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Genetic analysis of Drosophila anti-viral immunity

Reference	BB/E005470/1
Principal Investigator / Supervisor	Professor Michael Ashburner
Co-Investigators / Co-Supervisors	Dr Luis Teixeira
Institution	University of Cambridge
Department	Genetics
Funding type	Research
Value (£)	489,351
Status	Completed
Type	Research Grant
Start date	06/11/2006
End date	05/11/2009
Duration	36 months

Abstract

Multi-cellular organisms must defend themselves from invading pathogens. In vertebrates this is achieved through the integration of the adaptive and innate immune responses. The fruit fly has been extensively used to study innate immunity. Basic mechanisms and molecules involved in innate immunity are conserved between flies and mammals. We aim to understand the innate immune response against viruses, using Drosophila melanogaster as a model system Most of what is known about Drosophila innate immunity concerns the responses to bacteria and fungi. Recently a Drosophila gene involved in anti-viral immunity was identified. Imler and colleagues (2005) have shown that the JAK/STAT pathway is required for the anti-viral response against Drosophila C virus (DCV). This proves that there are conserved innate immunity pathways against viruses between mammals and insects. We will do a genetic screen for virus-sensitive flies. We will make and screen a collection of 2000 P-element insertion lines. The assay will consist of feeding DCV to larvae and scoring for lethality. We will select the lines that show greater sensitivity to the virus and have higher titres of virus than control flies. From this set we will select a few genes for more detailed analysis. We will also make a detailed analysis of the Drosophila larvae response to DCV infection. We will first establish an infection method that can be controlled in time and space. We will then analyse the expression profiles of single tissues from infected and non-infected flies, at different time points. This analysis will give valuable information about the dynamics of DCV infection. It will also provide candidate genes that are involved in anti-viral response. These will be further studied. Finally we will study in detail the function of a few selected genes, preferentially with mammalian homologues. Traditional Drosophila genetic tools and tissue culture assays will be used.

Summary

Animals must defend themselves from invading pathogens. They do so by an immune response. The fruit fly, Drosophila melanogaster, has been extensively used to study the immune response to pathogens. Basic mechanisms and molecules involved in this response are conserved between flies and mammals. Moreover, discoveries made in Drosophila have prompted research in mammalian immunity. Most of what is known about the Drosophila immunity concerns the responses to bacteria and fungi. Recently, however, a study from Dr. Imler and colleagues, in Strasbourg, showed that there is also conservation between the anti-viral response of flies and mammals. The overall objective of this research is to understand how Drosophila recognizes and fights viral infections. The first objective of this research is to identify genes involved in anti-viral immunity. One way of identifying genes required to fight viral infections is to perform a genetic screen. We will first randomly generate a collection of potential mutants. This will consist on 2000 different fly lines, each one with a different transposon insertion. We will then feed Drosophila C Virus (DCV) to fly larvae and score the associated lethality for each mutant. The fly lines that show more sensitivity to the virus may have mutated genes that would normally play a role in the anti-viral response. Our aim is to identify a set of these genes. We will then analyse in detail a selection of these genes; we will select genes that are similar to mammalian genes so that the knowledge acquired in this research may be transferred to work in mammalian immunity. A different approach will be to identify genes that are activated by viral infection. Part of the reaction of an organism to viral infection is expected to be activation of genes involved in fighting that viral infection. Identifying these genes will elucidate how the anti-viral immune response acts. We will identify genes activated in virus-infected organs. We will also identifygenes activated in non-infected organs of infected animals. This will lead to a better understanding of how the whole organism reacts to a viral infection. The description of this reaction to a viral infection is important in itself and will also provide a list of genes to further analyse in detail. Finally, we will analyse in detail the function of selected genes. This analysis will be dependent, to great extent, on the nature of the genes. Drosophila is an excellent organism for genetic analysis. The genetics tools and techniques available to work with the fruit fly will allow a fast and detailed analysis. The anti-viral immune response of Drosophila is a promising field with much to explore. What is known so far indicates that understanding Drosophila response against viruses may lead to a better understanding of the mammalian response against viruses.

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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