{"id":{"repo_id":"the-open-u","oai_identifier":"oai:oro.open.ac.uk:52804"},"canonical_url":"https://search.dev.ndltd.org/etd/the-open-u/oai:oro.open.ac.uk:52804","repository":{"repo_id":"the-open-u","name":"The Open University","base_url":"https://oro.open.ac.uk/cgi/oai2"},"display":{"title":"The Influence Of Host Genetics And Different <i>Mycobacterium tuberculosis</i> Strains On Macrophage Functions And Clinical Outcome Of Tuberculosis Disease","abstract":"Only 5-10 % of <i>Mycobacterium tuberculosis (Mtb)</i> infected individuals develop active pulmonary TB (PTB), and around < 1 % develop disseminated TB meningitis (TBM). Macrophages are one of the first defense barriers, but it is unclear how their antimicrobial activities influence TB presentations and clinical outcomes. Many studies have shown host and bacterial genetics are important factors in TB susceptibility and progression. I hypothesized that an impairment of macrophage phagocytic function, under the influence of genetic factors, may help explain the pathogenesis of the transition from latent to active or disseminated TB, and that the virulence of clinical <i>Mtb</i> isolates are associated with <i>Mtb</i> lineages and distinct host immune responses. <br></br><br></br> I developed assays using ligand coated beads and <i>Mtb</i> reporter strain to measure the macrophage antimicrobial activities. Our assays were able to detect the variation in macrophage activities among different individuals. <br></br><br></br> I investigated the macrophage antimicrobial functions and its association with different TB phenotypes. I measured the macrophage activities in 43 latent TB (LTB) and active TB (ATB) cases combining 54 PTB and 60 TBM patients. Our results showed that macrophages treated with ligands displayed higher antimicrobial activities in LTB than ATB, but no difference between PTB and TBM. Whereas, in <i>Mtb</i>-infected macrophages from both LTB and ATB, proteolysis was reduced due to the modulation of <i>Mtb</i> and there was no difference in their ability to control <i>Mtb</i>. Our data also indicated that the antimicrobial activities of macrophages were ligand-specific or pathway-dependent. <br></br><br></br> The influence of host genetics on TB susceptibility was examined by the association of variants on phagocytic genes using a case-control study with 450 TBM, 450 PTB and 450 controls. Heterozygotes of Macrophage receptor with collagenous structure (MARCO) single nucleotide polymorphisms (SNPs) were associated with increased TB susceptibility, abnormal chest X-ray, infection by Beijing strains and also with impaired macrophage phagocytosis of ligand coated beads. <br></br><br></br> The virulence of <i>Mtb</i> strains was examined by observing cell lysis of macrophages infected with 159 <i>Mtb</i> strains. Virulence phenotype was grouped as low, moderate and high. High virulence was associated with Beijing lineage, reduced TNF-α and IL-6 and increased IL-1β concentration. <br></br><br></br> Overall, this thesis provides new insights into the influence of host and bacterial factors on TB susceptibility. It also provides a foundation for further studies on factors influencing TB susceptibility.","abstract_html":"Only 5-10 % of &lt;i&gt;Mycobacterium tuberculosis (Mtb)&lt;/i&gt; infected individuals develop active pulmonary TB (PTB), and around &lt; 1 % develop disseminated TB meningitis (TBM). Macrophages are one of the first defense barriers, but it is unclear how their antimicrobial activities influence TB presentations and clinical outcomes. Many studies have shown host and bacterial genetics are important factors in TB susceptibility and progression. I hypothesized that an impairment of macrophage phagocytic function, under the influence of genetic factors, may help explain the pathogenesis of the transition from latent to active or disseminated TB, and that the virulence of clinical &lt;i&gt;Mtb&lt;/i&gt; isolates are associated with &lt;i&gt;Mtb&lt;/i&gt; lineages and distinct host immune responses. &lt;br&gt;&lt;/br&gt;&lt;br&gt;&lt;/br&gt; I developed assays using ligand coated beads and &lt;i&gt;Mtb&lt;/i&gt; reporter strain to measure the macrophage antimicrobial activities. Our assays were able to detect the variation in macrophage activities among different individuals. &lt;br&gt;&lt;/br&gt;&lt;br&gt;&lt;/br&gt; I investigated the macrophage antimicrobial functions and its association with different TB phenotypes. I measured the macrophage activities in 43 latent TB (LTB) and active TB (ATB) cases combining 54 PTB and 60 TBM patients. Our results showed that macrophages treated with ligands displayed higher antimicrobial activities in LTB than ATB, but no difference between PTB