Lack of interferon-gamma confers impaired neutrophil granulocyte function and imparts prolonged survival of adult filarial worms in murine filariasis

We investigated the role of IFN-gamma in host defense during murine filaria sis. Using the fully permissive infection of BALB/c mice with the rodent fi laria Litomosoides sigmodontis, we show that interferon (IFN)-gamma is esse ntial for encapsulation of adult filarial worms in inflammatory nodules and for normal worm clearance. IFN-gamma knockout (KO) mice had only one third of the nodules of wild-type mice but displayed a more than twofold increas e in worm burden and increased microfilaremia. Neutrophil granulocytes, but not macrophages or eosinophils, appear to directly control worm load and n odule formation. Neutrophils, which we showed earlier to be essential for t he encapsulation process in the thoracic cavity, where the worms reside, we re diminished at this location in IFN-gamma KO compared to wild-type mice; they also displayed strongly reduced chemotactic and phagocytic activity co mpared to neutrophils of controls. This argues for a distinct defect in neu trophil activation accounting for the low formation of inflammatory nodules . Tumor necrosis factor-alpha, a major neutrophil-activating cytokine expre ssed by macrophages in the thoracic cavity around the worms, was highly ind uced in wild-type but absent in KO mice. Diminished activation of neutrophi ls seems to be a general hallmark of IFN-gamma KO mice, since neutrophils f rom uninfected KO mice also showed a reduction in chemotactic and phagocyti c activity when induced by casein. In conclusion, these data are the first to define an IFN-gamma -dependent immune effector mechanism in murine filar ial infection, i.e. neutrophil-mediated control of the adult worm load. (C) 2001 Editions scientifiques et medicales Elsevier SAS.