title: NOD2 dependent neutrophil recruitment is required for early protective immune responses against infectious Litomosoides sigmodontis L3 larvae.
abstract: Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) recognizes muramyl dipeptide (MDP) of bacterial cell walls, triggering NFκB-induced pro-inflammation. As most human pathogenic filariae contain Wolbachia endobacteria that synthesize the MDP-containing cell wall precursor lipid II, NOD2's role during infection with the rodent filaria Litomosoides sigmodontis was investigated. In NFκB reporter-cells, worm-extract containing Wolbachia induced NOD2 and NOD1. NOD2-deficient mice infected with L. sigmodontis had significantly more worms than wildtype controls early in infection. Increased worm burden was not observed after subcutaneous infection, suggesting that protective NOD2-dependent immune responses occur within the skin. Flow cytometry demonstrated that neutrophil recruitment to the skin was impaired in NOD2-/-mice after intradermal injection of third stage larvae (L3), and blood neutrophil numbers were reduced after L. sigmodontis infection. PCR array supported the requirement of NOD2 for recruitment of neutrophils to the skin, as genes associated with neutrophil recruitment and activation were downregulated in NOD2-/-mice after intradermal L3 injection. Neutrophil depletion before L. sigmodontis infection increased worm recovery in wildtype mice, confirming that neutrophils are essential against invading L3 larvae. This study indicates that NOD-like receptors are implemented in first-line protective immune responses against filarial nematodes.
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Jesuthas
authors.initials: J
authors.lastname: Ajendra
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Specht
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ziewer
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schiefer
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Pfarr
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Marijo
authors.initials: M
authors.lastname: Parčina
authors.affiliation: Institute of Nutritional Medicine, University Hohenheim, Stuttgart, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kufer
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.|German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Hoerauf
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Hübner
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000818:Animals; D002473:Cell Wall / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D005368:Filariasis / Q000276:immunology*; D005370:Filarioidea; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007107:Immune System; D007814:Larva; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D064307:Microbiota; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology*; D015398:Signal Transduction; D012867:Skin / Q000382:microbiology / Q000469:parasitology; D035423:Thoracic Cavity / Q000469:parasitology
chemical_list: D016207:Cytokines; D008024:Ligands; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D000119:Acetylmuramyl-Alanyl-Isoglutamine