title: The rhesus rotavirus gene encoding VP4 is a major determinant in the pathogenesis of biliary atresia in newborn mice.
abstract: Biliary atresia (BA) is a devastating disease of childhood for which increasing evidence supports a viral component in pathogenesis. The murine model of BA is induced by perinatal infection with rhesus rotavirus (RRV) but not with other strains of rotavirus, such as TUCH. To determine which RRV gene segment(s) is responsible for pathogenesis, we used the RRV and TUCH strains to generate a complete set of single-gene reassortants. Eleven single-gene "loss-of-function" reassortants in which a TUCH gene replaced its RRV equivalent and 11 single-gene "gain-of-function" reassortants in which an RRV gene replaced its TUCH equivalent were generated. Newborn BALB/c mice were inoculated with the reassortants and were monitored for biliary obstruction and mortality. In vitro, the ability to bind to and replicate within cholangiocytes was analyzed. Infection of mice with the "loss-of-function" reassortant R(T(VP4)), where gene 4 from TUCH was placed on an RRV background, eliminated the ability of RRV to cause murine BA. In a reciprocal fashion, the "gain-of-function" reassortant T(R(VP4)) resulted in murine BA with 88% mortality. Compared with those for RRV, R(T(VP4)) binding and titers in cholangiocytes were significantly attenuated, while T(R(VP4)) binding and titers were significantly increased over those for TUCH. Reassortants R(T(VP3)) and T(R(VP3)) induced an intermediate phenotype. RRV gene segment 4 plays a significant role in governing tropism for the cholangiocyte and the ability to induce murine BA. Gene segment 3 did not affect RRV infectivity in vitro but altered its in vivo effect.
authors.affiliation: Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Bryan
authors.initials: B
authors.lastname: Donnelly
authors.forename: Alexander
authors.initials: A
authors.lastname: Bondoc
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Mohanty
authors.forename: Monica
authors.initials: M
authors.lastname: McNeal
authors.forename: Richard
authors.initials: R
authors.lastname: Ward
authors.forename: Karol
authors.initials: K
authors.lastname: Sestak
authors.forename: Shan
authors.initials: S
authors.lastname: Zheng
authors.forename: Greg
authors.initials: G
authors.lastname: Tiao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001656:Biliary Atresia / Q000401:mortality / Q000473:pathology* / Q000821:virology*; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D011995:Recombination, Genetic; D012376:Rodent Diseases / Q000473:pathology / Q000821:virology; D012401:Rotavirus / Q000472:pathogenicity*; D012400:Rotavirus Infections / Q000150:complications* / Q000401:mortality / Q000473:pathology*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D036022:Capsid Proteins; C060339:VP4 protein, Rotavirus; D037521:Virulence Factors