The goal of these studies is to determine the mechanisms utilized by mouse neutrophils to control helminth infections. Previous studies have demonstrated that neutrophils are required for killing larval Strongyloides stercoralis in na?ve and immunized mice. The proposed studies will determine the molecular mechanisms used by neutrophils to kill the worm and methods used by antibody to accelerate parasite killing by neutrophils. These studies will provide an in depth analysis of how neutrophils control extracellular pathogens, and the findings will have applicability to our understanding of granulocyte control of bacterial, fungal and parasitic infections. The objective of Specific Aim 1 is to develop a comprehensive, sequential understanding of how mouse neutrophils kill the worms in the absence of antibody. It is clear from our previous studies that optimal neutrophil killing of the larvae results only after stimulation of the neutrophils with factors derived from macrophages and vice versa. We will decipher how neutrophils interact with macrophage derived factors to kill the parasites. The mechanisms and molecules used by the neutrophils to trap and then kill these non-phagocytosable pathogens will be determined.
In Specific Aim 2 we will determine how larval killing by neutrophils is accelerated and amplified by the presence of parasite-specific antibody. It will be determined if the increase in efficiency of immune killing of parasites by neutrophils is dependent on direct interaction between antibody and neutrophils or by an effect of antibody on the behavior of the parasites promoting killing by neutrophils.
This grant is a comprehensive assessment of the mechanisms used by neutrophils to control worm infections. Studies in mice will provide the direction for future studies on the human antibody and cellular response to the human pathogen Strongyloides stercoralis. This proposal has the potential of leading to new vaccine approaches and therapies for strongyloidiasis.
