Abstract

Lymphatic filariasis, onchocerciasis and loiasis are widespread neglected tropical diseases causing serious public health problems and impacting the socio-economic climate in endemic communities. More than 100 million people currently suffer from filarial infections but disease-related symptoms and infection-induced immune mechanisms are still ambiguous. Although most infected individuals have dominant Th2 and regulatory immune responses leading to a homeostatic regulated state, filarial-induced overt pathology like lymphedema, dermal pathologies or blindness can occur. Interestingly, besides dominant Th2 and regulatory T cell activation, increased Th17-induced immune responses were associated with filarial infection and overt helminth-induced pathology in humans. However, the immunological mechanisms of Th17 cells and the release of IL-17A during filarial infections remain unclear. To decipher the role of IL-17A during filarial infection, we naturally infected IL-17A−/− and wildtype C57BL/6 mice with the rodent filariae Litomosoides sigmodontis and analysed parasite development and immune alterations. Our study reveals that infected IL-17A-deficient C57BL/6 mice present reduced worm burden on days 7 and 28 p.i. but had longer adult worms on day 28 p.i. in the thoracic cavity (TC), the site of infection. In addition, infiltration of CD4+ T cells, CD4+Foxp3+ regulatory T and functional CD4+Rorγt+pStat3+ Th17 cells in the TC was reduced in IL-17A-deficient mice accompanied by reduced eotaxin-1 and CCL17 levels. Furthermore, mediastinal lymph node cells isolated from IL-17A−/− mice showed increased filarial-specific IFN-γ but not IL-4, IL-6, or IL-21 secretion. This study shows that Th17 signalling is important for host immune responses against filarial infection but appears to facilitate worm growth in those that reach the TC.

Highlights

  • Factors that distinguish interleukin 17 (IL-17) CD4+ T cells from other Th populations include their regulation by the defined transcription factors: STAT3 and RORγτ in mouse; the aryl hydrocarbon receptor; and the requirement of IL-1β, IL-6 and TGF-β for their development (Korn et al 2009)

  • Our previous studies have shown that peripheral blood mononuclear cells (PBMCs) isolated from amicrofilaremic lymphatic filariasis (LF) patients secrete more IL-17 levels upon activation with αCD3/ αCD28 compared to endemic normals (Arndts et al 2012) and that Th17 cell frequencies are elevated in hyperreactive onchocerciasis and reduced in endemic normals accompanied with elevated CD4+IFN-γ+ frequencies (Katawa et al 2015)

  • Increased CD4+IL-17A+ basal levels in filarial-infected (Mansonella perstans and/or Wuchereria bancrofti) patients from Mali (Metenou et al 2010) and increased IL-17A secretion from PBMCs derived from microfilaria-positive LF patients upon αCD3/αCD28 stimulation (Arndts et al 2012) imply a critical role of Th17 immune responses during LF infection

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Summary

Introduction

Factors that distinguish interleukin 17 (IL-17) CD4+ T cells from other Th populations include their regulation by the defined transcription factors: STAT3 (signal transducer and activator of transcription 3) and RORγτ (retinoic acid receptorrelated orphan receptor-γτ) in mouse; the aryl hydrocarbon receptor; and the requirement of IL-1β, IL-6 and TGF-β (transforming growth factor β) for their development (Korn et al 2009). Our previous studies have shown that PBMCs isolated from amicrofilaremic LF patients secrete more IL-17 levels upon activation with αCD3/ αCD28 compared to endemic normals (Arndts et al 2012) and that Th17 cell frequencies are elevated in hyperreactive onchocerciasis and reduced in endemic normals accompanied with elevated CD4+IFN-γ+ frequencies (Katawa et al 2015). Despite these observations, the immunological mechanisms associated with parasite control and disease progression in regard to Th17 signalling are not fully understood

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