title: Signaling through Galphai2 protein is required for recruitment of neutrophils for antibody-mediated elimination of larval Strongyloides stercoralis in mice.
abstract: The heterotrimeric guanine nucleotide-binding protein Galphai2 is involved in regulation of immune responses against microbial and nonmicrobial stimuli. Galphai2-/- mice have a selectively impaired IgM response consistent with a disorder in B cell development yet have augmented T cell effector function associated with increased production of IFN-gamma and IL-4. The goal of the present study was to determine if a deficiency in the Galphai2 protein in mice would affect the protective immune response against Strongyloides stercoralis, which is IL-4-, IL-5-, and IgM-dependent. Galphai2-/- and wild-type mice were immunized and challenged with S. stercoralis larvae and analyzed for protective immune responses against infection. Galphai2-/- mice failed to kill the larvae in the challenge infection as compared with wild-type mice despite developing an antigen-specific Th2 response characterized by increased IL-4, IL-5, IgM, and IgG. Transfer of serum collected from immunized Galphai2-/- mice to naïve wild-type mice conferred passive protective immunity against S. stercoralis infection thus confirming the development of a protective antibody response in Galphai2-/- mice. Differential cell analyses and myeloperoxidase assays for quantification of neutrophils showed a significantly reduced recruitment of neutrophils into the microenvironment of the parasites in immunized Galphai2-/- mice. However, cell transfer studies demonstrated that neutrophils from Galphai2-/- mice are competent in killing larvae. These data demonstrate that Galphai2 signaling events are not required for the development of the protective immune responses against S. stercoralis; however, Galphai2 is essential for the recruitment of neutrophils required for host-dependent killing of larvae.
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
authors.forename: Udaikumar M
authors.initials: UM
authors.lastname: Padigel
authors.forename: Louis
authors.initials: L
authors.lastname: Stein
authors.forename: Kevin
authors.initials: K
authors.lastname: Redding
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nolan
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Schad
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: David
authors.initials: D
authors.lastname: Abraham
mesh_terms: D000818:Animals; D000909:Antibodies, Helminth / Q000276:immunology*; D002478:Cells, Cultured; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism*; D006790:Host-Parasite Interactions; D007113:Immunity, Innate; D007814:Larva / Q000276:immunology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D017171:Strongyloides stercoralis / Q000276:immunology*; D013322:Strongyloidiasis / Q000276:immunology*
chemical_list: D000909:Antibodies, Helminth; D051960:GTP-Binding Protein alpha Subunit, Gi2