Interplay between oxygen sensing mechanisms and hepatitis B virus replication
<p>Hepatitis B virus (HBV) preferentially replicates in the liver, a naturally hypoxic organ with an oxygen gradient from 8-4% in the periportal and pericentral regions, respectively. The hypoxia inducible factor (HIF) pathway is the most well studied mammalian oxygen sensing mechanism and is...
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| Бусад зохиолчид: | |
| Формат: | Дипломын ажил |
| Хэл сонгох: | English |
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2021
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| Нөхцлүүд: |
| _version_ | 1826309263723593728 |
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| author | Liu, PJ |
| author2 | McKeating, J |
| author_facet | McKeating, J Liu, PJ |
| author_sort | Liu, PJ |
| collection | OXFORD |
| description | <p>Hepatitis B virus (HBV) preferentially replicates in the liver, a naturally hypoxic organ with an oxygen gradient from 8-4% in the periportal and pericentral regions, respectively. The hypoxia inducible factor (HIF) pathway is the most well studied mammalian oxygen sensing mechanism and is frequently perturbed by pathological states including infection and inflammation. However, the majority of in vitro studies have investigated HBV at atmospheric oxygen tensions (18%) where low oxygen sensing mechanisms are inactive and consequently their role in viral replication may be overlooked. Therefore, this thesis studied the interplay between HBV replication and oxygen sensing mechanisms.</p>
<p>Chronic hepatitis B (CHB) is associated with an increased expression of HIF gene transcripts. Further interrogation of a cohort of patients with CHB shows an association between inflammatory responses and HIF transcription. Importantly, this observation is not recapitulated in state-of-art in vitro, in vivo, and de novo HBV infection model systems.</p>
<p>HIF regulates target genes via HIF responsive elements (HREs), and the discovery of two evolutionarily conserved HREs in the HBV genome prompted experiments to understand the role of HIFs in viral replication. HIF siRNA silencing experiments in vitro and in vivo demonstrate a positive role for HIFs in regulating HBV replication.</p>
<p>As other oxygen sensing mechanisms have been identified in addition to the HIF pathway, further experiments assessed the role of hypoxia and HIF independent mechanisms in regulating HBV transcription. Data suggests that hypoxia positively regulates HBV transcription through both HIF dependent and independent mechanisms. Further investigations reveal that low oxygen downregulates the HBV host restriction factor Smc6 through HIF independent mechanisms. In addition, the cysteamine (2-aminoethanethol) dioxygenase oxygen sensing pathway regulated interleukin-32 may have anti-viral activities that are repressed under hypoxia.</p>
<p>Collectively, this thesis presents evidences demonstrating key regulatory interactions between HBV and hypoxia, revealing novel therapeutic directions.</p> |
| first_indexed | 2024-03-07T07:31:34Z |
| format | Thesis |
| id | oxford-uuid:3a3144c9-ac8c-4c66-a052-50963205f716 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:31:34Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:3a3144c9-ac8c-4c66-a052-50963205f7162023-01-27T15:37:02ZInterplay between oxygen sensing mechanisms and hepatitis B virus replicationThesishttp://purl.org/coar/resource_type/c_db06uuid:3a3144c9-ac8c-4c66-a052-50963205f716HepatitisHIFHBVOxygen sensingVirologyHepatitis B virusLiverPHDHepatologyHypoxiaEnglishHyrax Deposit2021Liu, PJMcKeating, JRatcliffe, PWing, P<p>Hepatitis B virus (HBV) preferentially replicates in the liver, a naturally hypoxic organ with an oxygen gradient from 8-4% in the periportal and pericentral regions, respectively. The hypoxia inducible factor (HIF) pathway is the most well studied mammalian oxygen sensing mechanism and is frequently perturbed by pathological states including infection and inflammation. However, the majority of in vitro studies have investigated HBV at atmospheric oxygen tensions (18%) where low oxygen sensing mechanisms are inactive and consequently their role in viral replication may be overlooked. Therefore, this thesis studied the interplay between HBV replication and oxygen sensing mechanisms.</p> <p>Chronic hepatitis B (CHB) is associated with an increased expression of HIF gene transcripts. Further interrogation of a cohort of patients with CHB shows an association between inflammatory responses and HIF transcription. Importantly, this observation is not recapitulated in state-of-art in vitro, in vivo, and de novo HBV infection model systems.</p> <p>HIF regulates target genes via HIF responsive elements (HREs), and the discovery of two evolutionarily conserved HREs in the HBV genome prompted experiments to understand the role of HIFs in viral replication. HIF siRNA silencing experiments in vitro and in vivo demonstrate a positive role for HIFs in regulating HBV replication.</p> <p>As other oxygen sensing mechanisms have been identified in addition to the HIF pathway, further experiments assessed the role of hypoxia and HIF independent mechanisms in regulating HBV transcription. Data suggests that hypoxia positively regulates HBV transcription through both HIF dependent and independent mechanisms. Further investigations reveal that low oxygen downregulates the HBV host restriction factor Smc6 through HIF independent mechanisms. In addition, the cysteamine (2-aminoethanethol) dioxygenase oxygen sensing pathway regulated interleukin-32 may have anti-viral activities that are repressed under hypoxia.</p> <p>Collectively, this thesis presents evidences demonstrating key regulatory interactions between HBV and hypoxia, revealing novel therapeutic directions.</p> |
| spellingShingle | Hepatitis HIF HBV Oxygen sensing Virology Hepatitis B virus Liver PHD Hepatology Hypoxia Liu, PJ Interplay between oxygen sensing mechanisms and hepatitis B virus replication |
| title | Interplay between oxygen sensing mechanisms and hepatitis B virus replication |
| title_full | Interplay between oxygen sensing mechanisms and hepatitis B virus replication |
| title_fullStr | Interplay between oxygen sensing mechanisms and hepatitis B virus replication |
| title_full_unstemmed | Interplay between oxygen sensing mechanisms and hepatitis B virus replication |
| title_short | Interplay between oxygen sensing mechanisms and hepatitis B virus replication |
| title_sort | interplay between oxygen sensing mechanisms and hepatitis b virus replication |
| topic | Hepatitis HIF HBV Oxygen sensing Virology Hepatitis B virus Liver PHD Hepatology Hypoxia |
| work_keys_str_mv | AT liupj interplaybetweenoxygensensingmechanismsandhepatitisbvirusreplication |