Calicivirus Enteritis in an Intestinal Transplant Recipient

Histo-blood group antigen (HBGA) phenotypes have been associated with susceptibility to human noroviruses (HuNoVs). Our aims were: (i) to determine the patterns of A/H HBGA expression in buccal and intestinal tissues of gnotobiotic (Gn) pigs; (ii) to determine if virus-like particles (VLPs) of HuNoV genogroup I (GI) and GII bind to A- or H-type tissues; (iii) to compare A/H expression and VLP binding patterns and confirm their binding specificities by blocking assays; (iv) to develop a hemagglutination inhibition test using buccal cells from live pigs to determine the Gn pig's A/H phenotype and to match viral strains with previously determined HuNoV VLP binding specificities; and (v) to determine the A/H phenotypes and compare these data to the infection outcomes of a previous study of 65 Gn pigs inoculated with HuNoV GII/4 strain HS66 and expressing A and/or H or neither antigen on their buccal and intestinal tissues (S. Cheetham, M. Souza, T. Meulia, S. Grimes, M. G. Han, and L. J. Saif, J. Virol. 80:10372-10381, 2006). We found that the HuNoV GI/GII VLPs of different clusters bound to tissues from four pigs tested (two A+ and two H+). The GI/1 and GII/4 VLPs bound extensively to duodenal and buccal tissues from either A+ or H+ pigs, but surprisingly, GII/1 and GII/3 VLPs bound minimally to the duodenum of an A+ pig. The VLP binding was partially inhibited by A-, H1-, or H2-specific monoclonal antibodies, but was completely blocked by porcine mucin. Comparing the A/H phenotypes of 65 HS66-inoculated Gn pigs from our previous study, we found that significantly more A+ and H+ pigs (51%) than non-A+ and non-H+ pigs (12.5%) shed virus. From the 22 convalescent pigs, significantly more A+ or H+ pigs (66%) than non-A+ or H+ pigs (25%) seroconverted.

Section: Discussioncontrasting

confidence: 53%

Binding Patterns of Human Norovirus-Like Particles to Buccal and Intestinal Tissues of Gnotobiotic Pigs in Relation to A/H Histo-Blood Group Antigen Expression

Cheetham

Souza

McGregor

et al. 2007

“…Human noroviruses are thought to have an enteric tropism limited to the upper intestinal tract, since intestinal biopsies from volunteers challenged with NV or Hawaii virus show villous broadening and blunting in the jejunum and an infiltration of mononuclear cells (1,14,63,64). Similar pathology is seen in biopsies from pediatric transplant patients with high-volume diarrhea associated with human norovirus infection (38,51). However, the site of human norovirus replication in vivo has not been demonstrated.…”

Section: Mnv Has a Tropism For Macrophages And Dendritic Cellsmentioning

confidence: 55%

“…In addition, studies using MNV suggest that humans with compromised adaptive immune responses may experience disseminated, long-term norovirus infection. While human norovirus infection outside the gastrointestinal tract has not been documented, several cases of prolonged norovirus shedding (4 months to Ͼ2 years) have been described in transplant patients with compromised adaptive immune systems (21,38,39,51,53).…”

