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Brugia malayi infection in ferrets - A small mammal model of lymphatic filariasis.

ABSTRACT: The lack of effective short-course therapies for treatment of the adult stage of filarial worms is a major limitation in the global effort to eliminate lymphatic filariasis. Studies using current small mammal models of lymphatic filariasis are limited by difficulties in quantifying adult worm numbers and in assessing lymphatic anatomy and function.Here, we re-established Brugia malayi infection of ferrets as a model for lymphatic filariasis and demonstrated parasitological, immunological, and histological parallels with human infection. Subcutaneous injection of L3 larvae into a hind-footpad resulted in a mean of 18 adult worms recovered 16 weeks post-infection, primarily from the draining inguinal and femoral lymphatics of the injected limb. Infected ferrets developed microfilaremia, with patency lasting from 12-26 weeks post-infection. Quantitative PCR assessing cytokine transcription by antigen-stimulated lymph node cells demonstrated a mixed Th1/Th2 response occurring during early infection. Immunoregulation with production of down-regulatory cytokine IL-10 occurred just prior to peak microfilaremia. Histological analysis revealed progressive inflammation of the lymphatic vessel walls, with intimal thickening and disorganization of collagen fibers. Inflammation was observed as early as 8 weeks post-infection and extended into the perivascular and subcutaneous tissues by 16 weeks post-infection. Finally, we developed a novel ferret PET/CT lymphoscintigraphy method demonstrating substantial changes in lymphatic anatomy and function as early as 3 weeks post-infection, with progression over the course of infection.B. malayi infection of ferrets is a robust model of human lymphatic filariasis that can be utilized to study efficacy of novel antifilarial agents against adult worms residing within lymphatic vessels. In conjunction with PET/CT lymphoscintigraphy, this model can also be used to investigate pathogenesis of lymphatic dysfunction in lymphatic filariasis and efficacy of medications aimed at reversing lymphatic dysfunction after clearance of adult worms.

SUBMITTER: Jackson-Thompson BM

PROVIDER: S-EPMC5895066 | biostudies-other | 2018 Mar

REPOSITORIES: biostudies-other

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Brugia malayi infection in ferrets - A small mammal model of lymphatic filariasis.

Jackson-Thompson Belinda M BM Kim So Young SY Jaiswal Shalini S Scott Jessica R JR Jones Scott R SR Morris C Paul CP Fite J Judd JJ Laurie Karen K Hoy Andrew R AR Dardzinski Bernard J BJ Mitre Edward E

PLoS neglected tropical diseases 20180330 3

<h4>Background</h4>The lack of effective short-course therapies for treatment of the adult stage of filarial worms is a major limitation in the global effort to eliminate lymphatic filariasis. Studies using current small mammal models of lymphatic filariasis are limited by difficulties in quantifying adult worm numbers and in assessing lymphatic anatomy and function.<h4>Methodology/principal findings</h4>Here, we re-established Brugia malayi infection of ferrets as a model for lymphatic filarias ...[more]

PMID: 29601572

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Project description:Brugia malayi is a causative agent of lymphatic filariasis, a major tropical disease. The infective L3 parasite stage releases immunomodulatory proteins including the venom allergen-like proteins (VALs), which are members of the SCP/TAPS (Sperm-coating protein/Tpx/antigen 5/pathogenesis related-1/Sc7) superfamily. BmVAL-1 is a major target of host immunity with >90% of infected B. malayi microfilaraemic cases being seropositive for antibodies to BmVAL-1. This study is part of ongoing efforts to characterize the structures and functions of important B. malayi proteins. Recombinant BmVAL-1 was produced using a plant expression system, crystallized and the structure was solved by molecular replacement and refined to 2.1 Å, revealing the characteristic alpha/beta/alpha sandwich topology of eukaryotic SCP/TAPS proteins. The protein has more than 45% loop regions and these flexible loops connect the helices and strands, which are longer than predicted based on other parasite SCP/TAPS protein structures. The large central cavity of BmVAL-1 is a prototypical CRISP cavity with two histidines required to bind divalent cations. The caveolin-binding motif (CBM) that mediates sterol binding in SCP/TAPS proteins is large and open in BmVAL-1 and is N-glycosylated. N-glycosylation of the CBM does not affect the ability of BmVAL-1 to bind sterol in vitro. BmVAL-1 complements the in vivo sterol export phenotype of yeast mutants lacking their endogenous SCP/TAPS proteins. The in vitro sterol-binding affinity of BmVAL-1 is comparable with Pry1, a yeast sterol transporting SCP/TAPS protein. Sterol binding of BmVAL-1 is dependent on divalent cations. BmVAL-1 also has a large open palmitate-binding cavity, which binds palmitate comparably to tablysin-15, a lipid-binding SCP/TAPS protein. The central cavity, CBM and palmitate-binding cavity of BmVAL-1 are interconnected within the monomer with channels that can serve as pathways for water molecules, cations and small molecules.

Project description:BackgroundLymphatic filariasis (LF), often referred to as elephantiasis, has been identified as one of the 17 neglected tropical diseases by the World Health Organization. Currently, there are no vaccines available to treat this infection in humans. Therefore, with the objective of devising a novel preventive measure, we exploited an immunoinformatics approach to design a multi-epitope-based subunit vaccine for LF, that can elicit a variety of immune responses within the host. In this study, different B cell, TC cell, and TH cell-binding epitopes were screened from the antigenic proteins of Brugia malayi and they were passed through several immunological filters to determine the optimal epitopes.ResultsAs a result, 15 CD8+, 3 CD4+, and 3 B cell epitopes were found to be prominent, antigenic, non-toxic, immunogenic and non-allergenic. The presence of conformational B cell epitopes and cytokine-inducing epitopes confirmed the humoral and cell-mediated immune response that would be triggered by the constructed vaccine model. Following that, the selected epitopes and TLR-4-specific adjuvant were ligated by appropriate peptide linkers to finalize the vaccine construct. Protein-protein docking of the vaccine structure with the TLR4 receptor predicted strong binding affinity and hence putatively confirms its ability to elicit an immune response. Further, the efficiency of the vaccine candidate to provide a long-lasting protective immunity was assessed by in silico immune simulation. The reverse translated vaccine sequence was also virtually cloned in the pET28a (+) plasmid after the optimization of the gene sequence.ConclusionSo taken together, by monitoring the overall in silico assessment, we hypothesize that our engineered peptide vaccine could be a viable prophylactic approach in the development of vaccines against the threat of human lymphatic filariasis.Graphical abstractSupplementary informationThe online version contains supplementary material available at 10.1186/s42269-023-01013-0.

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Brugia malayi infection in ferrets - A small mammal model of lymphatic filariasis.

Publications

Brugia malayi infection in ferrets - A small mammal model of lymphatic filariasis.

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