title: Age-dependent TLR3 expression of the intestinal epithelium contributes to rotavirus susceptibility.
abstract: Rotavirus is a major cause of diarrhea worldwide and exhibits a pronounced small intestinal epithelial cell (IEC) tropism. Both human infants and neonatal mice are highly susceptible, whereas adult individuals remain asymptomatic and shed only low numbers of viral particles. Here we investigated age-dependent mechanisms of the intestinal epithelial innate immune response to rotavirus infection in an oral mouse infection model. Expression of the innate immune receptor for viral dsRNA, Toll-like receptor (Tlr) 3 was low in the epithelium of suckling mice but strongly increased during the postnatal period inversely correlating with rotavirus susceptibility, viral shedding and histological damage. Adult mice deficient in Tlr3 (Tlr3(-/-)) or the adaptor molecule Trif (Trif(Lps2/Lps2)) exerted significantly higher viral shedding and decreased epithelial expression of proinflammatory and antiviral genes as compared to wild-type animals. In contrast, neonatal mice deficient in Tlr3 or Trif did not display impaired cell stimulation or enhanced rotavirus susceptibility. Using chimeric mice, a major contribution of the non-hematopoietic cell compartment in the Trif-mediated antiviral host response was detected in adult animals. Finally, a significant age-dependent increase of TLR3 expression was also detected in human small intestinal biopsies. Thus, upregulation of epithelial TLR3 expression during infancy might contribute to the age-dependent susceptibility to rotavirus infection.
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pott
authors.forename: Silvia
authors.initials: S
authors.lastname: Stockinger
authors.forename: Natalia
authors.initials: N
authors.lastname: Torow
authors.forename: Anna
authors.initials: A
authors.lastname: Smoczek
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lindner
authors.forename: Gerald
authors.initials: G
authors.lastname: McInerney
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
authors.forename: Oliver
authors.initials: O
authors.lastname: Pabst
authors.forename: André
authors.initials: A
authors.lastname: Bleich
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Hornef
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000375:Aging; D000818:Animals; D004198:Disease Susceptibility; D006801:Humans; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D007421:Intestine, Small / Q000276:immunology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051192:Receptors, Pattern Recognition / Q000096:biosynthesis; D012401:Rotavirus / Q000472:pathogenicity*; D012400:Rotavirus Infections / Q000276:immunology* / Q000821:virology*; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017201:Virus Shedding
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051192:Receptors, Pattern Recognition; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse