The role of miR-132 in the immune response to pathogens
Lead Research Organisation:
University of York
Department Name: Biology
Abstract
Infectious diseases are the second most common cause of death worldwide. Infections are particularly dangerous for people with weak immune systems, such as children, malnourished individuals, or individuals suffering from AIDS. Discovering the ways through which our body normally fights an infection and boosting these mechanisms in high-risk individuals is a valuable approach to treating, curing, or preventing diseases caused by infection. This is the main focus of our research plan. We are particularly interested in a class of genes that was recently discovered. These genes are called 'microRNAs' and unlike normal genes, do not generate proteins. Until ten years ago these parts of our genome were considered to be junk DNA, but we now know that they are as important as normal 'protein-coding' genes. In particular, we have discovered that miR-132 is a microRNA that normally prevents an exaggerated response to infection (an unnecessarily strong immune response would also lead to serious illness). We found that pathogens exploit this genetic Achilles' heel to escape from the immune system. These pathogens include viruses and parasites that significantly contribute to the global disease burden, especially in developing countries and among HIV-infected individuals. In particular, our studies suggest that miR-132 controls multiple arms of the immune response to the causative infectious agents of diseases such as Leishmaniasis. In addition, our studies indicate that inhibiting the activity of miR-132 boosts the anti-pathogen immune response. Therefore, we propose that blocking the action of miR-132 could limit infection with a broad range of pathogens and delay or prevent disease. To test this, we will investigate in detail how miR-132 works during infection and test the potential of anti-miR-132 drugs in experimental models of infection. In the proposed research programme, we aim to uncover crucial secrets of how our body fights infection and set the basis for the clinical use of agents that antagonize miR-132 for the treatment of infectious diseases.
Technical Summary
An appropriate immune response requires coordination of a multitude of initiating, amplifying and resolving signals and processes. Understanding the mechanisms that ensure an optimal equilibrium between activating and regulatory immune processes is of utmost importance for the treatment of infectious diseases. In this project, we propose that microRNAs act as molecular integrators of the immune response through their ability to concurrently regulate expression of several genes in a tissue- and cellular state-specific manner. In particular, we will investigate the function of miR-132, a critical component of the regulatory arm of the innate immune response. We have recently found that genetic deletion of miR-132 provides protection against infection and infection-associated tissue remodeling. Our studies suggest that miR-132 negatively regulates inflammation by simultaneously limiting the interferon response and promoting angiogenesis. These findings will be used as a solid platform in the proposed project, which will investigate in-depth the effects of miR-132 on the inflammatory response to infection. Using unique gene knockout models and a tractable in vivo infection model, we will dissect the mechanisms employed by miR-132 at the cellular and molecular level, focusing on the role of miR-132 in macrophages and endothelial cells and its interactions with p300, a master transcriptional co-activator, and Rasa1, a fundamental signaling effector. In addition to gaining crucial insight into immunological mechanisms, the proposed studies will reveal how miR-132 interacts with its targets in a context-dependent manner to perform its function in different cell types. Therefore this project will result in significant conceptual advancements in the fields of immunology and microRNA biology, and also set the foundation towards the development of novel therapeutic approaches in infectious diseases.
