Eosinophil-derived IL-4 promotes nematode growth in an innate context

It has become increasingly clear in recent years that the function for eosinophils in health and disease is highly varied. Recent studies have revealed novel functions for eosinophils in metabolism and tissue regeneration. Such mechanisms have strong potential to be relevant in worm infections in which parasites rely on host metabolism for nutrients that support worm growth or reproduction. The aim of this study was to investigate the mechanism underlying the observation that eosinophils promote growth of Trichinella spiralis larvae in skeletal muscle. Our results indicate that normal larval growth requires IL-4 and STAT6 signaling that are intrinsic to eosinophils. Support of growth by eosinophil-derived IL-4 occurs independently of adaptive immunity. Host gene expression in skeletal muscle was compatible with a regenerative response to invasion by newborn larvae and a shift in the source of energy in infected tissue. Furthermore, the presence of eosinophils suppressed local inflammation while also influencing nutrient homeostasis in muscle. Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, compatible with enhancement of glucose uptake and storage of glycogen by larvae that is known to occur. The results suggest that eosinophil-derived IL-4 may promote larval growth by altering nutrient metabolism in infected muscle. Our findings document a novel interaction between worms and host, in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth. Whole diaphragms from WT, Rag1-/- and PHIL mice were harvested at 0, 2 and 7 days post-infection of mice with 25,000 Trichinella spiralis newborn larvae (administered retro-orbitally) and preserved in RNAlater (Qiagen). Two to three replicate mice were used for each condition.