Metabolic Dysregulation in Hepacivirus Infection of Common Marmosets (Callithrix jacchus)

Abstract

Chronic hepatitis C has been associated with metabolic syndrome that includes insulin resistance, hepatic steatosis and obesity. These metabolic aberrations are risk factors for disease severity and treatment outcome in infected patients. Experimental infection of marmosets with GBV-B serves as a tangible, small animal model for human HCV infection, and while virology and pathology are well described, a full investigation of clinical disease and the metabolic milieu is lacking. In this study six marmosets were infected intravenously with GBV-B and changes in hematologic, serum biochemical and plasma metabolic measures were investigated over the duration of infection. Infected animals exhibited signs of lymphocytopenia, but platelet and RBC counts were generally stable or even increased. Although most animals showed a transient decline in blood glucose, infection resulted in several fold increases in plasma insulin, glucagon and glucagon-like peptide 1 (GLP-1). All infected animals experienced transient weight loss within the first 28 days of infection, but also became hypertriglyceridemic and had up to 10-fold increases in adipocytokines such as resistin and plasminogen activator inhibitor 1 (PAI-1). In liver, moderate to severe cytoplasmic changes associated with steatotic changes was observed microscopically at 168 days post infection. Collectively, these results suggest that GBV-B infection is accompanied by hematologic, biochemical and metabolic abnormalities that could lead to obesity, diabetes, thrombosis and atherosclerosis, even after virus has been cleared. Our findings mirror those found in HCV patients, suggesting that metabolic syndrome could be conserved among hepaciviruses, and both mechanistic and interventional studies for treating HCV-induced metabolic complications could be evaluated in this animal model.

Hepatic immunopathology during occult hepacivirus re-infection

“…In addition, the liver of all 4 animals exhibited virus-induced hepatitis. Our previous reports showed primary GBV-B infection could also induce lymphocytic infiltration along with fibrotic and steatotic changes even after clearance of viremia (Manickam et al, 2016; Manickam et al, 2017). In this study we observed mild (in 02–10) to severe (01–10) microscopic hepatitis and fibrotic lesions in all four re-infected animals.…”

Diseases of the Gastrointestinal System

“…Progression occurs despite clearance of the virus from plasma [124,125]. These changes are associated with concomitant changes in plasma insulin and glucagon levels consistent with metabolic dysregulation [126]. While acute experimental infection is not associated with notable clinical signs, one may see an elevation in serum ALT, ALP, and/or LDH clinically.…”

Utility of Common Marmoset (Callithrix jacchus) Embryonic Stem Cells in Liver Disease Modeling, Tissue Engineering and Drug Metabolism

“…Several C. jacchus models have been described for both spontaneous and experimentally induced obesity with hyperglycemia and hypertriglyceridemia. These marmoset models were generated with diverse agents, such as human adenovirus-36 (Ad-36) [ 100 ], GBV-B [ 101 ], adult high calorie diet [ 102 ], and exposure to glucocorticoids [ 103 ].…”

“…They gained substantial weight in the 28-week period of the study, and blood samples revealed Ad-36 antibodies in the liver, and elevated serum levels of cholesterol and triglycerides [ 100 ]. In another investigation, marmosets that were infected intravenously with GBV-B, had a significant increase in their insulin, glucagon and glucagon-like peptide 1 in the plasma, became hypertriglyceridemic and had up to a 10-fold increase in adipocytokines [ 101 ]. In the liver, cytoplasmic changes associated with steatosis were observed at 168 days post-infection in all infected animals ranging from mild to severe steatosis.…”

“…In the liver, cytoplasmic changes associated with steatosis were observed at 168 days post-infection in all infected animals ranging from mild to severe steatosis. Most infected animals showed acute hypoglycemia and lipid accumulation in hepatocytes indicating hepatic steatosis, and hepatomegaly [ 101 ]. In the experimental model of glucocorticoid-induced MetS, pregnant marmosets were given the synthetic glucocorticoid dexamethasone orally for one week during the early or late gestation [ 103 ].…”