Eosinophils Preserve Parasitic Nematode Larvae by Regulating Local Immunity

Abstract

Eosinophils play important roles in regulation of cellular responses under conditions of homeostasis or infection. Intestinal infection with the parasitic nematode, Trichinella spiralis induces a pronounced eosinophilia that coincides with establishment of larval stages in skeletal muscle. We have shown previously that in mouse strains in which the eosinophil lineage is ablated, large numbers of T. spiralis larvae are killed by nitric oxide, implicating the eosinophil as an immune regulator. In this report, we show that parasite death in eosinophil-ablated mice correlates with reduced recruitment of IL-4+ T cells and enhanced recruitment of iNOS producing neutrophilsto infected muscle, as well as increased iNOS in local F4/80+CD11b+Ly6C+ macrophages. Actively growing T. spiralis larvae were susceptible to killing by NO in vitro, while mature larvae were highly resistant. Growth of larvae was impaired in eosinophil-ablated mice, potentially extending the period of susceptibility to the effects of NO and enhancing parasite clearance. Transfer of eosinophils into eosinophil-ablated ΔdblGATA mice restored larval growth and survival. Regulation of immunity was not dependent upon eosinophil peroxidase (EPO) or major basic protein 1 (MBP) and did not correlate with activity of the indoleamine 2,3-dioxygenase (IDO) pathway. Our results suggest that eosinophils support parasite growth and survival by promoting accumulation of Th2 cells and preventing induction of iNOS in macrophages and neutrophils. These findings begin to define the cellular interactions that occur at an extra-intestinal site of nematode infection in which the eosinophil functions as a pivotal regulator of immunity.

The expanding role(s) of eosinophils in health and disease

“…The resulting excessive host inflammatory responses led to the death of the resident parasite and, in turn, significant muscle pathology/necrosis. The failure of nurse cells to thrive in eosinophil-deficient mice was rescued by intravenous transfer of eosinophils into the mice, 26 demonstrating a direct role for eosinophils in aiding helminth survival while at the same time dampening the inflammatory response of the host. The mechanisms of this eosinophil-mediated macrophage regulation remain to be defined, yet studies by Stolarski et al that demonstrated eosinophil release of IL-4 and IL-13 polarized macrophage toward an M2 phenotype suggest a mechanism by which eosinophils directly modulate local Th2 polarization conditions to protect the resident parasite.…”

“…Recent studies by Gebreselassie et al 26 and Fabre et al 27 in the mouse may have provided a solution to this quandary, suggesting a unique role for eosinophils not in parasite killing but instead for parasite survival. Specifically, Trichinella spiralis has a 2-stage life cycle whereby newborn larvae convert a muscle cell into a nurse cell for the developing parasite.…”

“…In the absence of eosinophils, the number of nurse cells is dramatically reduced in infected mice. 27 Furthermore, in the absence of eosinophils, infiltrating Th2 T cells are reduced and recruited macrophages have enhanced iNOS expression, 26 suggesting that, in the absence of eosinophilmediated Th2 cytokine production, iNOS-expressing inflammatory macrophages (M1 type) outnumber the alternatively activated macrophages (M2 type). The resulting excessive host inflammatory responses led to the death of the resident parasite and, in turn, significant muscle pathology/necrosis.…”

Participation of MyD88 and Interleukin-33 as Innate Drivers of Th2 Immunity to Trichinella spiralis

“…he parasitic nematode Trichinella spiralis induces potent Th2 responses that both clear intestinal infections and regulate immunity in extraintestinal sites (1)(2)(3)(4)(5). The innate cellular and molecular drivers of Th2 immunity appear to vary among nematode infections, and the identification of mechanisms that initiate Th2 responses continues to be an area of active research (reviewed in reference 6).…”

Costs and Benefits of Immunity to Worm Infection

“…Thus, the benefit to the host of its own survival is attached to the cost of continued shedding of eggs and perpetuation of the parasite in the environment and host population. In recent years, additional examples of Th2 responses that support parasitic worm survival have been described for other tissue-dwelling worms (15)(16)(17). In contrast, effective clearance of worms that colonize the intestine has been shown in several models to be mediated by various Th2-dependent mechanisms (18).…”