Rotavirus Viremia and Extraintestinal Viral Infection in the Neonatal Rat Model

Rotavirus Viremia and Extraintestinal Viral Infection in the Neonatal Rat Model,10.1128/JVI.80.10.4820-4832.2006,Journal of Virology,Sue E. Crawford,D

Rotavirus Viremia and Extraintestinal Viral Infection in the Neonatal Rat Model   (Citations: 29)
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Rotaviruses infect mature, differentiated enterocytes of the small intestine and, by an unknown mechanism, escape the gastrointestinal tract and cause viremia. The neonatal rat model of rotavirus infection was used to determine the kinetics of viremia, spread, and pathology of rotavirus in extraintestinal organs. Five-day-old rat pups were inoculated intragastrically with an animal (RRV) or human (HAL1166) rotavirus or phosphate- buffered saline. Blood was collected from a subset of rat pups, and following perfusion to remove residual blood, organs were removed and homogenized to analyze rotavirus-specific antigen by enzyme-linked immu- nosorbent assay and infectious rotavirus by fluorescent focus assay or fixed in formalin for histology and immunohistochemistry. Viremia was detected following rotavirus infection with RRV and HAL1166. The RRV 50% antigenemia dose was 1.8 103 PFU, and the 50% diarrhea dose was 7.7 105 PFU, indicating that infection and viremia occurred in the absence of diarrhea and that detecting rotavirus antigen in the blood was a more sensitive measure of infection than diarrhea. Rotavirus antigens and infectious virus were detected in multiple organs (stomach, intestines, liver, lungs, spleen, kidneys, pancreas, thymus, and bladder). His- topathological changes due to rotavirus infection included acute inflammation of the portal tract and bile duct, microsteatosis, necrosis, and inflammatory cell infiltrates in the parenchymas of the liver and lungs. Colocal- ization of structural and nonstructural proteins with histopathology in the liver and lungs indicated that the histological changes observed were due to rotavirus infection and replication. Replicating rotavirus was also detected in macrophages in the lungs and blood vessels, indicating a possible mechanism of rotavirus dissemination. Extraintestinal infectious rotavirus, but not diarrhea, was observed in the presence of passively or actively acquired rotavirus-specific antibody. These findings alter the previously accepted concept of rotavirus pathogenesis to include not only gastroenteritis but also viremia, and they indicate that rotavirus could cause a broad array of systemic diseases in a number of different organs. Rotaviruses, responsible for most cases of gastroenteritis in children under the age of five worldwide, have been thought to cause mucosal infections restricted to the mature, differentiated enterocytes of the small intestine. However, an increasing number of reports indicate that rotavirus escapes the gastrointestinal tract. Rotavirus antigen and RNA were detected in serum samples from approximately 65% of children with rotavirus diarrhea, in- dicating that antigenemia and possibly viremia occur during ro- tavirus infection (4, 7, 16). In other reports, rotavirus antigen and/or RNA was detected in the central nervous systems, spleens, hearts, kidneys, testes, and bladders of children who died during rotavirus infections (23, 29-32, 35, 42); in liver biopsies from infants with cholestatic disease (47); and in respiratory secretions, lung cells, or the microvasculature of hearts from children and adults with respiratory infections or cardiorespiratory failure (11, 41, 48, 56) and rotavirus gastroenteritis. These case reports sup- port the concept that rotavirus can escape the intestine and pos- sibly infect cells in a variety of organs, but the sites and prevalence of extraintestinal infection and whether rotavirus can be the eti- ologic agent of extraintestinal disease have not been established.
Journal: Journal of Virology - J VIROL , vol. 80, no. 10, pp. 4820-4832, 2006
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