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 (JH −/−) 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.
Highlights
Intestinal helminths present a major global health burden, in developing countries
In summary we have shown that antibodies in the presence of helminth antigens can elicit a novel subtype of IL-4 receptor alpha chain (IL-4Ra) independent alternatively activated macrophages, which we refer to as helminth-antibody activated macrophages (HAAM)
Mice deficient in antibodies or activating antibody receptors exhibit impaired early immunity to H. polygyrus bakeri challenge infections Our previous work on antibody mediated protective immunity against Heligmosomoides polygyrus bakeri (Hp) has largely been focused on late time points after challenge infection, when adult worms can be found in the lumen of the small intestine [30]
Summary
Intestinal helminths present a major global health burden, in developing countries. Patients that are infected with nematodes such as Ascaris lumbricoides, Trichuris trichuria or Necator americanus often develop severe pathology and impaired responsiveness to vaccines [1] [2] [3] [4]. 2 billion people are infected with intestinal nematodes, with the most severe infections often found within school children [5] [6]. Such infections can be treated by chemotherapy, worm burdens typically reach pretreatment levels within 6 months [7] [5]. No efficacious vaccines against intestinal nematodes are available to date, making an improved understanding of host immunity imperative
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