2) quorum-sensing molecule. Deletion of the gene encoding the synthetic enzyme for AI-2 substrate, luxS, leads to either no change or, paradoxically, an increase in in vivo bacterial virulence. Deletion of rbsA and lsrA genes, ABC transport components interacting with AI-2, synergistically disrupted AI-2 signaling patterns and resulted in an over 50-fold decrease in Y. pestis CO92 virulence in a mouse model. Deletion of luxS from the ΔrbsAΔlsrA strain reverted the virulence phenotype similar to wild-type CO92. Administration of AI-2 in mice infected with the ΔrbsAΔlsrAΔluxS mutant strain attenuated this triple mutant. Role of AI-2 signaling genes that modulated bacterial virulence was determined by RNAseq. Characterization of AI-2 signaling in Y. pestis should lead to re-examination of AI-2 systems in other pathogens and may represent a broad-spectrum therapeutic target to combat antibiotic-resistant bacteria.","abstract_html":"Identification of new virulence factors in Yersinia pestis, the causative agent of plague, and understanding their molecular mechanisms during an infection process are necessary in designing a better vaccine or to formulate an appropriate therapeutic intervention. By using a high-throughput, signature-tagged mutagenic approach, we screened 5,088 mutants of Y. pestis CO92. From this screen, 118 clones showing impairment in disseminating to spleen were obtained. In a subsequent screen, 20/118 mutants exhibited attenuation when tested individually in a mouse model of bubonic plague, with 10/20 aforementioned mutants providing 40% or higher survival rates at an infectious dose of 40 LD50. Upon sequencing, six of the attenuated mutants carried interruptions in genes encoding hypothetical proteins or proteins with putative functions. In-frame deletion mutation of two of the genes identified from the screen were also found to exhibit some attenuation at 11-12 LD50 in a mouse model of pneumonic plague. Likewise, among the remaining 18 signature-tagged mutants, 9 were also attenuated (40-100%) at 12 LD50 in a pneumonic plague mouse model. Combinatorial deletions including the newly identified genes, rbsA and vasK, were significantly attenuated in pneumonic plague models. Interestingly, rbsA gene products have been associated with a highly conserved inter-bacterial signaling system mediated by autoinducer-2 (AI-2) quorum-sensing molecule. Deletion of the gene encoding the synthetic enzyme for AI-2 substrate, luxS, leads to either no change or, paradoxically, an increase in in vivo bacterial virulence. Deletion of rbsA and lsrA genes, ABC transport components interacting with AI-2, synergistically disrupted AI-2 signaling patterns and resulted in an over 50-fold decrease in Y. pestis CO92 virulence in a mouse model. Deletion of luxS from the ΔrbsAΔlsrA strain reverted the virulence phenotype similar to wild-type CO92. Administration of AI-2 in mice infected with the ΔrbsAΔlsrAΔluxS mutant strain attenuated this triple mutant. Role of AI-2 signaling genes that modulated bacterial virulence was determined by RNAseq. Characterization of AI-2 signaling in Y. pestis should lead to re-examination of AI-2 systems in other pathogens and may represent a broad-spectrum therapeutic target to combat antibiotic-resistant bacteria.","abstract_has_math":false,"creators":["Fitts, Eric Charles"],"institution":"The University of Texas Medical Branch at Galveston","degree_name":"Microbiology and Immunology (Doctoral)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Chopra, Ashok"],"committee_chairs":[],"committee_members":["Peterson, Johhny","Motin, Vladimir","Stevenson-Lerner, Heather","Lathem, Wyndham"],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T05:50:59Z","subjects":["Yersinia pestis","quorum sensing","autoinducer-2","virulence factor","luxS"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2152.3/11155","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Chopra, Ashok"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Peterson, Johhny","Motin, Vladimir","Stevenson-Lerner, Heather","Lathem, Wyndham"]},{"key":"dc:creator","label":"Author","values":["Fitts, Eric Charles"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2019-03-13T20:25:38Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2019-03-13T20:25:38Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Microbiology and Immunology (Doctoral)"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["The University of Texas Medical Branch at Galveston"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Yersinia pestis","quorum sensing","autoinducer-2","virulence factor","luxS"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/2152.3/11155"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Identification of new virulence factors in Yersinia pestis, the causative agent of plague, and understanding their molecular mechanisms during an infection process are necessary in designing a better vaccine or to formulate an appropriate therapeutic intervention. By using a high-throughput, signature-tagged mutagenic approach, we screened 5,088 mutants of Y. pestis CO92. From this screen, 118 clones showing impairment in disseminating to spleen were obtained. In a subsequent