Non-Human Primate Models of Viral and Autoimmune Diseases of the Gastrointestinal Tract
Over past 12 years, Dr. Sestak’s research focus at Tulane was predominantly directed towards infectious and autoimmune diseases of the gastrointestinal tract such as enteric calicivirus, rotavirus infections and gluten-sensitive enteropathy. The main objective is the development and translational use of non-human primate models to address those issues of immunity, pathogenesis and prevention that cannot be readily dealt with in clinical studies. Dr. Sestak’s studies and collaborations led to isolation and in vitro adaptation of two groups of novel enteric viruses (rhesus rota- and caliciviruses), first ever description and recognition of rhesus gluten-sensitive enteropathy as the model for human celiac disease plus other models of human diseases. These models and agents are now available for intra- and inter-institution collaborative studies.
Gluten Sensitivity, Celiac Disease and Non-Celiac Gluten Sensitivity
It is estimated that there are at least 3 million people in the United States affected with celiac disease. Overall population prevalence ranges between 0.5-2% whereas certain predisposition groups show much higher numbers. The classical celiac disease is characterized by an autoimmune reaction against tissue transglutaminase in the small intestine of genetically predisposed individuals although other organs and tissues including the liver, skin, bones, reproductive and CNS can also be affected. Recent epidemiological surveys indicate that geographical distribution of CD is associated with genetic background and consumption of cereal grains.
A chronic diarrheal disease named “Gluten-Sensitive Enteropathy” (GSE) was described first in 2008 by Dr. Sestak’s group in a subset of captive rhesus monkeys fed gluten-containing chow. The presence of intestinal tissue transglutaminase autoantibodies, anti-gliadin serum antibodies, decreased resorption of nutrients, decreased xenobiotic metabolism, villous atrophy, lowered diversity of gut microbiome, chronic diarrhea, weight loss, cancer predisposition and immunogenetic (MHC II-linked) association were all reported in GS rhesus macaques. In GS macaques and in celiac patients, GSE can be induced by dietary gluten. In reverse, administration of gluten-free diet typically results in both species in disease remission. In addition to treating the selected captive GS rhesus macaques with gluten-free diet, there is a high interest from the commercial and academic sectors to utilize these animals in biomedical research, with novel celiac therapy approaches. Our group currently collaborates with Arcadia Biosciences on evaluation of proprietary therapies involving reduced gluten cereals. In addition, we currently work with other companies on preparation of project(s) for evaluation of novel immunotherapies for treatment of celiac disease. Another, tissue transglutaminase-independent and more prevalent form of gluten sensitivity e.g. non-celiac gluten sensitivity, was recently identified in humans and macaques.
Rotavirus
Rotaviruses are the primary cause of severe diarrhea in young children and are responsible for ca. 500,000 deaths in the world each year - despite that efficacious rotavirus vaccines are already available. In 2004-2005, Dr. Sestak’s group isolated and characterized the new rotavirus strain of rhesus monkey origin named TUCH. Over past 10 years, TUCH rotavirus was used extensively by several groups in studies that focused on recombinant vaccine development, molecular evolution of naturally emerging, animal-human rotaviruses, VP6 rotavirus protein T-cell epitope mapping, and pathogenesis of pediatric biliary atresia. Recent collaborative studies with Cincinnati’s Children’s Hospital focused on function of rhesus rotavirus VP4 structural protein. It was determined that specificity of rhesus VP4 governs induction of biliary atresia in a mouse model. Because neonatal obstructive cholangiopathy e.g. biliary atresia remains the most common indication for pediatric liver transplantation in the United States, it is anticipated that rhesus-derived rotaviruses including TUCH will remain valuable research tool in studies that aim at the development of novel therapy approaches for biliary atresia.
Rhesus Enteric Caliciviruses
According to CDC, human noroviruses (NoVs) are annually worldwide responsible for more than one million hospitalizations and over 200,000 deaths in children less than 5 years of age. In the U.S. alone, an estimated 23 million cases of acute gastroenteritis, including 70,000 hospitalizations and 800 deaths are attributed to NoV infections each year. No robust in vivo or in vitro model exists to study human NoVs. Dr. Sestak’s group discovered and characterized in 2008 a new group of enteric caliciviruses of rhesus monkey host origin with the name Recovirus. Prototype of this new group of enteric caliciviruses is the Tulane Virus. Rhesus enteric caliciviruses are closely related to human NoVs and in contrast to human NoVs, can be grown in vitro. Since 2008, numerous studies were conducted with Tulane Virus to study enteric calicivirus biology and pathogenesis. Some of these investigations (with non-human primates as well as with human patients) revealed that rhesus enteric caliciviruses can infect not only macaques but also humans where they can produce an acute, diarrhea-like illness. Because of their biological features e.g. capability to grow in vitro and to cause gastroenteritis and fever, we plan to continue utilizing rhesus enteric caliciviruses as human NoV model.
Gut Microbiome Studies
Composition of the gut microflora affects health and metabolism of its host. Due to biological similarities and evolutionary closeness with humans, captive non-human primates represent valuable resource in biomedical research. Controlled studies that evaluate impact of diet, age, gender, genetics, environment, disease, cohabitation, exercise and other factors on the composition of gut microbiome are currently being performed. Ongoing work focuses on the differences in gut microbiome composition of captive rhesus macaques with chronic bacterial colitis, gluten-sensitive enteropathy and healthy controls. For the first time, the evidence was generated suggesting that above chronic inflammatory conditions of rhesus macaques significantly differ from each other – by composition of gut microflora. New collaborative studies utilizing these models, with emphasis on pathogenesis and therapy of gut dysbiosis, are planned for near future.
