Active Viremia in Rotavirus-Infected Mice

Blutt, Sarah E.; Fenaux, Martijn; Warfield, Kelly L.; Greenberg, Harry B.; Conner, Margaret E.

doi:10.1128/jvi.00329-06

Cited by 42 publications

(41 citation statements)

References 30 publications

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“…Similarly, an accumulating body of work shows that rotavirus infection, which has long been assumed to cause infection of only the gastrointestinal tract, is associated with extraintestinal viremic dissemination and histopathological changes in additional tissues (3,4,7,8,15). We believe that the present study warrants a similar consideration of potential extraintestinal spread of human noroviruses.…”

Section: (E and F) Intestinal Homogenates (E) And Sera (F) From 129 Amentioning

confidence: 76%

Murine Norovirus 1 Infection Is Associated with Histopathological Changes in Immunocompetent Hosts, but Clinical Disease Is Prevented by STAT1-Dependent Interferon Responses

Mumphrey

Changotra

Moore

et al. 2007

J Virol

199

248

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Human noroviruses are the major cause of nonbacterial epidemic gastroenteritis worldwide. However, little is known regarding their pathogenesis or the immune responses that control them because until recently there has been no small animal model or cell culture system of norovirus infection. We recently reported the discovery of the first murine norovirus, murine norovirus 1 (MNV-1), and its cultivation in macrophages and dendritic cells in vitro. We further defined interferon receptors and the STAT-1 molecule as critical in both resistance to MNV-1-induced disease in vivo and control of virus growth in vitro. To date, neither histopathological changes upon infection nor viral replication in wild-type mice has been shown. Here we extend our studies to demonstrate that MNV-1 replicates and rapidly disseminates to various tissues in immunocompetent mice and that infection is restricted by STAT1-dependent interferon responses at the levels of viral replication and virus dissemination. Infection of wild-type mice is associated with histopathological alterations in the intestine (mild inflammation) and the spleen (red pulp hypertrophy and white pulp activation); viral dissemination to the spleen, liver, lung, and lymph nodes; and low-level persistent infection in the spleen. STAT-1 inhibits viral replication in the intestine, prevents virus-induced apoptosis of intestinal cells and splenocytes, and limits viral dissemination to peripheral tissues. These findings demonstrate that murine norovirus infection of wild-type mice is associated with initial enteric seeding and subsequent extraintestinal spread, and they provide mechanistic evidence of the role of STAT-1 in controlling clinical norovirus-induced disease.

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Section: (E and F) Intestinal Homogenates (E) And Sera (F) From 129 Amentioning

confidence: 76%

Murine Norovirus 1 Infection Is Associated with Histopathological Changes in Immunocompetent Hosts, but Clinical Disease Is Prevented by STAT1-Dependent Interferon Responses

Mumphrey

Changotra

Moore

et al. 2007

J Virol

199

248

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“…Of note, TNF-␣ and IFN-␥ have been reported to be in the plasma of children with febrile acute RV infection (42). Interestingly, despite the fact that RV antigen and infectious virus are present in the plasma of a high percentage of recently infected children or mice, it has been impossible to detect RV-infected blood B cells in these samples (7,49). Our findings of the preferential RV infection of antigen-experienced B cells provide one possible explanation to this observation, since young children have low frequencies of mBC, which are more susceptible to RV infection and, if infected, would quickly die, preventing their detection in circulation (Fig.…”

Section: Discussionmentioning

confidence: 91%

Rotavirus Differentially Infects and Polyclonally Stimulates Human B Cells Depending on Their Differentiation State and Tissue of Origin

