Eosinophil proteins and their role during filarial infection

Abstract

Summary In the current work, the role of eosinophil effector proteins in filarial infections was investigated. It focused on how eosinophils contribute to the immobilization and elimination of MF through both the formation of extracellular DNA traps (ETosis) and the release of granule proteins – in particular MBP and EPO. Using mouse models, including KO mice for MBP and EPO, and comparisons with natural hosts (cotton rats), it was shown that these proteins are crucial for inhibiting MF motility and contribute significantly to eosinophil-mediated parasite control. Another focus of the current work was the immunomodulatory function of eosinophils, particularly through the production of IL-4. The study demonstrated that eosinophils represent an essential and early source of IL-4 during infection with L. sigmodontis, thereby acting as potent initiators and amplifiers of type 2 immune responses. Although alternative macrophage activation could be maintained without eosinophils, their presence was crucial for effective Th2 polarisation, as evidenced by the reduced number of CD4⁺ T cells and lower levels of IL-5 and IL-13 in eosinophil-deficient dblGATA mice. This highlights the non-redundant role of eosinophil-derived IL-4 in the establishment of a functional Th2 milieu, which could not be compensated by other IL-4-producing cells such as ILC2s or Th2 cells. In addition, this work addressed possible mechanisms of IL-4 induction in eosinophils, pointing to epithelial-derived alarmins (IL-33, IL-25, TSLP) and helminth components sensed via PRRs (e.g. TLR7, Dectin-1) as potential triggers. Transcriptional regulators such as STAT6, GATA-1 and NFAT were identified as candidates in the regulation of IL-4 production in eosinophils, although these mechanisms require further elucidation. One interesting aspect of the study was the comparison of L. sigmodontis infections in a mouse model and the natural host, the cotton rat (Sigmodon hispidus). It was found that eosinophils of cotton rats are less effective in immobilizing MF than those of mice. This observation suggests host-specific adaptations of the parasite, potentially involving immune evasion strategies targeting eosinophil function, such as suppression of IL-4 production or resistance to ETosis. Finally, the translational implications of these results were underpinned by further findings of the working group showing that eosinophil-driven type 2 immunity can exert beneficial metabolic effects. L. sigmodontis infection and LsAg administration improved glucose tolerance and insulin sensitivity in diet-induced obese mice in an eosinophil-dependent manner, especially in adipose tissue, where eosinophils support the maintenance of alternatively activated macrophages. In summary, the present dissertation provides new insights into the dual role of eosinophils: on the one hand, they act as direct effector cells that contribute to parasite control via ETosis and cytotoxic granule proteins (MBP, EPO) and on the other hand, they emerge as critical immunoregulatory cells through their early and localized production of IL-4, shaping the adaptive Th2 response. These findings contribute to a better understanding of the complex interplay between host and parasite and could enable new therapeutic approaches against filarial infections in the future.