RRV-infected Mice Research Articles

Rotavirus Infection Accelerates Type 1 Diabetes in Mice with Established Insulitis

Infection modulates type 1 diabetes, a common autoimmune disease characterized by the destruction of insulin-producing islet beta cells in the pancreas. Childhood rotavirus infections have been associated with exacerbations in islet autoimmunity. Nonobese diabetic (NOD) mice develop lymphocytic islet infiltration (insulitis) and then clinical diabetes, whereas NOD8.3 TCR mice, transgenic for a T-cell receptor (TCR) specific for an important islet autoantigen, show more rapid diabetes onset. Oral infection of infant NOD mice with the monkey rotavirus strain RRV delays diabetes development. Here, the effect of RRV infection on diabetes development once insulitis is established was determined. NOD and NOD8.3 TCR mice were inoculated with RRV aged > or = 12 and 5 weeks, respectively. Diabetes onset was significantly accelerated in both models (P < 0.024), although RRV infection was asymptomatic and confined to the intestine. The degree of diabetes acceleration was related to the serum antibody titer to RRV. RRV-infected NOD mice showed a possible trend toward increased insulitis development. Infected males showed increased CD8(+) T-cell proportions in islets. Levels of beta-cell major histocompatibility complex class I expression and islet tumor necrosis factor alpha mRNA were elevated in at least one model. NOD mouse exposure to mouse rotavirus in a natural experiment also accelerated diabetes. Thus, rotavirus infection after beta-cell autoimmunity is established affects insulitis and exacerbates diabetes. A possible mechanism involves increased exposure of beta cells to immune recognition and activation of autoreactive T cells by proinflammatory cytokines. The timing of infection relative to mouse age and degree of insulitis determines whether diabetes onset is delayed, unaltered, or accelerated.

MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication

Biliary atresia is a disease of newborns that results in obliteration of the biliary tree. Infection of mice with rhesus rotavirus (RRV) results in a cholangiopathy mirroring human disease. The Mitogen Associated Protein Kinase (MAPK) signaling pathway can be activated by viral binding to cell-surface receptors. We hypothesized that RRV infection of cholangiocytes results in activation of MAPK signaling. Extrahepatic bile ducts from BALB/c pups or immortalized cholangiocytes subjected to RRV infection or control were analyzed, using Western blots, for phosphorylated members of the MAPK family: p38, ERK 1/2, JNK 1/2, and downstream transcription factors. Inhibitors of the MAPK were used to downregulate activity. Viral replication and cytolysis in cholangiocytes were evaluated post-MAPK inhibition. Phosphorylation of all MAPK increased in RRV-infected mice and cholangiocytes. Several downstream transcription factors had increased activity in vitro. Inhibition of p38 and ERK 1/2 resulted in decreased viral replication. ERK 1/2 inhibition decreased cytolysis without affecting viral entry or binding. RRV infection of cholangiocytes resulted in increased MAPK signaling. Inhibition of p38 and ERK 1/2 influenced the ability of rotavirus to replicate. These novel findings provide insight into the signaling cascade involved in RRV-induced cholangiocyte injury.

Complement Contributes to Inflammatory Tissue Destruction in a Mouse Model of Ross River Virus-Induced Disease

Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus, are mosquito-borne viruses that cause significant human disease worldwide, including explosive epidemics that can result in thousands to millions of infected individuals. Similar to infection of humans, infection of C57BL/6 mice with RRV results in severe monocytic inflammation of bone, joint, and skeletal muscle tissues. We demonstrate here that the complement system, an important component of the innate immune response, enhances the severity of RRV-induced disease in mice. Complement activation products were detected in the inflamed tissues and in the serum of RRV-infected wild-type mice. Furthermore, mice deficient in C3 (C3(-/-)), the central component of the complement system, developed much less severe disease signs than did wild-type mice. Complement-mediated chemotaxis is essential for many inflammatory arthritides; however, RRV-infected wild-type and C3(-/-) mice had similar numbers and composition of inflammatory infiltrates within hind limb skeletal muscle tissue. Despite similar inflammatory infiltrates, RRV-infected C3(-/-) mice exhibited far less severe destruction of skeletal muscle tissue. In addition to these studies, complement activation was also detected in synovial fluid from RRV-infected patients. Taken together, these findings indicate that complement activation occurs in the tissues of humans and mice infected with RRV and suggest that complement plays an essential role in the effector phase, but not the inductive phase, of RRV-induced arthritis and myositis.

Immune responses in rhesus rotavirus-challenged BALB/c mice treated with bifidobacteria and prebiotic supplements.

Bifidobacterium species (B. bifidum and B. infantis), with or without prebiotic compounds (arabino-galactan, short-chain fructo-oligosaccharide, iso-malto-dextrins), were orally fed to Balb/c pups (n = 192) to evaluate their potential synergistic effects on modulating the course of rhesus rotavirus (RRV) infection, as well as their ability to mediate the associated mucosal and humoral immune responses. Rotavirus-specific IgA and IgG in serum, rotavirus antigen, and specific IgA in feces were measured by ELISA. Mucosal total IgA and IgG levels were determined in Peyer's patches by flow cytometry. Significantly delayed onset (p = 0.001) and early resolution (p < 0.001) of diarrhea were observed in bifidobacteria-treated, RRV-infected mice compared with RRV-infected control mice. Supplementation with prebiotic compounds did not shorten the clinical diarrhea course more than that observed with bifidobacteria treatment alone. Rotavirus-specific IgA in feces was 16-fold elevated on d 5 postinfection in bifidobacteria-treated, RRV-infected mice compared with the RRV-infected alone group. In addition, the level of rotavirus-specific IgA in serum was four-fold higher in bifidobacteria-treated, RRV-infected litters versus mice challenged with RRV alone on 28 and 42 d postinfection. No enhancement of the immune response was found in RRV-infected mice that were treated with both bifidobacteria and prebiotic compounds over those treated with bifidobacteria only. The findings suggest that bifidobacteria may act as an adjuvant by modulating early mucosal and strong humoral rotavirus-specific immune responses, and mitigate severity of rotavirus-induced diarrhea.

Macrophage-induced muscle pathology results in morbidity and mortality for Ross River virus-infected mice.

Ross River virus (RRV) is an Australian alphavirus that is often responsible for chronic epidemic polyarthritis and myalgia in humans. Past studies have shown severe disruption of striated muscle fibers to be prominent in RRV pathology in mice; in the present study, macrophages were directly implicated as the primary mediators of muscle damage. General immunosuppressive therapies had only minor effects on mortality and morbidity in RRV-infected mice, with no inhibition of muscle damage. Treatment of mice with macrophage-toxic agents (e.g., silica) prior to RRV infection completely abrogated disease symptoms without significantly affecting titers of virus in organs. Further studies found that clinical signs of infection and muscle damage correlated with a massive influx of macrophages into hind leg muscle, whereas no such infiltrate or damage was observed for silica-treated mice. These observations are significant for the human disease context, as monocytic cells have been detected in the synovial effusions of persons with epidemic polyarthritis.