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Both human epidemiologic data and animal studies suggest that low serum vitamin D increases the risk of inflammatory bowel disease (IBD) and consequently IBD-associated colorectal cancer. We tested the hypothesis that vitamin D deficiency increases the risk for colitis-associated colon cancer (CAC) by using an established CAC mouse model, 129-Smad3tm1Par/J (Smad3–/–) mice, which have defective transforming growth factor β-signaling and develop colitis and CAC after the administration of dextran sodium sulfate (DSS). After determining a dietary regimen that induced chronic vitamin D deficiency in Smad3–/– mice, we assessed the effects of vitamin D deficiency on CAC. Decreasing dietary vitamin D from 1 IU/g diet (control diet) to 0.2 IU /g diet did not decrease serum 25-hydroxyvitamin D (25(OH)D) levels in Smad3–/– mice. A diet devoid of vitamin D (< 0.02 IU/g diet [no added vitamin D]; vitamin D-null) significantly decreased serum 25(OH)D levels in mice after 2 wk (null compared with control diet: 8.4 mg/mL compared with 12.2 ng/mL) and further decreased serum levels to below the detection limit after 9 wk but did not affect weight gain, serum calcium levels, bone histology, or bone mineral density. In light of these results, Smad3–/– mice were fed a vitamin D–null diet and given DSS to induce colitis. Unexpectedly, DSS-treated Smad3–/– mice fed a vitamin D–null diet had improved survival, decreased colon tumor incidence (8% compared with 36%), and reduced the incidence and severity of colonic dysplasia compared with mice fed the control diet. These effects correlated with increased epithelial cell proliferation and repair early in the disease, perhaps reducing the likelihood of developing chronic colitis and progression to cancer. Our results indicate that vitamin D deficiency is beneficial in some cases of CAC, possibly by promoting intestinal healing.

Murine norovirus (MNV) infection is highly prevalent in laboratory mice. Although MNV infection does not typically induce clinical disease in most laboratory mice, infection may nonetheless affect mouse models of disease by altering immune responses. We previously reported that MNV altered the bacterial-induced mouse model of inflammatory bowel disease (IBD) using Helicobacter-infected Mdr1a–/– mice. Therefore, we hypothesized that MNV infection would exacerbate another mouse model of IBD, the T-cell adoptive transfer (AT) model. In this model, Helicobacter infection is used to accelerate the progression of IBD induced by AT of naïve CD4+CD45RBhigh T cells into B6.129S7- Rag1tm1Mom/J (Rag1–/–) mice. We evaluated the effects of MNV infection in both Helicobacter-accelerated as well as Helicobacter-free AT models. In our studies, Helicobacter-infected Rag1–/– mice that received CD4+CD45RBhigh T cells through AT rapidly developed weight loss and typhlocolitis; MNV infection had no effect on disease severity or rate of progression. In the absence of Helicobacter infection, progression of IBD caused by AT of CD4+CD45RBhigh T cells was slower and typhlocolitis was less severe; this inflammation likewise was unaltered by MNV infection. These results indicate that MNV infection does not alter IBD progression and severity in the CD4+CD45RBhigh T-cell AT model in Rag1–/– mice.

Murine norovirus (MNV) is an RNA virus that can prove lethal in mice with impaired innate immunity. We found that MNV-4 infection of Stat1(−/−) mice was not lethal, but produced a 100% penetrant, previously undescribed lymphatic phenotype characterized by chronic-active lymphangitis with hepatitis, splenitis, and chronic cecal and colonic inflammation. Lesion pathogenesis progressed from early ileal enteritis and regional dilated lymphatics to lymphangitis, granulomatous changes in the liver and spleen, and, ultimately, typhlocolitis. Lesion development was neither affected by antibiotics nor reproduced by infection with another enteric RNA virus, rotavirus. MNV-4 infection in Stat1(−/−) mice decreased expression of vascular endothelial growth factor (Vegf) receptor 3, Vegf-c, and Vegf-d and increased interferon (Ifn)-γ, tumor necrosis factor-α, and inducible nitric oxide synthase. However, anti–IFN-γ and anti–tumor necrosis factor-α antibody treatment did not attenuate the histologic lesions. Studies in Ifnαβγr(−/−) mice suggested that canonical signaling via interferon receptors did not cause MNV-4–induced disease. Infected Stat1(−/−) mice had increased STAT3 phosphorylation and expressed many STAT3-regulated genes, consistent with our findings of increased myeloid cell subsets and serum granulocyte colony-stimulating factor, which are also associated with increased STAT3 activity. In conclusion, in Stat1(−/−) mice, MNV-4 induces lymphatic lesions similar to those seen in Crohn disease as well as hepatitis, splenitis, and typhlocolitis. MNV-4–infected Stat1(−/−) mice may be a useful model to study mechanistic associations between viral infections, lymphatic dysfunction, and intestinal inflammation in a genetically susceptible host.