and TBM. Whereas, in &lt;i&gt;Mtb&lt;/i&gt;-infected macrophages from both LTB and ATB, proteolysis was reduced due to the modulation of &lt;i&gt;Mtb&lt;/i&gt; and there was no difference in their ability to control &lt;i&gt;Mtb&lt;/i&gt;. Our data also indicated that the antimicrobial activities of macrophages were ligand-specific or pathway-dependent. &lt;br&gt;&lt;/br&gt;&lt;br&gt;&lt;/br&gt; The influence of host genetics on TB susceptibility was examined by the association of variants on phagocytic genes using a case-control study with 450 TBM, 450 PTB and 450 controls. Heterozygotes of Macrophage receptor with collagenous structure (MARCO) single nucleotide polymorphisms (SNPs) were associated with increased TB susceptibility, abnormal chest X-ray, infection by Beijing strains and also with impaired macrophage phagocytosis of ligand coated beads. &lt;br&gt;&lt;/br&gt;&lt;br&gt;&lt;/br&gt; The virulence of &lt;i&gt;Mtb&lt;/i&gt; strains was examined by observing cell lysis of macrophages infected with 159 &lt;i&gt;Mtb&lt;/i&gt; strains. Virulence phenotype was grouped as low, moderate and high. High virulence was associated with Beijing lineage, reduced TNF-α and IL-6 and increased IL-1β concentration. &lt;br&gt;&lt;/br&gt;&lt;br&gt;&lt;/br&gt; Overall, this thesis provides new insights into the influence of host and bacterial factors on TB susceptibility. It also provides a foundation for further studies on factors influencing TB susceptibility.","abstract_has_math":false,"creators":["Trinh Thi Bich Tram"],"institution":"The Open University","degree_name":"phd","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017-12","date_published":"2017-12","updated_at":"2026-07-24T05:02:35Z","subjects":[],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Trinh Thi Bich Tram"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2017-12-20"]},{"key":"dc:date.issued","label":"Date","values":["2017-12"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["ARRAY(0x7ffb74111fb8)"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["The Open University"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://oro.open.ac.uk/52804/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["phd"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://oro.open.ac.uk/52804/1/Tram%20PhD%20thesis-%20for%20binding.pdf","https://oro.open.ac.uk/52804/7/180207_Thesis_Deposition_Form_updated.docx","https://oro.open.ac.uk/52804/8/180207_Trinh_GRADPROG_ARC.docx","https://oro.open.ac.uk/52804/9/180207_Trinh_Library_memo.doc"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Only 5-10 % of <i>Mycobacterium tuberculosis (Mtb)</i> infected individuals develop active pulmonary TB (PTB), and around < 1 % develop disseminated TB meningitis (TBM). Macrophages are one of the first defense barriers, but it is unclear how their antimicrobial activities influence TB presentations and clinical outcomes. Many studies have shown host and bacterial genetics are important factors in TB susceptibility and progression. I hypothesized that an impairment of macrophage phagocytic function, under the influence of genetic factors, may help explain the pathogenesis of the transition from latent to active or disseminated TB, and that the virulence of clinical <i>Mtb</i> isolates are associated with <i>Mtb</i> lineages and distinct host immune responses. <br></br><br></br> I developed assays using ligand coated beads and <i>Mtb</i> reporter strain to measure the macrophage antimicrobial activities. Our assays were able to detect the variation in macrophage activities among different individuals. <br></br><br></br> I investigated the macrophage antimicrobial functions and its association with different TB phenotypes. I measured the macrophage activities in 43 latent TB (LTB) and active TB (ATB) cases combining 54 PTB and 60 TBM patients. Our results showed that macrophages treated with ligands displayed higher antimicrobial activities in LTB than ATB, but no difference between PTB and TBM. Whereas, in <i>Mtb</i>-infected macrophages from both LTB and ATB, proteolysis was reduced due to the modulation of <i>Mtb</i> and there was no difference in their ability to control <i>Mtb</i>. Our data also indicated that the antimicrobial activities of macrophages were ligand-specific or pathway-dependent. <br></br><br></br> The influence of host genetics on TB susceptibility was examined by the association of variants on phagocytic genes using a case-control study with 450 TBM, 450 PTB and 450 controls. Heterozygotes of Macrophage receptor with collagenous structure (MARCO) single nucleotide polymorphisms (SNPs) were associated with increased TB susceptibility, abnormal chest X-ray, infection by Beijing strains and also with impaired macrophage phagocytosis of ligand coated beads. <br></br><br></br> The virulence of <i>Mtb</i> strains was examined by observing cell lysis of macrophages infected with 159 <i>Mtb</i> strains. Virulence phenotype was grouped as low, moderate and high. High virulence was associated with Beijing lineage, reduced TNF-α and IL-6 and increased IL-1β concentration. <br></br><br></br> Overall, this thesis provides new insights into the influence of host and bacterial factors on TB susceptibility. It also provides a foundation for further studies on factors influencing TB susceptibility."