VIRAL HEPATITIS - SELECTED ISSUES OF PATHOGENESIS AND DIAGNOSTICS Edited by Sergey L. Mukomolov Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics Edited by Sergey L. Mukomolov Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. 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Used under license from Shutterstock.com First published October, 2011 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics, Edited by Sergey L. Mukomolov p. cm. ISBN 978-953-307-760-4 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface VII Chapter 1 HBV & HCV Immunopathogenesis 1 Megha U. Lokhande, Joaquín Miquel, Selma Benito and Juan-R Larrubia Chapter 2 Toll Like Receptors in Chronic Viral Hepatitis – Friend and Foe 41 Ruth Broering, Mengji Lu and Joerg F. Schlaak Chapter 3 Immunopathogenesis and Immunotherapy for Viral Hepatitis 65 Yukihiro Shimizu Chapter 4 Evolution of Viral Hepatitis: Role of Psychosocial Stress 83 Cristin Constantin Vere, Costin Teodor Streba, Ion Rogoveanu, Alin Gabriel Ionescu and Letitia Adela Maria Streba Chapter 5 Viral Hepatitis in Solid Organ Transplant Recipients 93 Lisa B. VanWagner and Josh Levitsky Chapter 6 Hepatitis A: Clinical, Epidemiological and Molecular Characteristics 127 Zahid Hussain Chapter 7 Structure and Function of the Hepatitis E Virus Capsid Related to Hepatitis E Pathogenesis 141 Zheng Liu, Yizhi Jane Tao and Jingqiang Zhang Preface There are five main causative agents of viral hepatitis, referred to as hepatitis viruses type A, B, C, D and E (HAV, HBV, HCV, HDV, HEV). These five viruses are of greatest concern because of the burden of illness and death. In according to World Health Organization (WHO) about 2 billion people worldwide have been infected with the HBV and about 350 million live with chronic infection. It is estimated that 600 000 persons die each year due to the acute or chronic consequences of hepatitis B: liver cirrhosis and cancer. Furthermore, it is estimated that 3–4 million people are infected with the HCV each year. 130–170 million people are chronically infected with HCV and at risk of developing liver cirrhosis and/or liver cancer. More than 350 000 people die from HCV-related liver diseases each year. Statistically, 60–70% of HCV chronically-infected persons develop chronic liver disease, 5-20% develop cirrhosis and 1–5% die from cirrhosis or liver cancer. Another big problem is related to fecal-orally transmitted HAV and HEV. The course of these two diseases is always acute and it does not lead to form chronic complications. However, we should remember; it is estimated that annually 1.4 milion cases of HAV infections is detected worldwide. Epidemics related to contaminated food or water can erupt explosively, such as an epidemic in Shanghai in 1988 that affected about 300 000 people. A mix HAV infection with chronic HBV or HCV related diseases could be lethal for patient. During the last years researchers have paid more attention to the HEV infection due to its appearance in non-endemic areas (like Europe for example) and a probable link to development of chronic liver disease. There are a lot of important issues regarding the viral hepatitis which needed to be studied: molecular biology of viruses, laboratory diagnostics, epidemiology, treatment etc. Special textbooks and monographs about these issues were published over the last decades. Taking in account this fact and rather fast progress in our understanding of the problem, the aim of our book is to focus on the important sections of the problem – immune pathogenesis of parenterally transmitted viral hepatitis and some aspects of hepatitis diagnostics. VIII Preface Seven chapters were prepared (by several groups of researchers) to share information and results of studies with specialists who work in the field of viral hepatitis and persons who are interested to learn about this problem. Dr Juan R Larrubia and his co-authors discuss the innate and adaptive immunity in the first chapter of the book entitled “HBV & HCV Immunopathogenesis”. The separate section of this chapter covers humoral and cellular response in case of acute and chronic HBV infection. It is emphasized that the specific CTLs play a central role in HBV&HCV immunopathogenesis. These cells are able to kill some infected hepatocytes inducing a minor liver damage, but also they secrete type-I cytokines responsible for non-cytopathic virus clearing. The next chapter prepared by Prof. Joerg F. Schlaak et al. focuses on the role of local innate immunity of the liver in the pathogenesis of chronic viral hepatitis. Activation of the Toll-like receptors (TLR) system leads to the expression of pro-inflammatory (IL-6, IL-12, TNF-α) as well as anti-inflammatory cytokines (IL-10) by responsive cell types. TLR7, -8 and -9 additionally initiate Interferon-α (IFN-α) expression after binding of their specific ligands. The authors separately discuss HBV, HCV and HDV innate immunity as well as peculiarities of immune response in case of co-infection of HBV and HCV. It was suspected that therapeutic manipulations of the hepatic TLR pathways are of high interest for the development of novel treatment strategies. These treatment strategies for viral hepatitis based on the immunopathogenesis knowledge are discussed in the chapter by Dr. Yukihiro Shimizu. The author discusses the developing of an optimal strategy to stimulate antiviral immune response with therapeutic potential, extensive analyses of immune mechanisms for successful viral eradication and immunosuppressive mechanisms induced by viral infection during persistent infection are required. These points are discussed at the beginning of the chapter, then followed by a discussion of immunotherapeutic approaches in both animal models and humans in the end. Dr. Costin Streba and co-authors consider pathogenesis of chronic hepatitis as the complete interaction between stress, neuroimmunomodulation and ultimately the onset and progress of viral infections. The influence of the endocrine response systems, such as the hypothalamic-pituitary-adrenal axis (HPA) or the sympathetic- adrenal-medullary (SAM) on the end function and outcome of the immune response are discussed in the chapter. Dr Josh Levitsky and Dr Lisa B. VanWagner rise a problem of viral hepatitis in the solid organ transplant recipients. The most important infectious agents which are frequent in allograft recipients are HBV and HCV. In addition, HEV is