Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene. The major cause of limited life span in CF patients is progressive lung disease. CF models have been generated in 4 species (mice, rats, ferrets, and pigs) to enhance our understanding of the CF pathogenesis. Sheep may be a particularly relevant animal to model CF in humans due to the similarities in lung anatomy and development in the two species. Here, we describe the generation of a sheep model for CF using CRISPR/Cas9 genome editing and somatic cell nuclear transfer (SCNT) techniques. We generated cells with CFTR gene disruption and used them for production of CFTR ^–/– and CFTR ^+/– lambs. The newborn CFTR ^–/– sheep developed severe disease consistent with CF pathology in humans. Of particular relevance were pancreatic fibrosis, intestinal obstruction, and absence of the vas deferens. Also, substantial liver and gallbladder disease may reflect CF liver disease that is evident in humans. The phenotype of CFTR ^–/– sheep suggests this large animal model will be a useful resource to advance the development of new CF therapeutics. Moreover, the generation of specific human CF disease–associated mutations in sheep may advance personalized medicine for this common genetic disorder.

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.

Neoplastic diseases in prosimians have been sporadically reported in the literature. To provide a comprehensive review of prosimian neoplasia, a retrospective evaluation of neoplasia in a large captive prosimian colony and an extensive literature review were performed. Primates that belong to the Order Primata, Suborder Prosimii with histologic evidence of neoplasia were included. One hundred twenty-three cases of spontaneous neoplasia were identified in 101 prosimians from the Duke Lemur Center, and 124 cases were reported in 116 prosimians in the literature. Overall, this review compiled a total of 247 neoplasms in 217 prosimians. Of the 217 affected animals, 88 of 217 were males (41%), 100 of 217 were females (46%), and sex was not reported in 29 of 217 (13%). Ages ranged from 2 days to 36 years. Prosimian families represented were Lemuridae (80/217 [37%]), Cheirogaleidae (61/217 [28%]), Galagidae (44/217 [20%]), Lorisidae (28/217 [13%]), and Indriidae (4/217 [2%]). The most commonly affected species were the gray mouse lemur (Microcebus murinus) (28/217 [13%]), thick-tailed greater bush baby (Otolemur crassicaudatus) (23/217 [11%]), and black lemur (Eulemur macaco) (19/217 [9%]). Organ systems affected, in order of descending occurrence, were digestive (75/247 [30%]), reproductive (40/247 [16%]), hematopoietic (34/247 [14%]), integumentary (28/247 [11%]), endocrine (26/247 [11%]), and urinary (17/247 [7%]). The respiratory, nervous, musculoskeletal, and cardiovascular systems were infrequently affected. The most common neoplasms were hepatocellular (32/247 [13%]), lymphoma and/or leukemia (29/247 [12%]), biliary (15/247 [6%]), and mammary neoplasms (12/247 [5%]). This article should serve as a valuable reference for the types and relative frequencies of neoplasms that occur in prosimian species.