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Innate Immunity and Hepatitis C Virus Infection: a Microarray’S View Buonaguro Et Al

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Innate Immunity and Hepatitis C Virus Infection: a Microarray’S View Buonaguro Et Al Innate immunity and hepatitis C virus infection: a microarray’s view Buonaguro et al. Buonaguro et al. Infectious Agents and Cancer 2012, 7:7 http://www.infectagentscancer.com/content/7/1/7 Buonaguro et al. Infectious Agents and Cancer 2012, 7:7 http://www.infectagentscancer.com/content/7/1/7 REVIEW Open Access Innate immunity and hepatitis C virus infection: a microarray’s view Luigi Buonaguro, Annacarmen Petrizzo, Maria Lina Tornesello and Franco M Buonaguro* Abstract Hepatitis C virus (HCV) induces a chronic infection in more than two-thirds of HCV infected subjects. The inefficient innate and adaptive immune responses have been shown to play a major pathogenetic role in the development and persistence of HCV chronic infection. Several aspects of the interactions between the virus and the host immune system have been clarified and, in particular, mechanisms have been identified which underlie the ability of HCV to seize and subvert innate as well as adaptive immune responses. The present review summarizes recent findings on the interaction between HCV infection and innate immune response whose final effect is the downstream inefficient development of antigen-specific adaptive immunity, thereby contributing to virus persistence. Keywords: HCV, Innate immunity, Pattern recognition receptors (PRRs), Interferon stimulated genes (ISGs), Systems biology Hepatitis C virus: a brief overview (p7 and NS2) and protein maturation (NS2 and NS3/4A Hepatitis C virus (HCV) is a Hepacivirus of the Flaviviridae complex) [10,12]. family, mainly involved in hepatic disorders, including HCV entry into hepatocytes is mediated by one of the chronic hepatitis which may progress to cirrhosis in about following putative receptors, such as the CD81 tetraspa- 10–20% of cases and further to hepatocellular carcinoma nin [13], the scavenger receptor class B type I [14], the (HCC) in 1–5% of cirrhotic patients [1]. Furthermore, tight junction proteins claudin [15,16] and occludin [17], HCV has also been implicated as one of the major etio- the latters conferring species specificity. logic factors for type II Mixed Cryoglobulinemia (MC), an autoimmune disease that may evolve into an overt B-cell non-Hodgkin’s lymphoma (NHL) in about 10% of MC Innate immune response to HCV patients [2-4]. As for all microbial infections, innate immune response HCV is an enveloped positive-strand RNA virus. Six plays a critical role in the control and resolution of HCV major HCV genotypes and more than 100 subtypes have infection providing signals for the efficient priming of been so far identified [5-7]. HCV genomic RNA contains the adaptive branch of immune response [18,19]. 0 0 a single open reading frame flanked by 5 and 3 untrans- In particular, the innate immunity is important in lated regions (UTRs) [8,9], which encodes for a single HCV infection to control viral dissemination and repli- large polyprotein, processed by cellular and viral pro- cation in order to allow an adequate downstream devel- teases to produce structural as well as non structural opment of antigen-specific humoral as well as cellular proteins [9,10]. responses [20]. The core (C) and envelope proteins (E1 and E2) are During the early phase of HCV infection, the viral structural components of the infectious particle [11], RNA load increases in the first few days and remains whereas the non structural (NS) proteins are required high throughout the incubation period, which lasts for for RNA replication (NS3–NS5B), particle assembly up to 10–12 weeks post-infection [21,22]. In such early stage, large amounts of type I interferons (IFN-α, IFN-β) * Correspondence: [email protected] may be produced by HCV-infected hepatocytes as well Molecular Biology and Viral Oncogenesis Unit, Istituto Nazionale Tumori as dendritic cells (DCs) to control viral replication [23]. “Fond. G. Pascale”, 80131, Naples, Italy © 2012 Buonaguro et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Buonaguro et al. Infectious Agents and Cancer 2012, 7:7 Page 3 of 12 http://www.infectagentscancer.com/content/7/1/7 Besides producing type I IFN, DCs represent the key cell innate immunity, whose result will lead to completely compartment of innate immunity, orchestrating the qual- different clinical outcomes ranging from resolution to ity and potency of downstream adaptive immune re- chronic viral infection. sponse. They are professional antigen presenting cells (APCs) able to uptake and process viral antigens, as well Pattern recognition receptors in sensing virus as release cytokines