emerging as an increasing cause of chronic hepatitis and even cirrhosis whilst HDV plays an important role in both co-infection and superinfection of HBV in solid organ transplant recipients in industrialized countries. This chapter focuses primarily on the epidemiology, transmission, clinical presentation and management of the primary hepatitis viruses following solid organ transplantation. Preface IX The last two chapters cover fecal-orally transmitted HAV and HEV. The chapter on hepatitis A infection prepared by Dr. Zahid Hussain is mostly concentrated on clinical course, epidemiology and molecular characteristics of the HAV. It is emphasized that the changes in epidemiological pattern would increase the disease burden. They may cause large community outbreaks and lead to increased healthcare cost. Prof. Zhang Jingqiang and co-authors share the results of their studies on structure and function of the HEV capsid protein. These studies using cryo-EM and X-ray crystallography techniques, with a variety of biochemical studies, have provided a detailed picture of HEV-LP formed by the expressed capsid protein. These architectures shed light on the understanding of the function of capsid such as the assembly mechanism of icosohedarl capsid, virus infection and antibody interaction. While preparing our book for print, we heard that the Nobel Prize Committee (field of physiology and medicine- year 2011 ) awarded Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" whilst Ralph M. Steinman received an award "for his discovery of the dendritic cell and its role in adaptive immunity". We are proud to say that our book is in line with these discoveries, because 3 chapters cover the problems of innate and adaptive immune response in case of viral hepatitis. Professor Sergey L. Mukomolov Head, Viral Hepatitis Laboratory, St. Petersburg Pasteur Institute, Russia [...]... activated by the recognition of stress-induced molecules and/ or the modulation of the quantity of major histocompatibility complex (MHC) class I molecules on the surface of infected cells (Moretta et al., 2005) 2 Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics NK and NKT cells can be rapidly recruited to the site of virus infection and have the potential to recognize infected cells before... decades, and it is organized as chromatin like structure (minichromosome) (Levrero et al., 2009) The cccDNA utilizes the cellular transcriptional machinery to produce all viral RNAs necessary for protein synthesis and viral replication 4 Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics From an immunological point of view, the cccDNA is extremely important since it will persist in most of. .. infection control 10 Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics 3 HCV immunopathogenesis The hepatitis C virus (HCV) is an enveloped; positive stranded RNA virus and represents the Hepacivirus genus in the Flaviviridae family It has been estimated that more than 170 million people are infected with HCV, since clinical identification and molecular cloning of HCV in late 1980s... 2008) Conversely, Programmed Death ligand-1 (PDL-1) mediated inhibition limits the expansion of Tregs by controlling STAT-5 phosphorylation (pSTAT-5) (Franceschini et al., 2009), which can diminish suppressive function of Tregs, lead to viral load control and ultimately ensure long-lasting survival of the host 18 Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics Fig 5 Scheme showing the... 2005a), IPS-1 (Foy et al., 2003) and oligomerization of MAVS, which is part of signaling process (Kawaguchi et al., 2004; Li et al., 2005a; Li et al., 2005b; Marie et al., 1998; Meylan et al., 2005; Sakamoto et al., 2000) Disruption of IRF-3 12 Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics activation occurred by NS3 protein action (Liu et al., 1999) and it has been shown with different... in absence of viral replication, single-stranded RNA and unmethylated cytosine-guanosine dinucleotide motifs (Fitzgerald-Bocarsly et al., 2008) A recent study reported that, in CHB patients, there was a reduction of TLR-9 expressions in pCDs, which correlates with an impaired IFN-alpha production by these cells (Xie et al., 2009) 6 Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics. .. the blockade of negative co-stimulatory pathways in addition to IL-10 could lead to the development of autoimmune diseases, which could prevent the use of this strategy as a therapeutic tool in humans Therefore, more research is necessary in this field 22 Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics before these strategies are suitable for the treatment of chronic viral infections... means neutralizing and non-neutralizing antibodies can endorse antiviral activity and pathogenesis (Guidotti & Chisari, 2006) Cellular immune response shows antiviral immunity by means of virus specific CD8 cytotoxic T lymphocytes (CTLs) and CD4 T helper cells, which play key effector and regulatory roles respectively These T cells take part in viral pathogenesis of HCV by direct killing of infected cells... list of suspects: in search of the immune pathogenesis of chronic hepatitis C J Hepatol 49, 1069-1078 HBV & HCV Immunopathogenesis 23 Alexopoulou, L., Holt, A C., Medzhitov, R & Flavell, R A (2001) Recognition of doublestranded RNA and activation of NF-kappaB by Toll-like receptor 3 Nature 413, 732738 Alter, H J., Purcell, R H., Holland, P V & Popper, H (1978) Transmissible agent in non-A, non-B hepatitis. .. Hepatitis - Selected Issues of Pathogenesis and Diagnostics On the other hand, the magnitude of CD8+ T cells response in acute HCV infection does not correlate with the clinical or viral outcome (Francavilla et al., 2004; Kaplan et al., 2007; Urbani et al., 2006a) Expression of a dysfunctional phenotype with weak proliferation, low IFN-γ production, impaired cytotoxicity and increased levels of the well known . VIRAL HEPATITIS - SELECTED ISSUES OF PATHOGENESIS AND DIAGNOSTICS Edited by Sergey L. Mukomolov Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics. produce all viral RNAs necessary for protein synthesis and viral replication. Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics 4 From an immunological point of view, the. control. Viral Hepatitis - Selected Issues of Pathogenesis and Diagnostics 10 3. HCV immunopathogenesis The hepatitis C virus (HCV) is an enveloped; positive stranded RNA virus and represents