Abstract

Despite long-term mass drug administration programmes, approximately 220 million people are still infected with filariae in endemic regions. Several research studies have characterized host immune responses but a major obstacle for research on human filariae has been the inability to obtain adult worms which in turn has hindered analysis on infection kinetics and immune signalling. Although the Litomosoides sigmodontis filarial mouse model is well-established, the complex immunological mechanisms associated with filarial control and disease progression remain unclear and translation to human infections is difficult, especially since human filarial infections in rodents are limited. To overcome these obstacles, we performed adoptive immune cell transfer experiments into RAG2IL-2Rγ-deficient C57BL/6 mice. These mice lack T, B and natural killer cells and are susceptible to infection with the human filaria Loa loa. In this study, we revealed a long-term release of L. sigmodontis offspring (microfilariae) in RAG2IL-2Rγ-deficient C57BL/6 mice, which contrasts to C57BL/6 mice which normally eliminate the parasites before patency. We further showed that CD4+ T cells isolated from acute L. sigmodontis-infected C57BL/6 donor mice or mice that already cleared the infection were able to eliminate the parasite and prevent inflammation at the site of infection. In addition, the clearance of the parasites was associated with Th17 polarization of the CD4+ T cells. Consequently, adoptive transfer of immune cell subsets into RAG2IL-2Rγ-deficient C57BL/6 mice will provide an optimal platform to decipher characteristics of distinct immune cells that are crucial for the immunity against rodent and human filarial infections and moreover, might be useful for preclinical research, especially about the efficacy of macrofilaricidal drugs.

Highlights

  • Almost 4 decades ago, vector control and mass drug administration (MDA) programmes against lymphatic filariasis (LF) and onchocerciasis have been initiated to eliminate these diseases [1, 2]

  • Since RAG2IL-2Rg-deficient C57BL/6 mice lack T, B and natural killer cells [55], we suggested that adoptive cell transfer experiments might reveal crucial immune cell subsets and immune mechanisms that are important for immunity against filariae

  • Several studies showed that filariae modulate immunity in humans through the induction of Th2 and regulatory T and B cell populations accompanied with the suppression of pro-inflammatory and Th1 immune responses to guarantee long-term survival and reproduction of the parasite [10,11,12,13,14,15,16,17,18,19, 63]

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Summary

Introduction

Almost 4 decades ago, vector control and mass drug administration (MDA) programmes against lymphatic filariasis (LF) and onchocerciasis have been initiated to eliminate these diseases [1, 2]. Several studies have characterized host immunity during filarial infections and revealed that filarial infections dampen and modulate host immune responses via the induction of regulatory B and T cell subsets, Th2 cell populations and distinct patterns of cytokines, chemokines and immunoglobulins accompanied with the suppression of Th1 and pro-inflammatory cell subsets [10,11,12,13,14,15,16,17,18] This immunomodulation leads in most infected people to an asymptomatic clinical picture which is essential for long-term survival of the parasites [19, 20], but is suggested to influence disease outcome of concomitant infections as well as vaccination efficacy [21,22,23]. Since RAG-deficient mice have been successfully infected with the human filaria Loa loa [34, 35] the implementation of the RAG2IL-2Rg-deficient C57BL/6 mouse model in combination with adoptive transfer experiments might be a useful platform to investigate immunity during human filarial infections

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