Modeling Severe Fever with Thrombocytopenia Syndrome Virus Infection in Golden Syrian Hamsters: Importance of STAT2 in Preventing Disease and Effective Treatment with Favipiravir

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease endemic in parts of Asia. The etiologic agent, SFTS virus (SFTSV; family Bunyaviridae, genus Phlebovirus) has caused significant morbidity and mortality in China, South Korea, and Japan, with key features of disease being intense fever, thrombocytopenia, and leukopenia. Case fatality rates are estimated to be in the 30% range, and no antivirals or vaccines are approved for use for treatment and prevention of SFTS. There is evidence that in human cells, SFTSV sequesters STAT proteins in replication complexes, thereby inhibiting type I interferon signaling. Here, we demonstrate that hamsters devoid of functional STAT2 are highly susceptible to as few as 10 PFU of SFTSV, with animals generally succumbing within 5 to 6 days after subcutaneous challenge. The disease included marked thrombocytopenia and inflammatory disease characteristic of the condition in humans. Infectious virus titers were present in the blood and most tissues 3 days after virus challenge, and severe inflammatory lesions were found in the spleen and liver samples of SFTSV-infected hamsters. We also show that SFTSV infection in STAT2 knockout (KO) hamsters is responsive to favipiravir treatment, which protected all animals from lethal disease and reduced serum and tissue viral loads by 3 to 6 orders of magnitude. Taken together, our results provide additional insights into the pathogenesis of SFTSV infection and support the use of the newly described STAT2 KO hamster model for evaluation of promising antiviral therapies. IMPORTANCE Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease for which there are currently no therapeutic options or available vaccines. The causative agent, SFTS virus (SFTSV), is present in China, South Korea, and Japan, and infections requiring medical attention result in death in as many as 30% of the cases. Here, we describe a novel model of SFTS in hamsters genetically engineered to be deficient in a protein that helps protect humans and animals against viral infections. These hamsters were found to be susceptible to SFTSV and share disease features associated with the disease in humans. Importantly, we also show that SFTSV infection in hamsters can be effectively treated with a broad-spectrum antiviral drug approved for use in Japan. Our findings suggest that the new SFTS model will be an excellent resource to better understand SFTSV infection and disease as well as a valuable tool for evaluating promising antiviral drugs

Pathogenesis of Rift Valley Fever Virus Aerosol Infection in STAT2 Knockout Hamsters

Rift Valley fever virus (RVFV) is an emerging pathogen capable of causing severe disease in livestock and humans and can be transmitted by multiple routes including aerosol exposure. Several animal models have been developed to gain insight into the pathogenesis associated with aerosolized RVFV infection, but work with these models is restricted to high containment biosafety level (BSL) laboratories limiting their use for antiviral and vaccine development studies. Here, we report on a new RVFV inhalation infection model in STAT2 KO hamsters exposed to aerosolized MP-12 vaccine virus by nose-only inhalation that enables a more accurate delivery and measurement of exposure dose. RVFV was detected in hepatic and other tissues 4–5 days after challenge, consistent with virus-induced lesions in the liver, spleen and lung. Furthermore, assessment of blood chemistry and hematological parameters revealed alterations in several liver disease markers and white blood cell parameters. Our results indicate that STAT2 KO hamsters develop a disease course that shares features of disease observed in human cases and in other animal models of RVFV aerosol exposure, supporting the use of this BSL-2 infection model for countermeasure development efforts

Veterinary Students’ Social Integration Transferring Across Multiple Campuses in Partnered Veterinary Medical Programs

The objective of this study is to evaluate factors that lead to more effective social integration of veterinary students from one campus as they join a larger cohort of peers on a new university campus. A survey of 24 thirdyear students from the Utah State University campus who transitioned to the Washington State University campus indicated that students who reported satisfaction with others\u27 attempts at helping them integrate into their new cohort were connected with a stronger perception of group cohesion and social support. Integration attempts from peers rather than WIMU faculty or staff were connected to the highest reported levels of satisfaction of areas assessed. Schools of veterinary medicine should find opportunities to support and encourage student-led integration initiatives

Data from: Serum biochemistry panels in African buffalo: Defining reference intervals and assessing variability across season, age and sex

Serum biochemical parameters can be utilized to evaluate the physiological status of an animal, and relate it to the animal’s health. In order to accurately interpret individual animal biochemical results, species-specific reference intervals (RI) must be established. Reference intervals for biochemical parameters differ between species, and physiological differences including reproductive status, nutritional resource availability, disease status, and age affect parameters within the same species. The objectives of this study were to (1) establish RI for biochemical parameters in managed African buffalo (Syncerus caffer), (2) assess the effects of age, sex, pregnancy, and season on serum biochemistry values, and (3) compare serum biochemistry values from a managed herd to a free-ranging buffalo herd and to values previously published for captive (zoo) buffalo. Season profoundly affected all biochemistry parameters, possibly due to changes in nutrition and disease exposure. Age also affected all biochemical parameters except gamma glutamyl transferase and magnesium, consistent with patterns seen in cattle. Sex and reproductive status had no detectable effects on the parameters that were measured. The biochemical profiles of managed buffalo were distinct from those observed in the free-ranging herd and captive buffalo. Biochemical differences between buffalo from captive, managed, and free-ranging populations may be related to nutritional restriction or lack of predation in the context of management or captivity. The reference intervals provided in this study, in addition to the seasonal and age-related patterns observed, provide a foundation for health investigations that may inform management strategies in this ecologically and economically important species

