Saucereau, YoannWilson, Thomas H.Tang, Matthew C. K.Moncrieffe, Martin C.Hardwick, Steven W.Chirgadze, Dimitri Y.Soares, Sandro G.Marcaida, Maria JoseGay, Nicholas J.Gangloff, Monique2022-09-122022-09-122022-09-122022-08-3010.1038/s41467-022-32690-6https://infoscience.epfl.ch/handle/20.500.14299/190634WOS:000847797500027Aedes aegypti can act as a vector for viral pathogens but the mechanism of viral resistance and evolving host-pathogen tolerance are poorly understood. Here the authors structurally characterise a duplicated pair of interacting Toll immunoreceptors and the cytokine ligand Spaetzle1C and show their dose-dependent function and mechanism of activation. Aedes aegypti has evolved to become an efficient vector for arboviruses but the mechanisms of host-pathogen tolerance are unknown. Immunoreceptor Toll and its ligand Spaetzle have undergone duplication which may allow neofunctionalization and adaptation. Here we present cryo-EM structures and biophysical characterisation of low affinity Toll5A complexes that display transient but specific interactions with Spaetzle1C, forming asymmetric complexes, with only one ligand clearly resolved. Loop structures of Spaetzle1C and Toll5A intercalate, temporarily bridging the receptor C-termini to promote signalling. By contrast unbound receptors form head-to-head homodimers that keep the juxtamembrane regions far apart in an inactive conformation. Interestingly the transcriptional signature of Spaetzle1C differs from other Spaetzle cytokines and controls genes involved in innate immunity, metabolism and tissue regeneration. Taken together our results explain how upregulation of Spaetzle1C in the midgut and Toll5A in the salivary gland shape the concomitant immune response.Multidisciplinary SciencesScience & Technology - Other Topicscystine-knot proteincryo-emdrosophila-melanogasternegative cooperativitycytokine spatzleimmune-responsereceptorligandrecognitionmechanismtext::journal::journal article::research article