Screening for virus miRNA that target the host innate immune response and inflammation
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Inflammation | .(JavaScript must be enabled to view this email address) |
Dr Motti Gerlic (Co-supervisor) |
Inflammation | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Inflammation | .(JavaScript must be enabled to view this email address) |
Details of project
The body’s first line of defense towards pathogens and tissue damage is the inflammatory response. One important class of regulators that limit inflammation are micro-RNAs (miRNAs), small nucleic acid-based molecules encoded in the human genome. It has also been discovered that some viruses produce miRNA [1], and this project will be the first to screen for how these might limit host inflammation to give the virus an advantage.
To do this we will take the following approaches:
- Debilitating viruses with many miRNA, like Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein Barr Virus (EBV), are difficult to work with and do not infect mice. Therefore we will transfer the KSHV/EBV miRNAs to the closely related Murine gammaherpesvirus 68 (MHV-68) [2] and infect cell lines and live mice to look for effects on the innate immune response and inflammation.
- Our second screening approach involves herpes simplex virus (HSV-1). We can deplete the miRNA which are expressed by HSV-1 using “sponge” technology [3]. Therefore we can create a cell population in which the HSV-1 miRNA are non-functional, and we can compare the inflammatory response to control cells.
- Finally we will take individual miRNA from KSHV, EBV or HSV-1 and determine the exact inflammatory pathway they control, and the specific target that they regulate.
We expect the outcome of this research to be a definitive catalogue of those miRNA in EBV, KSHV and HSV that regulate innate immune pathways and inflammation. Herpes viruses are responsible for extensive morbidity and mortality worldwide [4]. Some of these viruses are also implicated in the pathogenesis of lymphomas, such as Kaposi’s Sarcoma (KS). Learning how viruses use miRNAs to prevent inflammation will help develop new strategies to treat, vaccinate and prevent the spread of these diseases.
Project references
- Stern-Ginossar N, Elefant N, Zimmermann A, et al. Host immune system gene targeting by a viral miRNA. Science. 2007 317:376-81.
- Mount AM, Masson F, Kupresanin F, et al. Interference with dendritic cell populations limits early antigen presentation in chronic gamma-herpesvirus-68 infection. J Immunol 2010 185:3669-76.
- Ebert MS, Neilson JR, Sharp PA. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 2007 4:721-6.
- Koelle DM, Corey L. Herpes simplex: insights on pathogenesis and possible vaccines. Annual review of medicine 2008 59:381-95.
Research interests
Research in the Masters laboratory is focused on inflammation from the innate immune system. This can happen in many different contexts, for example during a bacterial or virus infection, when cells die during an organ or tissue transplant, or when genetic mutations activate innate immune pathways. The innate immune response is also fundamentally involved in the pathogenesis of many chronic inflammatory diseases like rheumatoid arthritis, Crohns disease and even type 2 diabetes.
Previously we have made discoveries relevant to all of these areas [1-4], and we maintain close links to industry and the clinic to make sure our discoveries can continue to have a direct effect on human health in the future. This is a particularly exciting time to be working on inflammation because so many new drugs are coming to the clinic, and we have the diverse research tools to determine where and why these can provide benefit.
Selected publications
- Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009 360:2426-37.
- Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol. 2009 27:21-68.
- Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol. 2010 11:897-904.
- Masters SL, Mielke LA, Cornish AL, et al. Regulation of interleukin-1 beta by interferon-gamma is species specific, limited by suppressor of cytokine signalling 1 and influences interleukin-17 production. EMBO Rep. 2010 11: 40-6.
Research theme
Infectious diseases
Scientific discipline
- Biochemistry
- Cell Biology
- Immunology
- Innate Immunity
- Molecular Biology