Tick galactosyltransferases are involved in \u03b1-Gal synthesis and play a role during Anaplasma phagocytophilum infection and Ixodes scapularis tick vector development

Alejandro Cabezas-Cruz,James J Valdés,Pedro J Espinosa,Ladislav Šimo,Margarita Villar Rayo,José De La Fuente,Pilar Alberdi,Lourdes Mateos-Hernández,Marinela Contreras

doi:10.1038/s41598-018-32664-z

Abstract

The carbohydrate Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) is produced in all mammals except for humans, apes and old world monkeys that lost the ability to synthetize this carbohydrate. Therefore, humans can produce high antibody titers against α-Gal. Anti-α-Gal IgE antibodies have been associated with tick-induced allergy (i.e. α-Gal syndrome) and anti-α-Gal IgG/IgM antibodies may be involved in protection against malaria, leishmaniasis and Chagas disease. The α-Gal on tick salivary proteins plays an important role in the etiology of the α-Gal syndrome. However, whether ticks are able to produce endogenous α-Gal remains currently unknown. In this study, the Ixodes scapularis genome was searched for galactosyltransferases and three genes were identified as potentially involved in the synthesis of α-Gal. Heterologous gene expression in α-Gal-negative cells and gene knockdown in ticks confirmed that these genes were involved in α-Gal synthesis and are essential for tick feeding. Furthermore, these genes were shown to play an important role in tick-pathogen interactions. Results suggested that tick cells increased α-Gal levels in response to Anaplasma phagocytophilum infection to control bacterial infection. These results provided the molecular basis of endogenous α-Gal production in ticks and suggested that tick galactosyltransferases are involved in vector development, tick-pathogen interactions and possibly the etiology of α-Gal syndrome in humans.

Highlights

Enzymatic glycosylation of proteins and lipids is a common and important biological process in prokaryotic and eukaryotic organisms
While β1-3 and β1-4 GALTs are widely distributed in Metazoa, α1-3 and α1-4 GALTs are limited to Craniata and Arthropods and Craniata, respectively (Supplementary Fig. S2)
We hypothesized that tick α1-4 and/or β1-4 GALT enzymes might be involved in the synthesis of the α1-3 GALTs that produce the glycan Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal) epitope

Summary

Introduction

Enzymatic glycosylation of proteins and lipids is a common and important biological process in prokaryotic and eukaryotic organisms. It was recently demonstrated that anti-α-Gal antibodies in ggta[1] KO mice blocked Plasmodium (P. berghei and P. yoelii) transmission by Anopheles mosquitoes through binding to α-Gal present on Plasmodium surface and subsequent activation of the complement cascade[4] This result suggested that the inactivation of genes encoding enzymes that synthetize α-Gal was a major evolutionary step toward resistance to pathogens containing α-Gal on their surface[18,19]. The presence of α-Gal on the surface of tick salivary proteins was associated to tick-induced allergy to red meat[3,20,21] It is currently unknown whether tick and mosquitoes can produce endogenous α-Gal[4,21], and whether α-Gal plays a role in vector-pathogen interactions. These enzymes play an important role during tick development and tick-A. phagocytophilum interactions

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Results

Discussion

Conclusion