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
Summary
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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