Planned Impact
A better understanding of the mechanisms underlying immunity can lead to improved treatment of infectious and autoimmune diseases. In this respect our proposal will provide significant clues regarding the role of microRNAs, and in particular miR-132, in inflammation. Our work will reveal microRNA-mediated mechanisms linking the vascular and inflammatory responses to infection. This will open up new routes for combinatorial therapies in infectious diseases, and identify therapeutic targets (such as miR-132) that act as hubs of multiple dysregulated, disease-associated processes during disease development. This is of notable value as miR-132 is a clinically targetable molecule. Basal expression of miR-132 outside the brain is low, but inducible upon pathological stress such as infection, autoimmune disease, and cancer. Our studies will focus on experimental models investigating the potential protective role of miR-132 inhibition against infection. Positive results in these models would have strong translational potential as the Locked Nucleic Acid (LNA) microRNA inhibitors used in our studies are clinically relevant (LNA inhibitors are currently used in the clinic as the first microRNA therapeutics) and do not cross the blood-brain barrier, which will prevent undesired effects in the brain where miR-132 basal expression is significant and functionally essential. During this project, we will study the function of miR-132 in an experimental model of infection. Therefore the primary future beneficiaries of our research could be individuals affected by complex infectious diseases, for which treatments are currently limited, such as Leishmaniasis. These conditions contribute significantly to the global disease burden. For example visceral Leishmaniasis is a major health problem in India and parts of South America (where leishmania infection is endemic), and a major cause of mortality and morbidity among immunosuppressed individuals, such as people infected with HIV, worldwide (including Europe and the UK). We expect that the proposed studies will be a major step towards the future use of anti-miR-132 agents for the treatment of these infectious diseases. Furthermore, our mechanistic findings will enhance our understanding of other conditions characterized by miR-132 induction such as chronic inflammatory conditions and cancer, which in the longer term could benefit individuals suffering with these diseases.
Publications
Bridge KS
(2017)
Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins.
in Cell reports
Foxler DE
(2018)
A HIF-LIMD1 negative feedback mechanism mitigates the pro-tumorigenic effects of hypoxia.
in EMBO molecular medicine
Hewitson JP
(2019)
miR-132 suppresses transcription of ribosomal proteins to promote protective Th1 immunity.
in EMBO reports
Bridgewood C
(2017)
IL-36? has proinflammatory effects on human endothelial cells.
in Experimental dermatology
Yee D
(2017)
microRNAs in the Lymphatic Endothelium: Master Regulators of Lineage Plasticity and Inflammation.
in Frontiers in immunology
Hewitson JP
(2020)
Malat1 Suppresses Immunity to Infection through Promoting Expression of Maf and IL-10 in Th Cells.
in Journal of immunology (Baltimore, Md. : 1950)
West KA
(2019)
Long Non-Coding RNA Function in CD4+ T Cells: What We Know and What Next?
in Non-coding RNA
Warner MJ
(2016)
S6K2-mediated regulation of TRBP as a determinant of miRNA expression in human primary lymphatic endothelial cells.
in Nucleic acids research
Heyam A
(2017)
Conserved asymmetry underpins homodimerization of Dicer-associated double-stranded RNA-binding proteins.
in Nucleic acids research
Leonov G
(2015)
Suppression of AGO2 by miR-132 as a determinant of miRNA-mediated silencing in human primary endothelial cells.
in The international journal of biochemistry & cell biology
Yee D
(2017)
MicroRNA-155 induction via TNF-a and IFN-? suppresses expression of programmed death ligand-1 (PD-L1) in human primary cells.
in The Journal of biological chemistry
Ashwin H
(2018)
Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis.
in Wellcome open research
Forrester S
(2019)
Tissue-specific transcriptomic changes associated with AmBisome® treatment of BALB/c mice with experimental visceral leishmaniasis.
in Wellcome open research
Heyam A
(2015)
Dissecting the roles of TRBP and PACT in double-stranded RNA recognition and processing of noncoding RNAs.