Prevalence of Exertional Rhabdomyolysis in Endurance Horses in the Pacific Northwestern United States

SUMMARY - REASONS FOR PERFORMING STUDY: Exertional rhabdomyolysis (ER) is a reported syndrome in competing endurance horses; however the prevalence and cause of ER in this population has not been defined. OBJECTIVES: To determine the prevalence of ER in a sample of endurance racing horses, and to investigate factors, including relevant genetic defects, contributing to the occurrence of rhabdomyolysis in this group. STUDY DESIGN: Prospective clinical study METHODS: Riders of 101 horses participating in one of four 50 mile distance races completed a comprehensive questionnaire regarding the medical history, management and performance of their horse. Serum creatine kinase activity (CK) was measured before and four hours after completion of exercise. Hair samples were analysed by PCR for the R309H mutation in the glycogen synthase gene (GYS1) responsible for Type 1 polysaccharide storage myopathy (PSSM) and the C7360G mutation in the ryanodine receptor 1 (RYR1) gene causing malignant hyperthermia (MH). RESULTS: Samples were obtained from 68 Arabians, 20 half-Arabians, and 13 horses of other breeds. Serum CK was above the resting reference interval (145-633 U/L) in 38 horses after racing (median 883 U/L, range 658–3,739) but was compatible with values previously reported in apparently healthy endurance horses. Pathologic ER was suspected to occur in four horses with serum CK activities exceeding 10,000 U/L four hours after racing (median 84,825 U/L; range 10,846 - 381,790) including three Arabians and one half-Arabian horse. GYS1 and RYR1 mutations were not present in hair samples from any horses. CONCLUSIONS: Exertional rhabdomyolysis occurred at a prevalence of 4.0% in a sample of horses participating in 50 mile distance events, and all affected horses were Arabian or half-Arabian. POTENTIAL RELEVANCE: The cause of ER in the endurance horse population remains unknown; however, ER in competing Arabian endurance horses is unlikely to be due to Type 1 PSSM or MH.Keywords: polysaccharide storage myopathy, horse, exercise, exertional rhabdomyolysi

Pathogenesis of Rift Valley Fever Virus Aerosol Infection in <i>STAT2</i> Knockout Hamsters

Rift Valley fever virus (RVFV) is an emerging pathogen capable of causing severe disease in livestock and humans and can be transmitted by multiple routes including aerosol exposure. Several animal models have been developed to gain insight into the pathogenesis associated with aerosolized RVFV infection, but work with these models is restricted to high containment biosafety level (BSL) laboratories limiting their use for antiviral and vaccine development studies. Here, we report on a new RVFV inhalation infection model in STAT2 KO hamsters exposed to aerosolized MP-12 vaccine virus by nose-only inhalation that enables a more accurate delivery and measurement of exposure dose. RVFV was detected in hepatic and other tissues 4&#8315;5 days after challenge, consistent with virus-induced lesions in the liver, spleen and lung. Furthermore, assessment of blood chemistry and hematological parameters revealed alterations in several liver disease markers and white blood cell parameters. Our results indicate that STAT2 KO hamsters develop a disease course that shares features of disease observed in human cases and in other animal models of RVFV aerosol exposure, supporting the use of this BSL-2 infection model for countermeasure development efforts

The location of African buffalo used in this study.

<p>The enclosure is located in the central portion of KNP near Satara and experiences only 500mm of rain per year, with the majority occurring during the summer months. Total size of the enclosure is 900 hectares, and is enclosed in a double fence to exclude large predators. The buffalo captured as part of the free-ranging herd were initially located in the south-eastern portion of the park centered around Lower Sabie, which experiences similar rainfall to the managed herd. The free-ranging herd was allowed to disperse as normal over the 4 years of the study which resulted in individuals being re-captured throughout the southern portion of the park, as far north as Olifants and spanning the geographic area the managed herd is maintained in [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176830#pone.0176830.ref025" target="_blank">25</a>].</p

Sample collection details.

<p>The number of samples collected from each age group across four seasons in a herd of managed buffalo contained in a 900 hectare enclosure within KNP.</p

Managed African buffalo serum biochemistry parameters across seasons.

<p>Within each parameter, shared letters indicate no significant difference across seasons. The heat map shows the percent difference between seasonal average value and overall average for each parameter, with red being very high concentration and white being very low concentration. All parameters were centered and transformed so that color varies on the same scale for each parameter.</p