Pathogenesis of Reovirus Gastrointestinal and Hepatobiliary Disease

We used the neonatal mouse model of rotavirus infection and virus strains SA11-clone 4 (SA11-Cl4) and Rhesus rotavirus (RRV) to examine the mechanism of the extraintestinal spread of viruses following oral inoculation. The spread-competent viruses, RRV and reassortant R7, demonstrated a temporal progression from the intestine, to the terminal ileum, to the mesenteric lymph nodes (MLN), and to the peripheral tissues. SA11-Cl4 was not found outside the intestine. Reassortant virus S7, which was unable to reach the liver in previous studies (E. C. Mossel and R. F. Ramig, J. Virol. 76:6502-6509, 2002), was recovered from 60% of the MLN, suggesting that there are multiple determinants for the spread of virus from the intestine to the MLN. Phenotypic segregation analysis identified RRV genome segment 6 (VP6) as a secondary determinant of the spread of virus to the MLN (P ‫؍‬ 0.02) in reassortant viruses containing segment 7 from the spreadincompetent parent. These data suggest that in the orally infected neonatal mouse, the extraintestinal spread of rotavirus occurs via a lymphatic pathway, and the spread phenotype is primarily determined by NSP3 and can be modified by VP6.

Section: Downloaded Fromsupporting

confidence: 58%

A Lymphatic Mechanism of Rotavirus Extraintestinal Spread in the Neonatal Mouse

Mossel

Ramig

2003

“…Guo et al (11) also observed infection of the intestine after intravenous inoculation of neonatal gnotobiotic pigs with a porcine enteric calicivirus, Cowden strain. Other investigators have suggested a pathway similar to the one described for reovirus (21), whereby virus in the blood reaches the ileum and infects crypt cells, possibly by attaching to the basolateral membrane (2, 18).…”

Section: Discussionmentioning

confidence: 93%

Viremia and Nasal and Rectal Shedding of Rotavirus in Gnotobiotic Pigs Inoculated with Wa Human Rotavirus

Azevedo

Yuan

Jeong

et al. 2005

Group A rotaviruses are the most common cause of dehydrating diarrhea in infants and young children worldwide, with more than 2 million hospitalizations yearly and approximately 440,000 deaths. It is estimated that 82% of rotavirus deaths occur in children in the poorest countries (23). Rotavirus transmission occurs mainly by the fecal-oral route, although respiratory transmission has been suggested to occur (7).Rotavirus infection was thought to be limited to the gastrointestinal tract. However, respiratory symptoms and rotavirus shedding in nasopharyngeal secretions have been reported in children with and without gastrointestinal symptoms (19,26,42). Rotavirus antigen was detected in the lung of 1 of 13 experimentally infected 3-week-old conventional pigs at postinoculation day 2 (30) and in liver and kidney specimens from immunodeficient children (9). Rotavirus RNA has also been detected in cerebrospinal fluid and blood of children with central nervous system disease (20,34). Recently, Blutt and colleagues (2) detected rotavirus antigenemia in the serum of children, mice, rabbits, and calves. They further demonstrated that serum from infected mice induced rectal rotavirus antigen shedding after oral inoculation of rotavirus-negative adult mice with the serum. Previously, another enteric virus, the porcine enteric calicivirus (PEC), has also been associated with transient viremia (infectious virus in serum) after oral inoculation of gnotobiotic pigs (11).We choose gnotobiotic pigs because they constitute an animal model of HRV-induced disease. Their gastrointestinal tract physiology and their development of mucosal immunity resemble that of humans. These similarities with HRV infections of infants allow us to establish correlations which could be applied for rotavirus vaccine development (14,25) The question addressed in our study was whether an attenuated human rotavirus and virulent HRV causes upper respiratory tract infections or viremia in naïve neonatal gnotobiotic pigs after various routes of inoculation. In this study we evaluated nasal and rectal virus shedding and viremia after oral, intranasal, feeding tube (gavage), and intravenous inoculation of neonatal gnotobiotic pigs with the Wa strain of attenuated HRV or virulent HRV. The presence of infectious virus in serum of gnotobiotic pigs after oral inoculation with Wa HRV was also investigated by oral and intravenous reinoculation of gnotobiotic pigs with a pool of the HRV-positive sera. MATERIALS AND METHODSVirus. The attenuated cell culture-adapted Wa strain HRV (P1A [8]G1), derived from the 27th HRV passage in African Green monkey kidney cells (MA104) and the virulent Wa HRV from pooled intestinal contents of gnotobiotic pigs were used for inoculation of the gnotobiotic pigs at doses of 5 ϫ 10 7

“…Studies of reovirus infectivity in animals and binding to isolated epithelial cells in culture have indicated that, after entry into the mucosa via M cell transcytosis, reovirus can adhere to basolateral membranes of epithelial cells as well as to subepithelial phagocytic cells (6,50). Because all of these sites would have been exposed on the tissue sections used for our viral overlay assays, we expected that the virus would adhere not only to apical M cell surfaces but also to many other sites within the mucosa.…”

Section: Discussionmentioning

confidence: 99%

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mentioning

confidence: 99%

The Viral σ1 Protein and Glycoconjugates Containing α2-3-Linked Sialic Acid Are Involved in Type 1 Reovirus Adherence to M Cell Apical Surfaces

Helander

Silvey

Mantis

et al. 2003

Reovirus is a nonenveloped, 85-nm icosahedral pathogen that enters the mouse intestinal Peyer's patch mucosa by adhering to M cells and then exploiting the antigen-transporting activity of these specialized epithelial cells (2,50,73). When introduced into the intestinal lumens of adult mice, reovirus type 1 Lang (T1L) adheres to the apical surfaces of M cells but generally not to those of enterocytes, which cover the vast majority of the mucosa. It is known that T1L infection of the mouse mucosa in vivo requires proteolytic processing of the viral outer capsid by enzymes in the intestinal lumen (6, 9, 45). The resulting infectious subviral particles (ISVPs) have a cleaved form of the membrane penetration protein 1, have lost the 1-protecting protein 3, and may have the viral hemagglutinin 1 in a more extended conformation than that found in virions (18,20,38,44,45,48). We have previously shown that conversion of T1L virions to ISVPs is required for adherence to M cells in adult mice (2), but neither the T1L protein that mediates binding nor the M cell component recognized by that protein has been identified.The 1 protein serves as the viral adhesin that mediates hemagglutination (HA) and binding to several different types of cultured cells (3,