Section: Adaptive Immunity Is Required To Clear Norovirus Infectionmentioning

confidence: 99%

Murine Norovirus: a Model System To Study Norovirus Biology and Pathogenesis

Wobus

Thackray

Virgin

2006

510

398

Human noroviruses are the major cause of nonbacterial, epidemic gastroenteritis worldwide (19,23,33,46) and cause significant numbers of endemic cases, as well. One study from 1999 estimated that, in the United States alone, human noroviruses cause 23 million cases of gastroenteritis and 50,000 hospitalizations per year (49). Norovirus outbreaks involve people of all ages and often occur in crowded locations, such as cruise ships, aircraft carriers, nursing homes, hospitals, schools, and restaurants (23). Noroviruses are classified as class B biological agents due to their high infectivity and stability and to the suddenness of outbreaks and the debilitating nature of the disease. Despite the significant economic impact and considerable morbidity caused by human noroviruses, no drug or vaccine is currently available to treat or prevent human norovirus disease. In addition, many aspects of norovirus biology are not well understood. This is due in large part to the absence of a cell culture system or small animal model for human noroviruses (16,23).Although most noroviruses have been associated with gastrointestinal disease in humans, noroviruses of cattle, swine and mice have also been identified (36,44,70). Of these potential experimental models, the murine norovirus (MNV) is the only norovirus that replicates in cell culture and in a small animal (36,75). Moreover, laboratory mice are a versatile and relatively inexpensive model for the analysis of viral pathogenesis. A recent analysis of a large number of mouse serum samples from research colonies in the United States and Canada identified MNV-1 reactive antibodies in 22.1% of serum samples (30). In addition, over 35 new isolates of MNV have been found in research colonies (GenBank accession no. DQ223041 to DQ223043 and DQ269192 to DQ269205; unpublished observations). Therefore, MNV is one of the most prevalent pathogens in research mice today. Independent of its value as a potential model for norovirus infection, the impact of MNV infection on biomedical research, which is highly dependent on mice as experimental models, may be of great significance.The MNV model system provides the first opportunity to understand the relationship between basic mechanisms of norovirus replication in tissue culture and pathogenesis in a natural host. The mouse model also provides an opportunity to use defined mutations in host genes to identify molecular components required for norovirus infection and for the host response to norovirus infection. To date, the MNV model system has revealed a tropism for cells of the hematopoietic lineage, specifically, macrophages and dendritic cells. In addition, in vivo studies using the MNV model system demonstrate a fundamental role for innate immune responses in the control of norovirus infection and an important role for adaptive immune responses in the clearance of norovirus infection from the intestine and other tissues.This review summarizes what is currently known about MNV, highlights parallels that may exist between murine and human...

“…No information is available on lesions in other portions of the intestines of these volunteers (9). Intestinal transplant pediatric patients that were diagnosed with HuNoV infection developed secretory or osmotic diarrhea (19,20,31). These patients had prolonged diarrhea (17 to 326 days) due to immunosuppressive therapy.…”

mentioning

confidence: 99%

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Cheetham

Souza

Meulia

et al. 2006

252

262

Human noroviruses (HuNoVs) are a major cause of foodborne gastroenteritis worldwide. Because they do not grow in cell culture and there is no animal model for HuNoVs, pathogenesis studies have been hampered. Thus, little is known about their replication strategies or induction of neutralizing antibodies.The limited information on their pathogenesis is from human volunteer studies of HuNoV infections in which villus atrophy in duodenal biopsies and presence of malabsorptive diarrhea were described (1,7,8). No information is available on lesions in other portions of the intestines of these volunteers (9). Intestinal transplant pediatric patients that were diagnosed with HuNoV infection developed secretory or osmotic diarrhea (19,20,31). These patients had prolonged diarrhea (17 to 326 days) due to immunosuppressive therapy. The detection of HuNoV RNA and the clinical symptoms remitted after reduction of the immunosuppressive therapy. Usually in exposed individuals, histologic lesions correlate with diarrhea, but in one report, lesions in volunteers who did not show clinical symptoms were described (42). There are also numerous reports of asymptomatic individuals who were infected with HuNoVs and shed virus in the feces (11, 28).Most past attempts to study these viruses in an animal model may have failed because (i) the human strains that were used were not closely related to the host animal NoV strains, (ii) sensitive detection techniques were lacking, and finally (iii) the role of histo-blood group antigen (HBGA) phenotypes in differential susceptibility of the host was unrecognized. Our goal was to adapt a HuNoV strain to replicate in the gnotobiotic (Gn) pig to develop an animal model for the study of HuNoV pathogenesis. Gnotobiotic pigs are good models for human enteric diseases (40) because pigs resemble humans in their gastrointestinal anatomy, physiology, and immune responses. The Gn pigs are immunocompetent at birth, but they lack maternal antibodies and previous or ongoing exposure to microbial agents, including caliciviruses.Recently, viral RNA genetically similar to that of human NoV GII (65 to 71% amino acid sequence identity in the capsid gene) was detected in pigs in Japan (46, 47) and Europe (22,48). In U.S. swine, our laboratory detected both viral RNA and virus particles similar to GII HuNoV (70% sequence identity in the capsid region) which were infectious for Gn pigs (50). Our approach to infect Gn pigs with a HuNoV was to use a GII strain that is closely related genetically to the identified GII porcine NoVs and that has a broad HBGA binding pattern because little information or reagents are available for pig HBGA. Additionally, we used sensitive assays and reagents including reverse transcription (RT)-PCR to detect fecal shedding, virus-like particles (VLPs) for serological assays, and antisera to these VLPs for antigen enzyme-linked immunosor-