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

Belinda M. Jackson-Thompson, So Young Kim, Shalini Jaiswal, Jessica R. Scott, Scott R. Jones, C. Paul Morris, Joshua Fite, Karen Laurie, Andrew R. Hoy, Bernard J. Dardzinski, Edward Mitre

Research output: Contribution to journalArticle

Abstract

Background: 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. Methodology/Principal findings: 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. Conclusions/Significance: 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.

Original languageEnglish (US)
Article numbere0006334
JournalPLoS Neglected Tropical Diseases
Volume12
Issue number3
DOIs
StatePublished - Mar 30 2018

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Brugia malayi
Filarial Elephantiasis
Ferrets
Mammals
Infection
Lymphoscintigraphy
Lymphatic Vessels
Anatomy
Tunica Intima
Cytokines
Inflammation
Groin
Subcutaneous Tissue
Subcutaneous Injections
Thigh
Interleukin-10
Larva
Collagen
Extremities
Lymph Nodes

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

Jackson-Thompson, B. M., Kim, S. Y., Jaiswal, S., Scott, J. R., Jones, S. R., Morris, C. P., ... Mitre, E. (2018). Brugia malayi infection in ferrets – A small mammal model of lymphatic filariasis. PLoS Neglected Tropical Diseases, 12(3), [e0006334]. https://doi.org/10.1371/journal.pntd.0006334

Brugia malayi infection in ferrets – A small mammal model of lymphatic filariasis. / Jackson-Thompson, Belinda M.; Kim, So Young; Jaiswal, Shalini; Scott, Jessica R.; Jones, Scott R.; Morris, C. Paul; Fite, Joshua; Laurie, Karen; Hoy, Andrew R.; Dardzinski, Bernard J.; Mitre, Edward.

In: PLoS Neglected Tropical Diseases, Vol. 12, No. 3, e0006334, 30.03.2018.

Research output: Contribution to journalArticle

Jackson-Thompson, BM, Kim, SY, Jaiswal, S, Scott, JR, Jones, SR, Morris, CP, Fite, J, Laurie, K, Hoy, AR, Dardzinski, BJ & Mitre, E 2018, 'Brugia malayi infection in ferrets – A small mammal model of lymphatic filariasis', PLoS Neglected Tropical Diseases, vol. 12, no. 3, e0006334. https://doi.org/10.1371/journal.pntd.0006334
Jackson-Thompson BM, Kim SY, Jaiswal S, Scott JR, Jones SR, Morris CP et al. Brugia malayi infection in ferrets – A small mammal model of lymphatic filariasis. PLoS Neglected Tropical Diseases. 2018 Mar 30;12(3). e0006334. https://doi.org/10.1371/journal.pntd.0006334
Jackson-Thompson, Belinda M. ; Kim, So Young ; Jaiswal, Shalini ; Scott, Jessica R. ; Jones, Scott R. ; Morris, C. Paul ; Fite, Joshua ; Laurie, Karen ; Hoy, Andrew R. ; Dardzinski, Bernard J. ; Mitre, Edward. / Brugia malayi infection in ferrets – A small mammal model of lymphatic filariasis. In: PLoS Neglected Tropical Diseases. 2018 ; Vol. 12, No. 3.
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abstract = "Background: 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. Methodology/Principal findings: 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. Conclusions/Significance: 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.",
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