Antibodies Trap Tissue Migrating Helminth Larvae and Prevent Tissue Damage by Driving IL-4Rα-Independent Alternative Differentiation of Macrophages

Abstract

Approximately one-third of the world's population suffers from chronic helminth infections with no effective vaccines currently available. Antibodies and alternatively activated macrophages (AAM) form crucial components of protective immunity against challenge infections with intestinal helminths. However, the mechanisms by which antibodies target these large multi-cellular parasites remain obscure. Alternative activation of macrophages during helminth infection has been linked to signaling through the IL-4 receptor alpha chain (IL-4Rα), but the potential effects of antibodies on macrophage differentiation have not been explored. We demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae and prevent tissue necrosis following challenge infection with the natural murine parasite Heligmosomoides polygyrus bakeri ( Hp). Mice lacking antibodies (J _H ^−/−) or activating Fc receptors (FcRγ ^−/−) harbored highly motile larvae, developed extensive tissue damage and accumulated less Arginase-1 expressing macrophages around the larvae. Moreover, Hp-specific antibodies induced FcRγ- and complement-dependent adherence of macrophages to larvae in vitro, resulting in complete larval immobilization. Antibodies together with helminth larvae reprogrammed macrophages to express wound-healing associated genes, including Arginase-1, and the Arginase-1 product L-ornithine directly impaired larval motility. Antibody-induced expression of Arginase-1 in vitro and in vivo occurred independently of IL-4Rα signaling. In summary, we present a novel IL-4Rα-independent mechanism of alternative macrophage activation that is antibody-dependent and which both mediates anti-helminth immunity and prevents tissue disruption caused by migrating larvae.

Author Summary

Intestinal helminths present a pressing problem in developing countries with approximately 2 billion people suffering from chronic infection. To date no successful vaccines are available and a detailed mechanistic understanding of anti-helminth immunity is urgently needed to improve strategies for prevention and therapy. Antibodies form a crucial component of protective immunity against challenge infections with intestinal helminths. However, the exact mechanisms by which antibodies target these large multi-cellular parasites have remained obscure. We now demonstrate that helminth-specific antibodies induce the rapid trapping of tissue migrating helminth larvae by activating phagocytes. In the absence of antibodies or their receptors, helminth-infected mice developed extensive tissue damage, revealing a novel role for antibodies in limiting parasite-caused tissue disruption. Furthermore, helminth-specific antibodies reprogrammed macrophages to express wound-healing factors such as the arginine-metabolizing enzyme Arginase-1. Interestingly, the Arginase-1 product L-ornithine directly impaired the motility of helminth larvae. In summary, our study provides detailed mechanistic insights into how antibodies can modulate phagocyte function to provide protection against a large multi-cellular parasite. Our findings suggest that novel anti-helminth vaccines should target the larval surface and activate wound-healing macrophages to provide rapid protection against tissue-disruptive larvae.