to efficiently prime both CD4+ helper infection T cells and CD8+ cytotoxic T lymphocytes (CTLs) [24]. The innate immune response to virus infection is acti- In particular, the subset of plasmacytoid DCs (pDCs) is vated when conserved motifs of microbial origin, known as considered the front line in antiviral immunity owing to pathogen-associated molecular patterns (PAMPs) are recog- their capacity to rapidly produce high amounts of type I nized by cell pattern recognition receptors (PRRs) [40]. interferon in response to viruses, upon recognition of viral The 3 major classes of PRRs include Toll-like receptors components and nucleic acids through Toll-like receptor (TLRs), RIG-I-like receptors (RLRs), and nucleotide (TLR) 7 and TLR9 [25,26]. To further support such role, oligomerization domain (NOD)-like receptors (NLRs) several reports show a decreased frequency of pDCs in [41-43]. Viral engagement of TLRs and RLRs leads to the peripheral blood of patients with chronic HCV infection activation of transcription factors, such as the IFN regu- and impaired production of IFN-α by pDCs from HCV latory factors (IRFs) and NF-κB, which in turn may lead patients [27-29]. Also, myeloid or conventional DCs to the activation of IRF3 target genes, type I IFN, and (cDCs) are programmed to produce IFN-α in response to proinflammatory cytokines [44]. viral infection upon interaction between viral double- So far, the role of NLRs in sensing RNA viruses is still stranded RNA-like molecule polyinosinic:polycytidylic unclear and they are primarily thought to be activated by acid (poly I:C) and TLR3 [30]. Moreover, cDCs produce intracellular stress signals (i.e. damage-associated molecu- high amounts of cytokines, such as IL-12, which has been lar patterns, DAMPs) [45]. In this regards, DAMPS derived shown to play an important role in stimulating IFN-γ pro- from HCV infected hepatocytes may play a critical role in duction from activated T cells, inducing the development promoting liver inflammation with immunopathological of type 1 (Th1) protective immune response [31,32]. In- effects. deed, a recent study showed that an increased number of Innate immune cells (i.e. monocytes, neutrophils, den- cDCs during acute HCV infection may be associated with dritic cells) are rapidly activated upon recognition of viral clearance, whereas a loss in the number of cDCs may infecting agents by a wide range of PRRs. Among them, increase the risk for development of chronic HCV infec- the Toll-like receptors are members of the interleukin-1 tion [33,34]. receptor (IL-1R) superfamily [46,47], characterized by a Also natural killer (NK) cells are potent antiviral leucine-rich repeat (LRR) domain in the extracellular re- effectors due to their contribution to virus elimination gion and an extracellular Toll/IL-1R (TIR) domain [48]. via direct killing of infected cells and cytokine produc- So far, 11 TLRs have been identified. TLR1, TLR2, tion [35]. Genetic factors appear to contribute to the TLR6 and TLR10 are closely related to the TLR2 subfam- level of NK cell responsiveness, as shown by the pres- ily, whereas, TLR7, TLR8 and TLR9 are closely related to ence of individual killer cell Ig-like receptor/human the TLR9 subfamily [49]. Each TLR has specific ligands, leukocyte antigen (KIR/HLA) compound genotypes cor- which allow the host to sense a wide diversity of patho- related with HCV clearance [36]. In particular, given that gens [50]. As a result of TLR stimulation, proinflamma- the interaction between KIRs expressed on NK cells and tory cytokines are released that activate the host immune HLA expressed on target cells plays a key role in NK cell response [51-53]. activation, it has been suggested that such genotypes are Most TLRs (except for TLR3) share a common signal- characterized by a higher sensitivity of NK cells with a fas- ling pathway, via the adaptor molecule, myeloid differenti- ter degranulation and IFN-γ release in vitro [37]. ation primary response protein 88 (MyD88) [54-56]. TLRs Nevertheless, innate immune response to HCV may recruit MyD88 via TIR domains, then MyD88 binds the also be detrimental inducing immunopathological effects IL-1R-associated kinase (IRAK) and the signal is propa- on the liver. NK-mediated killing of HCV-infected hepa- gated to tumor necrosis factor (TNF) receptor-associated tocytes and secretion of proinflammatory cytokines may factor-6 (TRAF6), for activation of NF-kB and mitogen- cause liver damage, stimulating cDCs to produce high activated protein kinases (MAPK). A second pathway amount of IFN- γ which, subsequently, activates hepatic involves the TIR-associated protein (TIRAP)/MyD88- macrophages to enhance local inflammation [38]. All adaptor-like (Mal) for TLR1/2, TLR2/6 and TLR4 signal-
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