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

Abstract

Background Mice 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. Methods Susceptible 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. Results Our 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. Conclusions These 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. Electronic supplementary material The online version of this article (10.1186/s13071-019-3502-z) contains supplementary material, which is available to authorized users.

IL-4 receptor dependent expansion of lung CD169+ macrophages in microfilaria-driven inflammation

“…Mf were counted in peripheral and cardiac blood of the WT and mutant mice. This revealed striking differences between the genotypes (Fig 3A and 3B): 63% of WT mice show circulating Mf (Mf pos ) but 83% of ΔdblGata1 and 100% of Il-4ra -/- /Il-5 -/- were Mf pos [23]. Moreover, Mf in peripheral blood and heart were more numerous in Il-4ra -/- /Il-5 -/- than in WT Mf pos mice, and ΔdblGata1 showed an intermediate phenotype (Fig 3A and 3B).…”

“…A few immune components have been identified as key players in controlling the microfilarial burden of mice (S2 Table). Filarial fertility is clearly controlled by Th2 responses as infections of ΔdblGata1 (eosinophil deficient) and Il-4ra -/- /Il-5 -/- (wider Th2 deficiency including defect in macrophage alternative activation) BALB/c mice result in 80 to 100% Mf pos mice [23] with 10 to 35 times higher microfilaremia. This is associated with an increase in the survival of filariae but also a better growth of the parasites and a more successful oogenesis.…”

“…These included six to ten weeks-old homozygous ΔdblGata1 female BALB/c mice, which present a deletion of a high-affinity GATA-binding site in the GATA-1 promoter leading to selective a loss of the eosinophil lineage [21]; six to ten weeks-old Il-4ra -/- /Il-5 -/- female BALB/c mice, which are deficient for the α chain of the IL-4 receptor (IL4-Ra) and thus lacking IL-4/IL-13 signaling and for IL-5, leading to an absence of alternative activation of macrophages and an impaired maturation and recruitment of eosinophils, and a substantial microfilaremia when infected with L . sigmodontis [15, 16, 19, 22, 23]. All animals were maintained in the MNHN animal facilities on a 12-hours light/dark cycle.…”

Microfilaria-dependent thoracic pathology associated with eosinophilic and fibrotic polyps in filaria-infected rodents

“…The proliferation and the alternative activation of these pleural macrophages is promoted by the interleukin (IL)-4 receptor and IL-33 (ST2) in L. sigmodontis infected BALB/c mice [ 32 ]. The alteration of IL-4/IL-5 signalling alters this cellular environment and leads to increased susceptibility to L. sigmodontis infection and influences adult worm burden and/or microfilaremia [ 24 , 33 , 34 ] as well as lung pathogenesis [ 24 , 33 ]. Particularly, a central role of IL-13 and IL-4 in macrophage activation and eosinophil recruitment and in lung pathogenesis has been highlighted in a recent analysis of cytokine and chemokine transcripts in the lungs of 70 days-infected BALB/c mice [ 24 ].…”

S100A8/S100A9 deficiency increases neutrophil activation and protective immune responses against invading infective L3 larvae of the filarial nematode Litomosoides sigmodontis

“…During these investigations type 1 [39][40][41][42] and type 2 immune responses have been identified as essential for protection against L. sigmodontis. As for type 2 immune responses the absence of IL-4 [43,44], IL-5 [45][46][47], IL-6 [48], eosinophil products such as eosinophil peroxidase (EPO), major basic protein (MBP) [49] and eosinophil-specific chemoattractant eotaxin 1 (CCL11) [50] led to an increased susceptibility to L. sigmodontis infection and increased the adult worm burden and/or microfilaremia [51]. As for type 1 immune responses, Saeftel et al demonstrated that the deficiency of IFN-γ led to an increased worm burden due to reduced neutrophil recruitment and encapsulation of adult worms compared to wildtype (WT) mice [42].…”