The Lyme Disease agent co-opts adiponectin receptor-mediated signaling in its arthropod vector
- Yale University, United States
- Yale University School of Medicine, United States
- University of Maryland, United States
Abstract
Adiponectin-mediated pathways contribute to mammalian homeostasis; however, little is known about adiponectin and adiponectin receptor signaling in arthropods. In this study, we demonstrate that Ixodes scapularis ticks have an adiponectin receptor-like protein (ISARL) but lack adiponectin - suggesting activation by alternative pathways. ISARL expression is significantly upregulated in the tick gut after Borrelia burgdorferi infection suggesting that ISARL-signaling may be co-opted by the Lyme disease agent. Consistent with this, RNA interference (RNAi)-mediated silencing of ISARL significantly reduced the B. burgdorferi burden in the tick. RNA-seq-based transcriptomics and RNAi assays demonstrate that ISARL-mediated phospholipid metabolism by phosphatidylserine synthase I is associated with B. burgdorferi survival. Furthermore, the tick complement C1q-like protein 3 interacts with ISARL, and B. burgdorferi facilitates this process. This study identifies a new tick metabolic pathway that is connected to the life cycle of the Lyme disease spirochete.
Data availability
The RNA-seq data are available in the Gene Expression Omnibus (GEO) repository at the National Center for Biotechnology Information under the accession number: GSE169293.
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The Lyme Disease agent co-opts adiponectin receptor-mediated signaling in its arthropod vectorNCBI Gene Expression Omnibus, GSE169293.
Article and author information
Author details
Funding
National Institutes of Health (AI126033)
- Erol Fikrig
National Institutes of Health (AI138949)
- Erol Fikrig
Steven and Alexandra Cohen Foundation
- Erol Fikrig
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Shaeri Mukherjee, University of California, San Francisco, United States
Ethics
Animal experimentation: Animal care and housing were performed according to the Guide for the Care and Use of laboratory Animals of National Institutes of Health, USA. All protocols in this study were approved by the Yale University Institutional Animal Care and Use Committee (YUIACUC) (approval number 2018-07941).
Version history
- Received: July 28, 2021
- Preprint posted: September 15, 2021 (view preprint)
- Accepted: November 4, 2021
- Accepted Manuscript published: November 16, 2021 (version 1)
- Version of Record published: December 2, 2021 (version 2)
- Version of Record updated: February 18, 2022 (version 3)
Copyright
© 2021, Tang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The Lyme Disease agent co-opts adiponectin receptor-mediated signaling in its arthropod vector
eLife 10:e72568.
https://doi.org/10.7554/eLife.72568
Further reading
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- Microbiology and Infectious Disease
- Structural Biology and Molecular Biophysics
African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but becomes covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance. To counter complement-mediated clearance, African trypanosomes have a cell surface receptor, ISG65, which binds to C3b and which decreases the rate of trypanosome clearance in an infection model. However, the mechanism by which ISG65 reduces C3b function has not been determined. We reveal through cryogenic electron microscopy that ISG65 has two distinct binding sites for C3b, only one of which is available in C3 and C3d. We show that ISG65 does not block the formation of C3b or the function of the C3 convertase which catalyses the surface deposition of C3b. However, we show that ISG65 forms a specific conjugate with C3b, perhaps acting as a decoy. ISG65 also occludes the binding sites for complement receptors 2 and 3, which may disrupt recruitment of immune cells, including B cells, phagocytes, and granulocytes. This suggests that ISG65 protects trypanosomes by combining multiple approaches to dampen the complement cascade.
