Susceptibility to L. sigmodontis infection is highest in animals lacking IL-4R/IL-5 compared to single knockouts of IL-4R, IL-5 or eosinophils

Stefan J Frohberger,Benedikt C Buerfent,Jesuthas Ajendra,Marc P Hübner,Wiebke Stamminger,Alexandra Ehrens,Katrin Gentil,Achim Hoerauf,Jayagopi Surendar

doi:10.1186/s13071-019-3502-z

Abstract

BackgroundMice are susceptible to infections with the rodent filarial nematode Litomosoides sigmodontis and develop immune responses that resemble those of human filarial infections. Thus, the L. sigmodontis model is used to study filarial immunomodulation, protective immune responses against filariae and to screen drug candidates for human filarial diseases. While previous studies showed that type 2 immune responses are protective against L. sigmodontis, the present study directly compared the impact of eosinophils, IL-5, and the IL-4R on the outcome of L. sigmodontis infection.MethodsSusceptible wildtype (WT) BALB/c mice, BALB/c mice lacking eosinophils (dblGATA mice), IL-5−/− mice, IL-4R−/− mice and IL-4R−/−/IL-5−/− mice were infected with L. sigmodontis. Analyses were performed during the peak of microfilaremia in WT animals (71 dpi) as well as after IL-4R−/−/IL-5−/− mice showed a decline in microfilaremia (119 dpi) and included adult worm counts, peripheral blood microfilariae levels, cytokine production from thoracic cavity lavage, the site of adult worm residence, and quantification of major immune cell types within the thoracic cavity and spleen.ResultsOur study reveals that thoracic cavity eosinophil numbers correlated negatively with the adult worm burden, whereas correlations of alternatively activated macrophage (AAM) numbers with the adult worm burden (positive correlation) were likely attributed to the accompanied changes in eosinophil numbers. IL-4R−/−/IL-5−/− mice exhibited an enhanced embryogenesis achieving the highest microfilaremia with all animals becoming microfilariae positive and had an increased adult worm burden combined with a prolonged adult worm survival.ConclusionsThese data indicate that mice deficient for IL-4R−/−/IL-5−/− have the highest susceptibility for L. sigmodontis infection, which resulted in an earlier onset of microfilaremia, development of microfilaremia in all animals with highest microfilariae loads, and an extended adult worm survival.

Highlights

Mice are susceptible to infections with the rodent filarial nematode Litomosoides sigmodontis and develop immune responses that resemble those of human filarial infections
IL‐4R, IL‐5 and eosinophils control the occurrence of microfilaremia, whereas IL‐5 and eosinophils impair adult worm survival and maintenance of microfilaremia In order to directly compare the impact of IL-4 receptor (IL-4R), IL-5, IL-4R/IL-5 and eosinophils on the development of L. sigmodontis infection, we analyzed the MF burden over time, the frequency of animals developing microfilaremia and determined total adult worm numbers and worm lengths at 71 dpi, which represents a time point around the microfilariae peak in WT animals, and at 119 dpi, a time point most WT animals cleared the infection and IL-4R−/−/IL-5−/−mice showed a first decline in the MF load
Microfilaremia persisted in IL-4R−/−/IL-5−/−, dblGATA, and IL-5−/− mice for > 120 dpi, while microfilaremia declined in IL-4R−/− and WT controls following 78 dpi (Fig. 1a)

Summary

Introduction

Mice are susceptible to infections with the rodent filarial nematode Litomosoides sigmodontis and develop immune responses that resemble those of human filarial infections. Parasitic filarial nematodes can cause debilitating diseases that stigmatize the affected individuals by causing blindness and severe dermatitis in onchocerciasis patients and lymphedema in limbs (elephantiasis) and scrotum (hydrocele) in lymphatic filariasis patients. Regulatory immune responses develop during human filarial infection that suppress both type 1 and type 2 immune responses [6, 7] These type 2 immune responses are associated with protective immune responses and the development of filarial pathology during onchocerciasis, as patients that develop hyperreactive onchocerciasis with severe skin disease have the strongest type 2 immune responses, but have reduced microfilariae (MF) levels [8, 9]. Development of lymphedema on the other hand has been associated with pronounced parasite-specific Th1 and Th17 responses [11]

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