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Dectin-3-targeted antifungal liposomes efficiently bind and kill diverse fungal pathogens
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  • Richard B. Meagher,
  • Quanita J. Choudhury,
  • Suresh Ambati,
  • Collin D. Link,
  • Xiaorong Lin,
  • Zachary Lewis
Richard B. Meagher
University of Georgia Department of Genetics

Corresponding Author:meagher@uga.edu

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Quanita J. Choudhury
University of Georgia Department of Microbiology
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Suresh Ambati
University of Georgia Department of Genetics
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Collin D. Link
University of Georgia Department of Microbiology
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Xiaorong Lin
University of Georgia Department of Microbiology
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Zachary Lewis
University of Georgia Department of Microbiology
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Abstract

DectiSomes are anti-infective drug-loaded liposomes targeted to pathogenic cells by pathogen receptors including the Dectins. We have previously used C-type lectin (CTL) pathogen receptors Dectin-1, Dectin-2, and DC-SIGN to target DectiSomes to the extracellular oligoglycans surrounding diverse pathogenic fungi and kill them. Dectin-3 (a.k.a. MCL, CLEC4D) is a CTL pathogen receptor whose known cognate ligands are partly distinct from other CTLs. We expressed and purified a truncated Dectin-3 polypeptide (DEC3) comprised of its carbohydrate recognition domain and stalk region. We prepared amphotericin B (AmB)-loaded pegylated liposomes (AmB-LLs) and coated them with this isoform of Dectin-3 (DEC3-AmB-LLs), and we prepared control liposomes coated with Bovine Serum Albumin (BSA-AmB-LLs). DEC3-AmB-LLs bound to the exopolysaccharide matrices of Candida albicans, Rhizopus delemar (f.k.a. R. oryzae), and Cryptococcus neoformans from one to several orders of magnitude more strongly than untargeted AmB-LLs or BSA-AmB-LLs. The data from our quantitative fluorescent binding assays were standardized using a CellProfiler program, AreaPipe, that was developed for this purpose. Consistent with enhanced binding, DEC3-AmB-LLs inhibited and/or killed C. albicans and R. delemar more efficiently than control liposomes, which significantly reduced the effective dose of AmB. In conclusion, Dectin-3 targeting has the potential to advance our goal of building pan-antifungal DectiSomes.
10 Feb 2023Submitted to Molecular Microbiology
12 Feb 2023Submission Checks Completed
12 Feb 2023Assigned to Editor
12 Feb 2023Reviewer(s) Assigned
17 Mar 2023Review(s) Completed, Editorial Evaluation Pending
19 Mar 2023Editorial Decision: Revise Minor
23 Aug 20231st Revision Received
24 Aug 2023Submission Checks Completed
24 Aug 2023Assigned to Editor
28 Aug 2023Reviewer(s) Assigned
04 Sep 2023Review(s) Completed, Editorial Evaluation Pending
21 Sep 2023Editorial Decision: Accept