title: NOD2 signaling contributes to the innate immune response against helper-dependent adenovirus vectors independently of MyD88 in vivo.
abstract: We previously demonstrated that Toll-like receptor/myeloid differentiation primary response gene 88 (MyD88) signaling is required for maximal innate and acquired [T helper cell type 1 (Th1)] immune responses following systemic administration of helper-dependent adenoviral vectors (HDAds). However, MyD88-deficient mice injected with HDAdLacZ exhibited only partial reduction of innate immune cytokine expression compared with wild-type mice, suggesting MyD88-independent pathways also respond to HDAds. We now show that NOD2, a nucleotide-binding and oligomerization domain (NOD)-like receptor known to detect muramyl dipeptides in bacterial peptidoglycans, also contributes to innate responses to HDAds, but not to humoral or Th1 immune responses. We established NOD2/MyD88 double-deficient mice that, when challenged with HDAds, showed a significant reduction of the innate response compared with mice deficient for either gene singly, suggesting that NOD2 signaling contributes to the innate response independently of MyD88 signaling following systemic administration of HDAds. In addition, NOD2-deficient mice exhibited significantly higher transgene expression than did wild-type mice at an early time point (before development of an acquired response), but not at a later time point (after development of an acquired response). These results indicate that the intracellular sensor NOD2 is required for innate responses to HDAds and can limit transgene expression during early phases of infection.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Masataka
authors.initials: M
authors.lastname: Suzuki
authors.forename: Racel
authors.initials: R
authors.lastname: Cela
authors.forename: Terry K
authors.initials: TK
authors.lastname: Bertin
authors.forename: Gautam
authors.initials: G
authors.lastname: Sule
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerullo
authors.forename: John R
authors.initials: JR
authors.lastname: Rodgers
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D057890:Epigenomics; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology*; D006378:Helper Viruses / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D015398:Signal Transduction; D019076:Transgenes
chemical_list: D053594:Myeloid Differentiation Factor 88; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger