Aleksei Suslov1, Tujana Boldanova2, Xueya Wang1, Stefan Wieland3, Markus H Heim4. 1. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland. 2. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland; Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland. 3. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland. Electronic address: stefan.wieland@unibas.ch. 4. Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland; Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland. Electronic address: markus.heim@unibas.ch.
Abstract
BACKGROUND & AIMS: Most viruses are detected at early stages of cell infection and induce an innate immune response mediated by production of interferons (IFNs). IFNs induce expression of hundreds of IFN-stimulated genes (ISGs). Infection of chimpanzees with hepatitis C virus, but not hepatitis B virus (HBV), induces ISG expression in the liver. HBV might not induce an innate immune response because it is not detected by pattern recognition receptors (the stealth properties of HBV) or because HBV suppresses IFN production or signaling despite detection by pattern recognition receptors. We studied innate immune signaling in liver biopsies from patients with different stages of chronic HBV infection and uninfected individuals (controls). METHODS: We obtained liver within 10 minutes after collection from 30 patients with chronic HBV infection (hepatitis B e antigen-positive or -negative, with or without hepatitis) and 42 controls (most with fatty liver disease). The liver tissues were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, in situ hybridization, HBV RNA quantification, and HBV genotyping; some specimens were incubated with toll-like receptor (TLR) ligands (polyinosinic-polycytidylic acid) or infected with Sendai virus and then analyzed. RESULTS: Liver specimens from patients with HBV infection were not expressing more IFN or ISGs than those from control patients, indicating that chronic HBV infection did not activate an innate immune response. However, liver specimens from patients with HBV infection did produce IFN and induce expression of ISGs following activation of TLR3 with poly(I:C) or Sendai virus infections, so the innate immune response is not suppressed in these tissues. CONCLUSION: Liver tissues from patients with chronic HBV infection do not have induction of an innate immune response, but this response can be activated by other factors (TLR3 binding, Sendai virus infection) in HBV-infected liver tissue. These findings support the hypothesis that HBV is invisible to pattern recognition receptors.
BACKGROUND & AIMS: Most viruses are detected at early stages of cell infection and induce an innate immune response mediated by production of interferons (IFNs). IFNs induce expression of hundreds of IFN-stimulated genes (ISGs). Infection of chimpanzees with hepatitis C virus, but not hepatitis B virus (HBV), induces ISG expression in the liver. HBV might not induce an innate immune response because it is not detected by pattern recognition receptors (the stealth properties of HBV) or because HBV suppresses IFN production or signaling despite detection by pattern recognition receptors. We studied innate immune signaling in liver biopsies from patients with different stages of chronic HBV infection and uninfected individuals (controls). METHODS: We obtained liver within 10 minutes after collection from 30 patients with chronic HBV infection (hepatitis B e antigen-positive or -negative, with or without hepatitis) and 42 controls (most with fatty liver disease). The liver tissues were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, in situ hybridization, HBV RNA quantification, and HBV genotyping; some specimens were incubated with toll-like receptor (TLR) ligands (polyinosinic-polycytidylic acid) or infected with Sendai virus and then analyzed. RESULTS: Liver specimens from patients with HBV infection were not expressing more IFN or ISGs than those from control patients, indicating that chronic HBV infection did not activate an innate immune response. However, liver specimens from patients with HBV infection did produce IFN and induce expression of ISGs following activation of TLR3 with poly(I:C) or Sendai virus infections, so the innate immune response is not suppressed in these tissues. CONCLUSION: Liver tissues from patients with chronic HBV infection do not have induction of an innate immune response, but this response can be activated by other factors (TLR3 binding, Sendai virus infection) in HBV-infected liver tissue. These findings support the hypothesis that HBV is invisible to pattern recognition receptors.
Authors: Benjamin Y Winer; Jenna M Gaska; Gabriel Lipkowitz; Yaron Bram; Amit Parekh; Lance Parsons; Robert Leach; Rohit Jindal; Cheul H Cho; Anil Shrirao; Eric Novik; Robert E Schwartz; Alexander Ploss Journal: Hepatology Date: 2019-08-09 Impact factor: 17.425
Authors: Carla S Coffin; Scott K Fung; Fernando Alvarez; Curtis L Cooper; Karen E Doucette; Claire Fournier; Erin Kelly; Hin Hin Ko; Mang M Ma; Steven R Martin; Carla Osiowy; Alnoor Ramji; Edward Tam; Jean Pierre Villeneuve Journal: Can Liver J Date: 2018-12-25