Absence of IL-17A in Litomosoides sigmodontis-infected mice influences worm development and drives elevated filarial-specific IFN-γ

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.Electronic supplementary materialThe online version of this article (10.1007/s00436-018-5959-7) contains supplementary material, which is available to authorized users.

IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type-2 immune response to nematode infection

“…For example enhanced IFNγ in Il17a- KO mice has been described in a viral infection, 28 experimental visceral leishmaniasis, and Toxoplasma gondii infection. 29 Evidence also exists in the context of helminth infection, where a lack of IL-17A drives elevated IFNγ during infection with the filarial nematode Litomosoides sigmondontis 30 or Schistosoma japonicum 31 and Schistosoma mansoni . 5 In contrast, IL-17A can promote IFNγ production during kidney-ischaemic reperfusion injury, 32 or Francisella tularensis infection.…”

Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases

“…Limited evidence suggests that T H17 cytokines, including IL-17A, IL-17F, IL-21, and IL-23, are elevated in human subjects with lymphatic filariasis as well as in animal models of human filariasis and this cytokine signature is associated with helminth-induced immunopathology in chronic lymphatic filariasis (Babu et al, 2009; Anuradha et al, 2014; Ritter et al, 2018).…”

Comparison of immune responses to Loa loa stage-specific antigen extracts in Loa loa-exposed BALB/c mice upon clearance of infection

“…For example, parasite load in humans vary strongly (e.g. microfilarial load) [17-19, 37, 47, 49] and results from the filarial mouse model L. sigmodontis are also based on different parasite loads when the natural infectious route via ticks is used [35,40,48]. Thus, comparisons of immune profiles in the mice groups following exposure to the different life stages are difficult to interpret and need cautious conclusions.…”