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf","application/vnd.openxmlformats-officedocument.wordprocessingml.document","application/msword"]},{"key":"dc:title","label":"Title","values":["The Influence Of Host Genetics And Different <i>Mycobacterium tuberculosis</i> Strains On Macrophage Functions And Clinical Outcome Of Tuberculosis Disease"]}]}],"canonical_facts":{"dc:creator":["Trinh Thi Bich Tram"],"dc:date":["2017-12-20"],"dc:date.issued":["2017-12"],"dc:description.abstract":["Only 5-10 % of <i>Mycobacterium tuberculosis (Mtb)</i> infected individuals develop active pulmonary TB (PTB), and around < 1 % develop disseminated TB meningitis (TBM). Macrophages are one of the first defense barriers, but it is unclear how their antimicrobial activities influence TB presentations and clinical outcomes. Many studies have shown host and bacterial genetics are important factors in TB susceptibility and progression. I hypothesized that an impairment of macrophage phagocytic function, under the influence of genetic factors, may help explain the pathogenesis of the transition from latent to active or disseminated TB, and that the virulence of clinical <i>Mtb</i> isolates are associated with <i>Mtb</i> lineages and distinct host immune responses. <br></br><br></br> I developed assays using ligand coated beads and <i>Mtb</i> reporter strain to measure the macrophage antimicrobial activities. Our assays were able to detect the variation in macrophage activities among different individuals. <br></br><br></br> I investigated the macrophage antimicrobial functions and its association with different TB phenotypes. I measured the macrophage activities in 43 latent TB (LTB) and active TB (ATB) cases combining 54 PTB and 60 TBM patients. Our results showed that macrophages treated with ligands displayed higher antimicrobial activities in LTB than ATB, but no difference between PTB and TBM. Whereas, in <i>Mtb</i>-infected macrophages from both LTB and ATB, proteolysis was reduced due to the modulation of <i>Mtb</i> and there was no difference in their ability to control <i>Mtb</i>. Our data also indicated that the antimicrobial activities of macrophages were ligand-specific or pathway-dependent. <br></br><br></br> The influence of host genetics on TB susceptibility was examined by the association of variants on phagocytic genes using a case-control study with 450 TBM, 450 PTB and 450 controls. Heterozygotes of Macrophage receptor with collagenous structure (MARCO) single nucleotide polymorphisms (SNPs) were associated with increased TB susceptibility, abnormal chest X-ray, infection by Beijing strains and also with impaired macrophage phagocytosis of ligand coated beads. <br></br><br></br> The virulence of <i>Mtb</i> strains was examined by observing cell lysis of macrophages infected with 159 <i>Mtb</i> strains. Virulence phenotype was grouped as low, moderate and high. High virulence was associated with Beijing lineage, reduced TNF-α and IL-6 and increased IL-1β concentration. <br></br><br></br> Overall, this thesis provides new insights into the influence of host and bacterial factors on TB susceptibility. It also provides a foundation for further studies on factors influencing TB susceptibility."],"dc:format":["application/pdf","application/vnd.openxmlformats-officedocument.wordprocessingml.document","application/msword"],"dc:identifier.uri":["https://oro.open.ac.uk/52804/1/Tram%20PhD%20thesis-%20for%20binding.pdf","https://oro.open.ac.uk/52804/7/180207_Thesis_Deposition_Form_updated.docx","https://oro.open.ac.uk/52804/8/180207_Trinh_GRADPROG_ARC.docx","https://oro.open.ac.uk/52804/9/180207_Trinh_Library_memo.doc"],"dc:language":["en"],"dc:publisher.department":["ARRAY(0x7ffb74111fb8)"],"dc:publisher.institution":["The Open University"],"dc:relation.isreferencedby":["https://oro.open.ac.uk/52804/"],"dc:title":["The Influence Of Host Genetics And Different <i>Mycobacterium tuberculosis</i> Strains On Macrophage Functions And Clinical Outcome Of Tuberculosis Disease"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["phd"]},"updated_at":"2026-07-24T05:02:35Z"}