Group A Rotavirus Infection and Age-Dependent Diarrheal Disease in Rats: a New Animal Model To Study the Pathophysiology of Rotavirus Infection

Abstract

Group A rotaviruses are major pathogens causing acute gastroenteritis in children and animals. To determine if group A rotavirus replicates and induces disease in rats, antibody-negative Lewis neonatal or adult rats were inoculated orally with tissue culture-adapted human (Wa, WI61, and HAL1166), simian (rhesus rotavirus [RRV] and SA11), bovine (WC3), lapine (ALA), or porcine (OSU) rotavirus strains, wild-type murine (EC wt ) rotavirus strain, or phosphate-buffered saline (PBS). Rotavirus infection in rats was evaluated by (i) clinical findings, (ii) virus antigen shedding or infectious virus titers in the feces or intestinal contents measured by enzyme-linked immunosorbent assay or fluorescent-focus assay, (iii) histopathological changes in the small intestine, (iv) distribution of rotavirus antigen in small-intestine sections by immunofluorescence, and (v) growth rate. Rotavirus infection of 5-day-old but not >21-day-old rats resulted in diarrhea that lasted from 1 to 10 days postinoculation. The severity of disease and spread of infection to naïve littermates differed depending on the virus strain used for inoculation. The duration of virus antigen shedding following infection was considerably prolonged (up to 10 days) in neonatal rats compared to that in 21-day-old rats (1 or 2 days). Based on lack of virus antigen shedding and disease induction, the murine EC wt rotavirus was the only strain tested that did not infect rats. Histopathological changes in the small-intestine mucosa of 5-day-old RRVinoculated rats but not of PBS-inoculated rats was limited to extensive enterocyte vacuolation in the ileum. In RRV-inoculated neonatal rats, rotavirus antigen was detected in the epithelial cells on the upper half of the intestinal villi of the jejunum and ileum. In addition, infection of neonatal rats with RRV but not with PBS resulted in reduced weight gain. Rats infected with group A rotaviruses provide a new animal model with unique features amenable to investigate rotavirus pathogenesis and the molecular mechanisms of intestinal development, including physiological factors that may regulate age-dependent rotavirus-induced diarrhea.Group A rotaviruses are the most common causative agents of acute gastroenteritis in children under 2 years of age and are also associated with diarrhea in the young of avian (chicken, turkey, and pigeon) and many mammalian (simian, porcine, bovine, ovine, caprine, equine, canine, feline, lapine, and murine) species (17,22). Rotavirus infection is primarily restricted to the villus epithelium of the small intestine, and the outcome of infection is age restricted. The impact of rotavirus disease in humans includes over 600,000 annual associated deaths in developing countries, and in the United States, annual economic losses due to rotavirus infections have been conservatively estimated at $1 billion (12,22,24,31,39,43,53,71). Therefore, development of a safe and effective rotavirus vaccine is a global priority.The use of animal models of rotavirus infection has provided key insights in...

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

“…Some of these studies have been developed in germ-free suckling rats (13), but Ciarlet et al (3) developed an extensive work in the characterization of diarrhea process in suckling L, with some heterologous RV strains . We set up our studies in W and L strains, and in older suckling animals (8 and 11 d old).…”

“…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).…”

“…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). RV infection in mice has been used to define some clinical features of the diarrhea process (4); however, only a few studies of RV infection have been performed in rats (3), and even fewer were focused on the immune response induced by the virus (6). The relationship of RV on the immune response and in the development and resolution of disease has not been well established.…”

Modulation of Human Intestinal Epithelial Cell IL-8 Secretion by Human Milk Factors

“…IL-1␤-stimulated IL-8 secretion was inhibited Abbreviations DMEM, Dulbecco's modified Eagle's medium EGF, epidermal growth factor Epo, erythropoietin FBS, fetal bovine serum IEC, intestinal epithelial cell NEC, necrotizing enterocolitis NF-B, nuclear factor B SV40, simian virus 40 TGF-␤, transforming growth factor-␤ TNF, tumor necrosis factor TsFHI, temperature-sensitive fetal human intestinal cells Evidence suggests that the intestinal epithelium is an active participant in gastrointestinal host defense and that intestinal epithelial-microbial interactions are developmentally regulated (1)(2)(3)(4). Children are more susceptible to severe diarrhea from rotavirus and vibrio cholera toxin than are adults (5), and animal models have demonstrated prolonged rotavirus shedding and an increased secretory response to cholera toxin in neonatal compared with adult rats (6). Necrotizing enterocolitis (NEC) is another disease of intestinal maturation and microbial interaction.…”

Molecular characterization of porcine rotavirus C in pigs with gastroenteritis in Thailand, 2011 – 2016

“…Rotaviruses are also important causes of diarrhea in animals and can manifest in 65 different disease severity depending on the age of the animals (Ciarlet et al, 2002; Neog et al, 66 2011;Pott et al, 2012;Riepenhoff et al, 1982). Although pigs of all ages are susceptible to 67 rotavirus infection, neonatal and even post-weaned piglets are frequently infected (Bohl et al, 68 1982;Lecce 1978).…”