in Wiley interdisciplinary reviews. RNA
Title | Messenger by Christy Ducker. Smith/Doorstop Books (10 Mar. 2017) ISBN-10: 1910367966 ISBN-13: 978-1910367964 |
Description | Dimitris Lagos wrote the preface in a published collection of poems by award-winning poet Christy Ducker and two film poems by Kate Sweeny who have won awards in international competitions (Festival Silencio in Lisbon; Rabbit Heart Film Festival). The works were based on work on RNA (A Scientist's Advice on Healing: https://vimeo.com/163933380) and infectious diseases such as leishmaniasis (Vaccine: https://vimeo.com/193369489). Christy and Kate were hosted by Dimitris Lagos for a year through a Wellcome Trust-funded residency. |
Type Of Art | Creative Writing |
Year Produced | 2017 |
Impact | A series of public engagement events (Festival of Ideas, Pint of Science). Awards for the artists involved (see above). |
URL | http://www.poetrybusiness.co.uk/shop/939/messenger |
Description | A UK underpinning platform to study immunology and immunopathology of COVID-19:The UK Coronavirus Immunology Consortium |
Amount | £6,552,119 (GBP) |
Funding ID | MR/V028448/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2020 |
End | 08/2022 |
Description | A multiscale model to minimise animal usage in leishmaniasis drug development |
Amount | £996,464 (GBP) |
Funding ID | NC/C013205/1 |
Organisation | National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) |
Sector | Public |
Country | United Kingdom |
Start | 09/2014 |
End | 09/2017 |
Description | MRC Global Challenges Research Fund Foundation Award |
Amount | £600,000 (GBP) |
Funding ID | MR/P024661/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 02/2019 |
Description | Proof of principle study for Illumina small RNA sequencing in York |
Amount | £5,232 (GBP) |
Organisation | University of York |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2015 |
End | 01/2016 |
Description | Travel support to present at the EMBL "Non-coding Genome" symposium |
Amount | £1,215 (GBP) |
Organisation | Hull York Medical School |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2015 |
End | 11/2015 |
Description | UK:Brazil Joint Centre Partnership in leishmaniasis |
Amount | £1,168,009 (GBP) |
Funding ID | MR/S019472/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2023 |
Description | CRACK-IT Phase 2: A multiscale model to minimise animal usage in Leishmaniasis drug development |
Organisation | London School of Hygiene and Tropical Medicine (LSHTM) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Co-I in a NC3Rs-funded consortium developing in silico simulations of visceral leishmaniasis. Involved in host transcriptomics interpretation. Contributing towards integration of transcriptomics into computational models of disease development. |
Collaborator Contribution | Paul Kaye leads the consortium. Simon Croft (LSHTM) and Jeremy Motram (University of York) provide expertise in leishmania pharmacology and pathogen genomics, respectively. Jon Timmis and Mark Coles (SimOmics) and Jim Austin (Sibulla) develop software and cloud infrastructure. |
Impact | No outputs yet. Multidisciplinary team including immunologists, pathogen biologists, pharmacologists, computer software developers, computer modelers. |
Start Year | 2015 |
Description | Hosted Wellcome Trust-funded Artist in Residence for 1 year |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Hosted a poet for one year who produced a pamplet on the theme of immunity, wounds and healing, and two film-poems by fellow-collaborator, Kate Sweeney. The pamplet, titled Messenger will be published i March 2017 by Smith & Doorstop. During the year, I have participated in events associated with this collaboration including talks in the Festival of Ideas and Events in York Art Gallery. This collaboration between Medical Sciences and Art has had a notable impact on lay audiences ("I never thought that poetry and science can work together") and provided new communication routes of my research on infectious diseases and non-coding RNAs to broader audiences. |
Year(s) Of Engagement Activity | 2016,2017 |
URL | https://www.york.ac.uk/c2d2/projects/artist/#tab-2 |
Description | Press release for discovery on how microRNAs affect immunity to infection |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | A press release from the University of York in relation to this manuscript: Hewitson JP, Shah KM, Brown N, Grevitt P, Hain S, Newling K, Sharp TV, Kaye PM, Lagos D. miR-132 suppresses transcription of ribosomal proteins to promote protective Th1 immunity. EMBO Rep. 2019 |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.york.ac.uk/news-and-events/news/2019/research/putting-the-brake-on-our-immune-systems-re... |
Description | Radio interview in BBC Radio York |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Radio interview in BBC Radio York as a result of the press release associated with this paper: Hewitson JP, Shah KM, Brown N, Grevitt P, Hain S, Newling K, Sharp TV, Kaye PM, Lagos D. miR-132 suppresses transcription of ribosomal proteins to promote protective Th1 immunity. EMBO Rep. 2019 |
Year(s) Of Engagement Activity | 2019 |