screen, 20/118 mutants exhibited attenuation when tested individually in a mouse model of bubonic plague, with 10/20 aforementioned mutants providing 40% or higher survival rates at an infectious dose of 40 LD50. Upon sequencing, six of the attenuated mutants carried interruptions in genes encoding hypothetical proteins or proteins with putative functions. In-frame deletion mutation of two of the genes identified from the screen were also found to exhibit some attenuation at 11-12 LD50 in a mouse model of pneumonic plague. Likewise, among the remaining 18 signature-tagged mutants, 9 were also attenuated (40-100%) at 12 LD50 in a pneumonic plague mouse model. Combinatorial deletions including the newly identified genes, rbsA and vasK, were significantly attenuated in pneumonic plague models. Interestingly, rbsA gene products have been associated with a highly conserved inter-bacterial signaling system mediated by autoinducer-2 (AI-2) quorum-sensing molecule. Deletion of the gene encoding the synthetic enzyme for AI-2 substrate, luxS, leads to either no change or, paradoxically, an increase in in vivo bacterial virulence. Deletion of rbsA and lsrA genes, ABC transport components interacting with AI-2, synergistically disrupted AI-2 signaling patterns and resulted in an over 50-fold decrease in Y. pestis CO92 virulence in a mouse model. Deletion of luxS from the ΔrbsAΔlsrA strain reverted the virulence phenotype similar to wild-type CO92. Administration of AI-2 in mice infected with the ΔrbsAΔlsrAΔluxS mutant strain attenuated this triple mutant. Role of AI-2 signaling genes that modulated bacterial virulence was determined by RNAseq. Characterization of AI-2 signaling in Y. pestis should lead to re-examination of AI-2 systems in other pathogens and may represent a broad-spectrum therapeutic target to combat antibiotic-resistant bacteria."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Novel Virulence Factors in the Pathogenesis of Yersinia pestis Infection, the Causative Agent of Plague"]}]}],"canonical_facts":{"dc:contributor.advisor":["Chopra, Ashok"],"dc:contributor.committeemember":["Peterson, Johhny","Motin, Vladimir","Stevenson-Lerner, Heather","Lathem, Wyndham"],"dc:creator":["Fitts, Eric Charles"],"dc:date.accessioned":["2019-03-13T20:25:38Z"],"dc:date.available":["2019-03-13T20:25:38Z"],"dc:description.abstract":["Identification of new virulence factors in Yersinia pestis, the causative agent of plague, and understanding their molecular mechanisms during an infection process are necessary in designing a better vaccine or to formulate an appropriate therapeutic intervention. By using a high-throughput, signature-tagged mutagenic approach, we screened 5,088 mutants of Y. pestis CO92. From this screen, 118 clones showing impairment in disseminating to spleen were obtained. In a subsequent screen, 20/118 mutants exhibited attenuation when tested individually in a mouse model of bubonic plague, with 10/20 aforementioned mutants providing 40% or higher survival rates at an infectious dose of 40 LD50. Upon sequencing, six of the attenuated mutants carried interruptions in genes encoding hypothetical proteins or proteins with putative functions. In-frame deletion mutation of two of the genes identified from the screen were also found to exhibit some attenuation at 11-12 LD50 in a mouse model of pneumonic plague. Likewise, among the remaining 18 signature-tagged mutants, 9 were also attenuated (40-100%) at 12 LD50 in a pneumonic plague mouse model. Combinatorial deletions including the newly identified genes, rbsA and vasK, were significantly attenuated in pneumonic plague models. Interestingly, rbsA gene products have been associated with a highly conserved inter-bacterial signaling system mediated by autoinducer-2 (AI-2) quorum-sensing molecule. Deletion of the gene encoding the synthetic enzyme for AI-2 substrate, luxS, leads to either no change or, paradoxically, an increase in in vivo bacterial virulence. Deletion of rbsA and lsrA genes, ABC transport components interacting with AI-2, synergistically disrupted AI-2 signaling patterns and resulted in an over 50-fold decrease in Y. pestis CO92 virulence in a mouse model. Deletion of luxS from the ΔrbsAΔlsrA strain reverted the virulence phenotype similar to wild-type CO92. Administration of AI-2 in mice infected with the ΔrbsAΔlsrAΔluxS mutant strain attenuated this triple mutant. Role of AI-2 signaling genes that modulated bacterial virulence was determined by RNAseq. Characterization of AI-2 signaling in Y. pestis should lead to re-examination of AI-2 systems in other pathogens and may represent a broad-spectrum therapeutic target to combat antibiotic-resistant bacteria."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/2152.3/11155"],"dc:subject":["Yersinia pestis","quorum sensing","autoinducer-2","virulence factor","luxS"],"dc:title":["Novel Virulence Factors in the Pathogenesis of Yersinia pestis Infection, the Causative Agent of Plague"],"dc:type":["Thesis"],"thesis:degree_level":["Doctoral"],"thesis:degree_name":["Microbiology and Immunology (Doctoral)"],"thesis:institution_name":["The University of Texas Medical Branch at Galveston"]},"updated_at":"2026-07-24T05:50:59Z"}