CEBR2-03
Molecular Genetic Markers Associated with the Development of Viral Hepatitis in Saudi Patients
Researchers:
د/ فهد المجحدي
د/ سعود العريفي
د/ أحمد القحطاني
د/ ماجد العقيل
د/ أيمن عبده
د/ محمد الأهدل
د/ فيصل سناي
د/ نامك كايا
Dr. Richard Tapping
Professor R.N.K. Bamezai
ABSTRACT:
Hepatitis B virus (HBV) and hepatitis C virus (HCV) constitute a serious public health problem worldwide. Hundreds of millions of people are infected in almost all parts of the world and infection with both viruses claim more than 2 million lives every year.
Viral hepatitis epidemiology reflects a complex web of inter-related factors: host, viruses, and environment. As a result, the exact mechanisms that determine the disease outcome are yet to be clearly defined. In addition to viral molecules, differences in susceptibility or resistance to HCV and HBV are attributed to the human genome. Numerous genetic polymorphisms in different genes and/or their promoters with various kinds of functions have been shown to be correlated with different manifestations of the disease.
Chemokines and Toll-like receptors (TLRs) and have emerged as essential molecules in regulating the effector mechanisms of the immune responses to pathogens. Various single nucleotide polymorphisms (SNPs) have been identified in several chemokines and TLRs and their associated molecules. Expression of these molecules could contribute to susceptibility to infections as well as to the underlying disease progression that leads to various types of diseases in HCV or HBV- infected patients.
This study will use state-of-the-art biotechnology, such as Pyrosequencing and Nanochips, to investigate the role of chemokines and TLRs and their associated molecules in HCV and HBV- infection. Various genetic polymorphisms in TLR2, TLR3, and the chemokines MCP-1, CXCR1, CXCR4, CXCR5, CXCR2 and RANTES (regulated on activation, normal T cell expressed and secreted) will be studied in HBV- and HCV- infected Saudi patients. Consequently, relationship between these genetic variations and different manifestations of the diseases caused by these viruses will be analyzed.
It is expected that results from this research will contribute to our understanding of how the genetic makeup of the Saudi patients determine the outcome of the disease.
OBJECTIVES:
Rational and goals of the study
As discussed above, Chemokines have been implicated in many aspects of immunity including hemopoietic cell migration, Thl/Th2 development, angiogenesis/angiostasis, cell recruitment, lymphoid trafficking and lymphoid organ development (Zlotnik and Yoshie, 2000, Viola and Luster, 2008). Previous reports have shown that infection with HBV or HCV are able to regulate the production and/ or distribution of various chemokines in vivo and in vitro. Therefore, it has been hypothesized that chemokines could contribute to the observed variation of the disease outcome caused by these two viruses in different individuals. This notion implies chemokines could present a legitimate target of therapeutic development. However, little is known about the contribution of various SNP’s in the genes or in the regulatory sequences of the genes encoding various chemokines during HBV or HCV infection. Other viral systems such as human immunodeficiency virus (HIV) have shown that certain SNP’s in these genes could modify the severity of the disease (An et al., 2002, Petersen et al., 2005. Modi et al., 2005, Modi et al., 2006). We speculate that genetic polymorphisms in the genes of chemokines could alsoinduce changes in the structure and/ or production of chemokines which could in turn affect their function in developing an effective immune response against HCV and HBV.
Additionally, several TLRs are responsive to viral antigenic exposure. Each of these genes could be proposed as candidates for studying the influence of the interaction of the innate immune system with viruses and the link with the adaptive immune system in the pathogenesis of these infectious agents (Akira, 2006; Barrera et al., 2006; Uematsu and Akira, 2006). Infection with viruses is known to produce a strong inflammatory reaction through production of cytokines and these responses are probably through activation of TLRs. For example, TLR-3 recognizes double-stranded viral RNA and TLR-7 was shown to recognize small antiviral compounds (Kopp and Medzhitov, 2003; Medzhitov and Janeway Jr., 2000).
Several studies have addressed the importance of TLRs in HCV and HBV infection. TLR-7 has been suggested to be important in controlling HCV infection in vitro. For example, the serine protease NS3/4A from HCV was shown to inhibit IFN-β gene expression by blocking the TLR-3 signaling pathway (Li et al., 2005). Moreover, protein expression analysis of human B cells infected with HCV in vitro revealed that among all TLRs only TLR-4 showed almost ten-fold higher expression compared to non-infected control cells. Other HCV proteins, namely core (CP) and nonstructural 3 (NS3) proteins were studied in relation to host-virus interaction. It was concluded that CP and NS3 trigger inflammatory pathway via the TLR-2 pathway (Dolganiuc et al., 2004).
The relationship between TLRs expression and HBV has also been studied. Indirect evidence was presented for the importance of TLRs on the outcome of HBV infection. HBV replication was almost completely abolished by the administration of TLR3, -4, -5, -7, and -9 ligands. The profound inhibition of HBV replication was suggested to be IFN-α/β-dependent as it was accompanied by intrahepatic induction of IFN-α/β mRNA expression and it was completely abolished in the absence of the IFN-α/β receptor. Also, in chronically HBV-infected patients, TLR-2 expression was significantly reduced in peripheral blood monocytes compared to healthy control individuals. This reduction could contribute to the establishment of persistent infection in humans (Riordan et al., 2006b).
Together, chemokines and TLRs have been shown to be extremely important in infections caused by viruses, bacteria and parasites. Furthermore, studies that show relationship between infectious diseases and host genetic polymorphisms in the Saudi population are extremely rare or nonexistent at all.
Objectives of the current study:
- Calculate the frequency of the following polymorphisms in Saudi patients infected with HBV or HCV
- Correlations between each genotype and the disease status will be investigated to draw useful conclusions about the importance of the genetic polymorphisms in Saudi patients in relation to HBV and HCV infection.