The NPC pathway and persistence of intracellular pathogens
<p>Intracellular pathogens have the ability to survive and replicate within host cells, resulting in their long-term cellular and systemic persistence. A pivotal strategy for achieving this persistence is through the prevention of phagosome-lysosome fusion. Studies by Fineran <em>et al.&...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2023
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| _version_ | 1826313471769182208 |
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| author | Weng, Y |
| author2 | Platt, F |
| author_facet | Platt, F Weng, Y |
| author_sort | Weng, Y |
| collection | OXFORD |
| description | <p>Intracellular pathogens have the ability to survive and replicate within host cells, resulting in their long-term cellular and systemic persistence. A pivotal strategy for achieving this persistence is through the prevention of phagosome-lysosome fusion. Studies by Fineran <em>et al.</em> have established a mechanistic link between <em>Mycobacterium tuberculosis (Mtb)</em> infection and Niemann-Pick disease type C (NPC), a rare lysosomal storage disorder. <em>Mtb</em> infection involves the shedding of microbial lipids that inhibit NPC1 in host cells. Our study has confirmed that the lipid-mediated inhibition of NPC1 is widespread in clinically relevant global human <em>Mtb</em> strains. However, we observed no such inhibition with lipid extracts from <em>Mycobacterium canettii</em>, an ancestral species of modern human <em>Mtb</em> strains. These findings imply that the evolution of NPC1 inhibition conferred greater virulence of <em>Mtb</em> strains. Analysis of sphingolipids revealed that <em>Mtb</em> H37Rv lipid extract manipulates sphingosine metabolism. By analysing the activity of fractionated <em>Mtb</em> H37Rv lipid and commercially obtained purified <em>Mtb</em> lipid components, we have identified several candidates, including SL-1 and PIMs, that may be involved in the inhibition of the NPC pathway. In addition, we have identified <em>Salmonella enterica</em> serovar Typhimurium (<em>S.</em> Typhimurium), another intracellular pathogen, which inhibits the host cell NPC pathway and induces NPC cellular phenotypes. We have found that NPC1 inhibition is independent of the effector protein secreted during infection, and that lipid extract from <em>S.</em> Typhimurium can induce comparable NPC cellular phenotypes to live infection models. Our study therefore shows for the first time the involvement of the NPC pathway in the persistence of multiple intracellular pathogens.</p> |
| first_indexed | 2024-09-25T04:13:57Z |
| format | Thesis |
| id | oxford-uuid:72fe402a-1416-48aa-8823-6e74d67fb37e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:13:57Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | oxford-uuid:72fe402a-1416-48aa-8823-6e74d67fb37e2024-07-11T12:48:55ZThe NPC pathway and persistence of intracellular pathogensThesishttp://purl.org/coar/resource_type/c_db06uuid:72fe402a-1416-48aa-8823-6e74d67fb37eMycobacteriaLysosomesPathogenic microorganismsSalmonellaLipidsNiemann-Pick diseasesEnglishHyrax Deposit2023Weng, YPlatt, FPlatt, N<p>Intracellular pathogens have the ability to survive and replicate within host cells, resulting in their long-term cellular and systemic persistence. A pivotal strategy for achieving this persistence is through the prevention of phagosome-lysosome fusion. Studies by Fineran <em>et al.</em> have established a mechanistic link between <em>Mycobacterium tuberculosis (Mtb)</em> infection and Niemann-Pick disease type C (NPC), a rare lysosomal storage disorder. <em>Mtb</em> infection involves the shedding of microbial lipids that inhibit NPC1 in host cells. Our study has confirmed that the lipid-mediated inhibition of NPC1 is widespread in clinically relevant global human <em>Mtb</em> strains. However, we observed no such inhibition with lipid extracts from <em>Mycobacterium canettii</em>, an ancestral species of modern human <em>Mtb</em> strains. These findings imply that the evolution of NPC1 inhibition conferred greater virulence of <em>Mtb</em> strains. Analysis of sphingolipids revealed that <em>Mtb</em> H37Rv lipid extract manipulates sphingosine metabolism. By analysing the activity of fractionated <em>Mtb</em> H37Rv lipid and commercially obtained purified <em>Mtb</em> lipid components, we have identified several candidates, including SL-1 and PIMs, that may be involved in the inhibition of the NPC pathway. In addition, we have identified <em>Salmonella enterica</em> serovar Typhimurium (<em>S.</em> Typhimurium), another intracellular pathogen, which inhibits the host cell NPC pathway and induces NPC cellular phenotypes. We have found that NPC1 inhibition is independent of the effector protein secreted during infection, and that lipid extract from <em>S.</em> Typhimurium can induce comparable NPC cellular phenotypes to live infection models. Our study therefore shows for the first time the involvement of the NPC pathway in the persistence of multiple intracellular pathogens.</p> |
| spellingShingle | Mycobacteria Lysosomes Pathogenic microorganisms Salmonella Lipids Niemann-Pick diseases Weng, Y The NPC pathway and persistence of intracellular pathogens |
| title | The NPC pathway and persistence of intracellular pathogens |
| title_full | The NPC pathway and persistence of intracellular pathogens |
| title_fullStr | The NPC pathway and persistence of intracellular pathogens |
| title_full_unstemmed | The NPC pathway and persistence of intracellular pathogens |
| title_short | The NPC pathway and persistence of intracellular pathogens |
| title_sort | npc pathway and persistence of intracellular pathogens |
| topic | Mycobacteria Lysosomes Pathogenic microorganisms Salmonella Lipids Niemann-Pick diseases |
| work_keys_str_mv | AT wengy thenpcpathwayandpersistenceofintracellularpathogens AT wengy npcpathwayandpersistenceofintracellularpathogens |