Narváez

Franco

Ángel

et al. 2010

J Virol

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Rotaviruses (RV) are the main cause of severe gastroenteritis in infants and are responsible for the death of approximately 600,000 young children annually around the world (54 and http://www.who.int/immunization monitoring/burden/rotavirus estimates/en/). At present, two live attenuated vaccines are licensed for use in humans, and both vaccines are highly protective against severe disease in developed countries (60,69). However, these oral vaccines induce lower levels of protection in children from developing countries, suggesting that the improvement of these vaccine or the development of new RV vaccines is warranted (32). Although the RV immune response has been extensively studied in both animals and humans, the immune factors that correlate with protection for natural infection or vaccination in people remain unclear, and this is an important obstacle for the development of the next generation of RV vaccines (2, 25).B cells play a critical role in the RV immune response, and both intestinal and systemic immunoglobulins (Ig) are associated with protection (25). For example, in the murine model, B-cell-but not T-cell-deficient mice are unable to establish long-lasting protective immunity against RV reinfection (26). The interaction of RV with B cells has been shown to be peculiar in many ways: the structural viral protein VP6 binds to an important fraction of human naive B cells via surface Ig (55, 58), and VP6 memory B cells (mBC) are enriched in the CD27 Ϫ IgG ϩ (58) and CD27 ϩ IgM ϩ subsets (66). VP6-specific naive B cells and, to a lesser extent, the mBC predominantly use the VH1-46 gene segment (66). Moreover, a massive Tcell-independent B cell activation and humoral response can be detected in vivo after oral RV infection in mice (10). However, the activation of these cells is probably viral strain dependent, since simian rhesus RV (RRV), but not bovine WC3 RV, has been shown to polyclonally stimulate a total antibodysecreting cell (ASC) response in intestinal organ fragment cultures (44). Although the principal immune function of B cells has been associated with the production of Ig, recent reports show that these cells also can play an important role in modulating the immune response independently of Ig through the production of cytokines like tumor necrosis factor alpha (TNF-␣), interleukin-6 (IL-6), and IL-10 and their related potential function as antigen-presenting cells (3,18,31,67).We and others have shown that RVs undergo systemic, extraintestinal replication in both immunodeficient and wild-type mice (16,24). In addition, a significant antigenemia and viremia is seen in most acutely infected children (8, 9). In particular, we have shown the in vivo replication of homologous and heterologous RV strains in B220 ϩ cells (a marker expressed by B cells or plasmacytoid dendritic cells [pDC]) obtained from murine mesenteric lymph node (24), and recently we also demonstrated that approximately 10% of primary human circulating B cells (CBC) are targets of RV infection in vitro (49).

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“…Severity of diarrhea was assessed by fecal material examination and by scoring stools from 1 to 4 (diarrhea index [DI]) based on color, texture, and amount. Scoring was as follows: normal feces (score of 1), loose yellow-green feces (2), totally loose yellow-green feces (3), high amount of watery feces (4). Incidence of diarrhea corresponded to the percentage calculated by dividing the number of diarrheic samples by the number of total samples collected each day.…”

Section: Methodsmentioning

confidence: 99%

“…They infect enterocytes of the small intestine and cause severe gastroenteritis and dehydration; high morbidity is described worldwide, and symptomatic treatment such as rehydration is the only way to control this disease (1,2). The pathophysiology of group A RV-associated diarrhea has been experimentally studied in several animal species and has helped to advance our knowledge about the infection process (3,4). Recently, some experimental animal models have been very helpful in demonstrating that RV replication also exists outside the intestine, sera, and tissues through the detection of RNA or infectious viruses (5).…”

Section: G Roup a Rotaviruses (Rvs)-nonenveloped Icosahedralmentioning

confidence: 99%

Characterization of Clinical and Immune Response in a Rotavirus Diarrhea Model in Suckling Lewis Rats

2007

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Group A rotaviruses (RVs) are the leading pathogens causing diarrhea in children and animals. The present study was designed to establish an experimental model of RV infection and immune response in suckling rats. Wistar (W) and Lewis (L) suckling rats were inoculated orally with two different doses of a simian RV SA-11 strain. RV infection was evaluated by growth rate and clinical indexes. Virus-shedding and serum anti-RV antibodies were measured by enzyme-linked immunosorbent assay (ELISA). Mucosal interferon-␥ (IFN␥), specific splenocyte proliferation, and spleen and intestinal intraepithelial lymphocyte (IEL) phenotype were analyzed. No diarrhea was observed in any inoculated Ws. All Ls developed acute moderate diarrhea, and a high score and incidence of diarrhea were found in rats infected with higher titers of RV. Specific humoral and cell systemic immune response was confirmed by splenocyte proliferation and by the presence of serum anti-RV antibodies. Moreover, RV infection induced changes in IEL composition, which showed an increase in the proportion of innate immune cells with respect to cells involved in acquired immunity. This acute moderate diarrhea process constitutes a good experimental model that also provides some immune biomarkers that may allow establishing modulation by drugs or diet components.

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Active Viremia in Rotavirus-Infected Mice

Cited by 42 publications

References 30 publications

Murine Norovirus 1 Infection Is Associated with Histopathological Changes in Immunocompetent Hosts, but Clinical Disease Is Prevented by STAT1-Dependent Interferon Responses

Murine Norovirus 1 Infection Is Associated with Histopathological Changes in Immunocompetent Hosts, but Clinical Disease Is Prevented by STAT1-Dependent Interferon Responses

Rotavirus Differentially Infects and Polyclonally Stimulates Human B Cells Depending on Their Differentiation State and Tissue of Origin

Characterization of Clinical and Immune Response in a Rotavirus Diarrhea Model in Suckling Lewis Rats

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