Diedel, induced by NF-kB pathway, regulates tolerance during Sindbis infection. Olivier Lamiable¹, Cordula Kemp¹, Friedemann Weber², Laurent Troxler¹, Nadege Pelte^3,4, Michael Boutros⁴, Charles Hetru¹, Jean-Luc Imler¹. 1) Institut de Biologie Moléculaire et Cellulaire CNRS UPR9022, Strasbourg, France; 2) Institut für Medizinische Mikrobiologie und Hygiene, Freiburg, Germany; 3) Donnelly Centre for Cellular and Biomolecular research, Toronto, Canada; 4) Department of Cell and Molecular Biology, Heidelberg University, Heidelberg, Germany.

   Infection of Drosophila by viruses leads to an innate immune response, which involves different facets. On one hand, the small interfering (si) RNA pathway contributes to the recognition and degradation of the viral RNAs. On the other hand, an inducible response contributes to the host defense, but the regulation of this response and the role of the induced effectors molecules are still poorly understood.Using genome-wide microarrays, we identified the gene Diedel (CG11501) that is strongly induced during Sindbis (SINV) infection. Diedel is an early response gene, which is also strongly induced by another arbovirus, Vesicular Stomatitis Virus (VSV). The gene encodes a 12 kDa circulating protein, secreted by the fat body upon infection. Induction of Diedel expression does not depend on the Jak/STAT pathway, or the NF-kB related transcription factor Relish, but is completely abolished in flies mutant for the gene encoding Dif, another NF-kB related transcription factor. In vitro and ex vivo analyses do not support the hypothesis that Diedel acts as an antiviral molecule. In vivo analyses of Diedel null mutant flies revealed a dual role for Diedel, first in viability during developmental and adult stages, and second in the tolerance to SINV infection. Indeed, Diedel mutant flies have similar viral loads than wild-type controls, but succumb more rapidly to SINV infection. Microarray analysis of infected mutant flies pointed to a strong increase of the inducible response to infection, suggesting that Diedel encodes a cytokine acting in the maintenance of homeostasis during viral infection.