The role of latency-associated viral miRNAs during human cytomegalovirus latent infection
Lead Research Organisation:
University of Cambridge
Department Name: Medicine
Abstract
Human cytomegalovirus (HCMV) establishes a latent infection in CD34+ progenitor cells and their monocyte derivatives. We have previously shown that major changes occur in cellular gene expression in latently infected cells due to expression of viral proteins encoded by a sub-set of latency-associated viral genes. Whilst we have identified a number of functions of latency-associated viral proteins, little is known about the role of virally encoded miRNAs or long non-coding RNAs during latent infection - yet, HCMV is known to encode at least 17 mature miRNAs and 3 long non-coding RNAs (lncRNA).
We have recently analysed the viral miRNAome during latent infection and identified a number viral miRNAs expressed to high levels in latency models using both primary myeloid cells as well as established myeloid cell lines.
One of these is the viral miRNA UL22A. Initial analyses have identified one target of UL22A to be the p110delta subunit of Phosphoinositide 3-kinase (PI3K).
This project will analyse the effect of UL22A-mediated down-regulation of p110delta on the establishment and maintenance of latent infection to help identify the rationale for viral-specific targeting of this cellular kinase.
Importantly, studies of acute myeloid leukaemia have shown that cells with low levels of p110delta display increased sensitivity to induction of cell death by topoisomerase inhibitors such as etoposide and this predicts that latently infected cells could be targeted by such inhibitors. Consequently, the project will not only aim to understand the role of p100delta down-regulation during latent infection but translate the effects of expression of this viral miRNA, on the cell, to novel therapies to target latency - a key aim of our ongoing research.
Similarly, we also will analyse the role, if any, of the viral 4.9kb lncRNA which has been postulated to be involved in maintenance of repression of viral lytic gene expression during latency. We will generate models of HCMV latency in which expression of the 4.9kb lncRNA is knocked down to establish the effect of lack of expression of this viral gene latent carriage.
We have recently analysed the viral miRNAome during latent infection and identified a number viral miRNAs expressed to high levels in latency models using both primary myeloid cells as well as established myeloid cell lines.
One of these is the viral miRNA UL22A. Initial analyses have identified one target of UL22A to be the p110delta subunit of Phosphoinositide 3-kinase (PI3K).
This project will analyse the effect of UL22A-mediated down-regulation of p110delta on the establishment and maintenance of latent infection to help identify the rationale for viral-specific targeting of this cellular kinase.
Importantly, studies of acute myeloid leukaemia have shown that cells with low levels of p110delta display increased sensitivity to induction of cell death by topoisomerase inhibitors such as etoposide and this predicts that latently infected cells could be targeted by such inhibitors. Consequently, the project will not only aim to understand the role of p100delta down-regulation during latent infection but translate the effects of expression of this viral miRNA, on the cell, to novel therapies to target latency - a key aim of our ongoing research.
Similarly, we also will analyse the role, if any, of the viral 4.9kb lncRNA which has been postulated to be involved in maintenance of repression of viral lytic gene expression during latency. We will generate models of HCMV latency in which expression of the 4.9kb lncRNA is knocked down to establish the effect of lack of expression of this viral gene latent carriage.
Organisations
People |
ORCID iD |
John Sinclair (Primary Supervisor) | |
Marianne Perera (Student) |
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013433/1 | 01/10/2016 | 30/04/2026 | |||
1799718 | Studentship | MR/N013433/1 | 01/10/2016 | 30/09/2020 | Marianne Perera |
Description | CMV Conference Award |
Amount | $495 (USD) |
Organisation | University of Alabama at Birmingham |
Sector | Academic/University |
Country | United States |
Start | 04/2019 |
End | 04/2019 |
Description | Microbiology Society Conference Grant |
Amount | £275 (GBP) |
Organisation | Microbiology Society |
Sector | Learned Society |
Country | United Kingdom |
Start | 04/2017 |
End | 05/2017 |
Description | Microbiology Society Travel Grant |
Amount | £750 (GBP) |
Organisation | Microbiology Society |
Sector | Learned Society |
Country | United Kingdom |
Start | 04/2019 |
End | 04/2019 |
Description | Trinity Hall Travel Award |
Amount | £800 (GBP) |
Organisation | University of Cambridge |
Department | Trinity Hall, Cambridge |
Sector | Private |
Country | United Kingdom |
Start | 07/2019 |
End | 08/2019 |
Description | Trinity Hall Travel Grant 2018 |
Amount | £700 (GBP) |
Organisation | University of Cambridge |
Sector | Academic/University |
Country | United Kingdom |
Start | 08/2018 |
End | 11/2018 |
Description | Oral Presentation - IHW2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | I gave an oral presentation at the International Herpesvirus Workshop 2019. This involved describing the most recent results I had obtained and discussing them with other researchers in the field. |
Year(s) Of Engagement Activity | 2019 |
URL | http://www.herpesvirusworkshop.com/2019/ |
Description | Oral Presentation UKCMV2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | I delivered an oral presentation on my research in the biennial UK CMV conference to around 60 other researchers in my field. The discussion and suggestions that followed this talk were very useful and have given me ideas for future work. |
Year(s) Of Engagement Activity | 2018 |
URL | http://ukcmv.cardiff.ac.uk/ |
Description | Poster Presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Presented a poster at the International CMV2019 conference in Birmingham, Alabama. This included talking to interested researchers in the field about my recent work and discussing future directions. |
Year(s) Of Engagement Activity | 2019 |
URL | http://www.cmv2019.org |
Description | Poster Presentation MicrobioSoc 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | I presented a poster on my work at the annual Microbiology Society conference. This allowed me to talk to researchers from different fields who shared information about different techniques and provided useful suggestions. |
Year(s) Of Engagement Activity | 2018 |
URL | https://microbiologysociety.org/event/annual-conference/annual-conference-2018.html |
Description | Poster presentation IHW 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | I gave a poster presentation on my research at the International Herpesvirus Workshop in 2017. This allowed me to exchange ideas with other researchers and provided me with valuable feedback on my work. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.herpesvirusworkshop.com/2017/ |
Description | Poster presentation IHW 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | I gave a poster presentation at the International Herpesvirus Workshop 2018. This was a useful opportunity to discuss my work with other researchers who work on similar projects, and to interchange ideas. |
Year(s) Of Engagement Activity | 2018 |
URL | http://www.herpesvirusworkshop.com/2018/ |