Structure and dynamics of Toll immunoreceptor activation in the mosquito Aedes aegypti

Yoann Saucereau, Thomas H. Wilson, Matthew C. K. Tang, Martin C. Moncrieffe, Steven W. Hardwick, Dimitri Y. Chirgadze, Sandro G. Soares, Maria Jose Marcaida, Nicholas J. Gay and Monique Gangloff ()
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Yoann Saucereau: University of Cambridge
Thomas H. Wilson: University of Cambridge
Matthew C. K. Tang: University of Cambridge
Martin C. Moncrieffe: University of Cambridge
Steven W. Hardwick: University of Cambridge
Dimitri Y. Chirgadze: University of Cambridge
Sandro G. Soares: University of Cambridge
Maria Jose Marcaida: Ecole Polytechnique Fédérale de Lausanne
Nicholas J. Gay: University of Cambridge
Monique Gangloff: University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32690-6

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