Murine noroviruses (MNVs) are highly prevalent in laboratory mice, can cause persistent infections, and have been shown to infect macrophages, dendritic cells, and B cells. To address the potential impact of MNV infection on research outcomes, numerous studies have been conducted with various mouse models of human disease and have generated mixed results, ranging from no impact to significant disease. Many of these studies included histologic evaluations after MNV infection, and these results have similarly been variable in terms of whether MNV induces lesions, despite the fact that localization of MNV by viral culture and molecular techniques have demonstrated systemic distribution regardless of mouse immune status. The aim of this review is to summarize the histologic findings that have been reported with MNV infection in several mouse models. The studies demonstrate that experimental infection of MNV in wild-type mice results in minimal to no histologic changes. In contrast, immunodeficient mice consistently have detectable MNV-induced lesions that are typically inflammatory and, in the most severe cases, accompanied by necrosis. In these, the liver is commonly affected, with more variable lesions reported in the lung, gastrointestinal tract, mesenteric lymph nodes, brain, and spleen. In specific disease models including atherosclerosis, MNV infection had a variable impact that was dependent on the mouse model, viral strain, timing of infection, or other experimental variables. It is important to recognize the reported MNV lesions to help discern the possible influence of MNV infection on data generated in mouse models.

Most viral infections in small mammals are transient and rarely produce clinical signs. When clinical signs do appear, they are often of a multifactorial etiology such as respiratory infection with Sendai virus and the bacteria M. pulmonis in rodents. Diagnosis is generally made based on clinical signs, while therapy involves treatment for concurrent bacterial infections and supportive care. Small mammals may carry zoonotic viruses such as LCMV, but natural infections are uncommon. Viral diseases are rare (or largely unknown) for hedgehogs, chinchillas, and prairie dogs, while no known naturally occurring, clinically relevant viral diseases exist for gerbils and sugar gliders. This article is intended to aid the clinician in identifying viral infections in small mammals and to help determine the significance each virus has during clinical disease.

Publisher Summary Performing basic experimental procedures on chinchillas can be a challenge due to their small size, their unique characteristics, and the limited amount of information available on the techniques. Procedures such as handling, restraint, collection of samples, or administration of compounds can all be done relatively stress-free with minimal complications when performed appropriately by skilled personnel. A thorough understanding and knowledge of the experimental procedure should be obtained prior to initiation to ensure the task is carried out properly. This chapter highlights basic experimental methods in chinchillas. Chinchillas are typically quiet and shy rodents, which can be easily handled if done so in a calm, quiet, and gentle manner that uses the least amount of restraint but is still firm enough so that the handler has good control of the animal. Collection of blood from the jugular vein of chinchillas is generally well tolerated by the awake, unsedated, or unanesthetized animal. Administration of compounds or fluids in chinchillas may be done by a variety of routes including oral, intravenous, intramuscular, subcutaneous, intraperitoneal, or intraosseous. The chinchilla is well known for its use as an animal model for auditory research and diseases of the ear.

Multiplex Fluorescent Immunoassay (MFI) is a sensitive and specific serologic test that allows simultaneous detection of antibodies to multiple viral and bacterial agents in a single reaction well. MFI is a high-throughput assay that offers several advantages over other prevalent assays, and some research animal diagnostic laboratories have adopted it as their primary technique. The authors present a detailed review of MFI and its application to laboratory animal diagnostics.