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The principal Afrotropical human malaria vector mosquito, Anopheles gambiae, remains a significant threat to global health. A critical component in the transmission of malaria is the ability of An. gambiae females to detect and respond to human-derived chemical kairomones in their search for blood meal hosts. The basis for host odor responses resides in olfactory receptor neurons (ORNs) that express chemoreceptors encoded by large gene families, including the odorant receptors (ORs) and the variant ionotropic receptors (IRs). While ORs have been the focus of extensive investigation, functional IR complexes and the chemical compounds that activate them have not been identified in An. gambiae. Here we report the transcriptional profiles and functional characterization of three An. gambiae IR (AgIr) complexes that specifically respond to amines or carboxylic acids - two classes of semiochemicals that have been implicated in mediating host-seeking by adult females but are not known to activate An. gambiae ORs (AgOrs). Our results suggest that AgIrs play critical roles in the detection and behavioral responses to important classes of host odors that are underrepresented in the AgOr chemical space.
Figure 1. AgIr transcript abundances in adult appendages and larval heads.Heat map depicting abundances of An. gambiae variant ionotropic receptors (AgIrs) in adult chemosensory tissues (data adapted from28). Scale color intensity indicates Reads Per Kilobase per Million reads (RPKM).
Figure 2. Expression of AgIr76b and AgOrco in An. gambiae antennae.(AâD) Double in situ hybridization using antisense RNA probes showing transcript localizations for the co-receptors AgIr76b (green) and AgOrco (red) are localized within distinct cells within adult female antennae. Yellow arrowheads indicate areas of overlap between green and red signals, due to spatial proximity of distinct cells. (EâH) In situ hybridization using an AgIr76b antisense RNA probe (green) plus immunohistochemical localization of AgOrco using an anti-Orco antibody (red). Scale bars ~50âμm.
Figure 3. Phylogenetic relationships among AgIR41-related receptors.(A) Pairwise amino acid percent identity matrix. (B) Cladograms based on sequence alignments of all AgIRs (circular cladogram) with AgIR41 clade (yellow circle) shown using the N-Methyl-D-Aspartate Receptor 1 (AgNMDAR1) as an outgroup. (C) Alignment of AgIR41a and AgIR41c amino acid sequences using the single letter code. Identical residues are indicated with black boxes over white text. Similar residues are shaded with gray boxes. Numbering indicates aligned positions, including gaps.
Figure 4. Functional analysis of AgIR41a and AgIR41c complexes in Xenopus laevis oocytes.(A) cRNAs encoding AgIr41a or AgIr41c (co-injected with AgIr25a and AgIr76b) elicit distinct profiles of chemically-evoked inward currents. Bars indicate mean normalized responses (+/â SEM) for each compound [10â4âM] compared with the maximum response to pyrrolidine. Lower case letters indicate significant differences among mean responses (41a complex, Pâ<â0.03 for all comparisons; 41c complex, Pâ<â0.01 for aâ-bâ and aâ-câ comparisons, Pâ<â0.07 for bâ-câ comparisons). nâ=â4 oocytes per trial. (B,C) Concentration-response profiles of AgIR41a (B) or AgIR41c (C) complexes in response to pyrrolidine (closed circles) plotted on log scales. EC50 values (open red circles) are shown. Each data point represents the mean+/â SD (bars). Mean EC50 values are significantly different (t-test; Pâ<â0.001). Representative TEVC traces showing inward current responses to increasing concentrations of pyrrolidine for each AgIR complex (top). nâ=â4 oocytes each.
Figure 5. Phylogenetic relationships among AgIR75-related receptors.(A) Pairwise amino acid percent identity matrix. (B) Cladograms based on sequence alignments of all AgIRs (circular cladogram) with AgIR75 clade (green) shown using the N-Methyl-D-Aspartate Receptor 1 (AgNMDAR1) as an outgroup. (C) Alignment of AgIR75k and AgIR75l amino acid sequences using the single letter code. Identical residues are indicated with black boxes over white text. Similar residues are shaded with gray boxes. Numbering indicates aligned positions, including gaps.
Figure 6. Functional analysis of the AgIR75k complex in Xenopus laevis oocytes.(A) cRNA encoding AgIr75k (co-injected with AgIr8a) elicits chemically-evoked inward currents in response to short chain carboxylic acids. Bars indicate mean normalized responses (+/â SEM) for each compound [10â4 M] compared with the maximum response to nonanoic acid. Lower case letters indicate significant differences among mean responses (Pâ<â0.01 for all comparisons). nâ=â13 oocytes per trial. (B) Concentration-response profiles of the AgIR75k complex in response to nonanoic (closed circles) plotted on a log scale. EC50 value (open red circle) is shown. Each data point represents the mean+/â SD (bars). Representative TEVC trace showing inward current responses to increasing concentrations of nonanoic acid for the AgIR75k complex (top). nâ=â8 oocytes each.
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