|Viruses and RNA Interference - CNRS URA 3015|
|HEAD||Dr. Maria-Carla SALEH / email@example.com|
|MEMBERS||Maria-Carla Saleh (PhD) Valérie Dorey (Technician) Isabelle Dulieu (Secretary) Bertsy Goic-Figueroa (PhD) Benjamin Obadia (PhD student) Nicolas Vodovar (PhD)
RNAi-mediated viral immunity in insects
The term arbovirus refers to a taxonomically diverse group of mostly RNA viruses that share a similar ecology and maintenance mechanism. The name arbovirus, for arthropod-borne virus, refers to a complex life cycle requiring horizontal transmission by an haematophagous arthropod vector/host between susceptible vertebrate hosts. Although most arboviruses cycle between the insect and small mammals or birds, increasingly frequent crossover events to domesticated animals and humans have resulted in both sporadic epidemics, as well as larger sweeping pandemics.
The economic and health impact of these emerging epidemics has dramatically increased interest into understanding how arboviruses evolve and maintain the ability to cycle between very different hosts. The emphasis of research is now shifting from studying arbovirus infection of human cells, to understanding how the virus behaves within the arthropod vector. Increasing evidence suggests that understanding and controlling the infection in the arthropod before crossover to the mammalian host may be key to combating arboviral infections.
In addition to cell type and tissue specific constraints exerted on the arbovirus by the arthropod host, insects have an active antiviral defense called RNA interference (RNAi) that is able to seek out and destroy viral RNA. The antiviral RNA silencing response of invertebrates is adaptive, potent and rapid; and has features similar to the peptide-based adaptive immunity of mammals. At the whole organism level, RNA silencing may also have the capacity to provide long-term memory, as has been detected in plants; which, after recovering from a virulent primary infection maintain an RNA silencing-mediated resistance to secondary infections.
Studying the antiviral RNAi response in the arthropod, such as in the model organism Drosophila melanogaster, could unravel the mechanisms by which insects harbor virusesand may identify new approaches to control virus replication in the vector, reducing by consequence, transmission events.
It is known that insects can persistently carry one or more viral pathogens at low levels, without signs of disease. Recently we have become interested in understanding the molecular basis underlying the switch from a persistent to an acute infection and the putative association of the RNAi mechanism in this switch. Drosophila C virus, Flock house virus and Drosophila X virus are capable of infecting Drosophilaand trigger an effective RNAi response that is essential for the insect to survive viral infection. These RNA viruses are pathogenic for Drosophila S2 cells upon acute infection although these cells possess a functional antiviral RNAi machinery. Interestingly, we have recently generated S2 cell lines that are persistently infected by these viruses without displaying any pathogenic effects. Persistently infected cells produce a similar amount of total viable viral particles compared to acute infection, and importantly these particles are capable of triggering a lethal infection in adult flies. Altogether, these data suggest that the persistent infection state is mainly controlled by the insect antiviral response.
We analyzed the RNAi-mediated antiviral response in both conditions, persistent and acute infection, in vitro and in vivo by deep sequencing. The viral siRNAs profiles show that the RNAi machinery is functional (mainly vsiRNAs of 21 nts length) and works in similar way in acute and persistent infection. Also, the RNAi response in S2 cells is equivalent to the one obtained in wild type flies (w1118). The phenomenon of persistence cannot then be explained by a deficiency or an increase in the RNAi response, since the viral genome is targeted in similar way. We have also shown that the presence in transof a viral suppressor other than the one carried for the virus being processed does not affect the way in which the RNAi machinery processes the virus.
All together these data suggest that viruses are diced and loaded in a similar way by the RNAi machinery regardless the infection beingin vitro, in vivo, acute or persistent. Thus viral siRNAs profiles provide a “fingerprint” and work as a “viral signature” for each virus.
Keywords: antiviral RNAi, arboviruses, viral suppressors, drosophila, small RNAs, deep seq
Saleh MC, Tassetto M, van Rij RP, Goic B, Gausson V, Berry B, Jacquier C, Antoniewski C, Andino R. (2009) Antiviral immunity in Drosophila requires systemic RNA interference spread. Nature.Mar 19;458(7236):346-50.
van Rij RP, Saleh MC, Berry B, Foo C, Houk A, Antoniewski C, Andino R. (2006) The RNA silencing endonuclease Argonaute 2 mediates specific antiviral immunity in Drosophila melanogaster.Genes Dev.2006 20: 2985-2995.
Saleh MC, van Rij RP, Hekele A, Gillis A, Foley E, O'farrell PH, Andino R. (2006) The endocytic pathway mediates cell entry of dsRNA to induce RNAi silencing. Nat Cell Biol.Aug;8(8):793-802.
b- Chapters in collective volumes
Goic B and Saleh MC.(2008) RNA interference and its role in antiviral defense. In Association des Anciens Elèves de l’Institut Pasteur(AAEIP). Dec;50(197):157-162
Goic B and Saleh MC.(2009) RNAi: an antiviral defense system in insects. In RNAi and Viruses: Current Innovations and Future Trends(Horizon Scientific Press). ISBN: 978-1-904455-56-1.
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