Persistent enteric muscle dysfunction and expulsion of T. spiralis infections depend partially upon IL-5 and eosinophils

Abstract

Interleukin (IL)-5 expression, eosinophilia and eosinophil activation have been shown to be increased early in the course of several gastrointestinal conditions including Crohn's disease, celiac disease and during enteric parasitic infections. However a functional role for eosinophils in either enteric host defense or in intestinal pathophysiology is unclear. IL-5 deficient (-/-) mice as well as their IL-5 +/+ controls were orally gavaged with 375 T. spiralis larvae for primary infections, and with a similar number for subsequent challenges. We measured isometric contraction of jejunal longitudinal muscle and counted adult worms as well as eosinophils within the infected small bowel, during both primary and challenge infections. In addition, as a measure of worm fecundity, we analyzed skeletal muscle larvae numbers. Following T. spiralis infection, intestinal eosinophil counts rose dramatically in IL-5 +/+ mice (0.8 to a maximum of 14.0 eosinophils/villus crypt unit (vcu)) during the primary infection and (1.0 to 9.5 eosinophils/vcu) in a subsequent infection. In contrast, no significant rise in eosinophil numbers was seen in IL-5 deficient mice. Increased tension development was observed in intestinal muscle from both IL-5 +/+ and IL-5 -/mice, over the course of infection and consisted of a rapid increase in tension by day 8 PI, followed by a smaller increase that was sustained over 21 days. While the magnitude of the rapid onset component was similar, that of the sustained component was significantly lower in IL-5 -/mice (1700 vs 1250 mg/mm2). Worm expulsion was also significantly reduced in the IL-5 deficient mice during the late stage of a primary infection (day 16 21 post-infection (PI)), with twice the number of worms recovered from IL-5 -/mice, compared to IL-5 +/+ mice. However there was no difference in the number of skeletal muscle larvae recovered. Subsequent T. spiralis infections showed an even greater dependence of intestinal worm expulsion upon the presence of IL-5 and eosinophils, with increased worm burdens evident in IL-5 4mice by as early as day 6 PI. These results indicate that IL-5 is essential for the generation of the intestinal eosinophilia that occurs during T. spiralis infections. In the absence of IL-5 and eosinophils, both parasite expulsion and the persistent increase in tension generation by muscle are reduced. Since differences between IL-5 +/+ and IL-5 -/mice emerged only after day 16 PI, these results indicate that eosinophils are not involved in the very early stages of expulsion, or in the initiation of altered muscle function. This study thus provides evidence that eosinophils play a role in enteric host defense and may be an important cell type in maintaining persistent motility disturbances following enteric infection and inflammation. Supported by MRC Canada.