The innate immune response induced by adenovirus, adenoviral vectors and other viruses

INTRODUCTION The structure of adenovirus Application of adenovirus Advantages and limitations of adenovirus for gene therapy and vaccination Disadvantages of adenovirus for gene therapy and vaccination Cell entry of adenovirus INNATE IMMUNITY INDUCED BY VIRUESE Pathogen recognition by TLRs on the cell surface Pathogen recognition by TLRs in the endosome Pathogen recognition by TLRs in the cytoplasm Pathogen recognition by NLRs Pathogen recognition by RLRs CONCLUSION AND FUTURE PERSPECTIVES REFERENCE ABSTRACT When pathogens invade cells, they initiate an innate immune response to clear the pathogen. Different pathogens induce different responses in different cell types because they express different PRRs, and the most important response is the production of inflammatory cytokines and type I interferon. Which cytokines are induced is dependent on the pathogen and the signaling pathways activated by them. Pattern recognition receptors (PRRs) paly a role in the connection between the pathogen and host signaling pathways. Innate immunity helps the host clear pathogens but sometime it impacts the effect of vaccines and gene therapy. Adenoviruses (Ads) can meet the need for geneWhen pathogens invade cells, they initiate an innate immune response to clear the pathogen. Different pathogens induce different responses in different cell types because they express different PRRs, and the most important response is the production of inflammatory cytokines and type I interferon. Which cytokines are induced is dependent on the pathogen and the signaling pathways activated by them. Pattern recognition receptors (PRRs) paly a role in the connection between the pathogen and host signaling pathways. Innate immunity helps the host clear pathogens but sometime it impacts the effect of vaccines and gene therapy. Adenoviruses (Ads) can meet the need for gene therapy and vaccination but a major limitation to its application as a vector, is that adenoviruses induce rapid and strong innate immune response that shorten the duration of the gene therapy and vaccination. So it is very important to uncover the mechanism by which viral vectors are recognized by the host innate immune system to develop more effective transgene and vaccine vectors. This review provides a summary of current knowledge of the interactions between the innate immune system and viruses, and then I will discuss the innate immune responses specifically induced by adenoviruses. INTRODUCTION Adenovirus was firstly isolated from adenoid tissue in the 1950’s (1). More than 50 serotypes of human adenovirus have been found, and they can be divided into six subgroups (A-F, group B can be subdivided into B1 and B2) based on sequence homology and on their ability to agglutinate red blood cells (2). Adenovirus infection can cause a broad spectrum of illnesses in immune-compromised and immune-competent hosts. They are the cause of a large number of acute febrile respiratory syndromes among military recruits. They are also the cause of ocular, respiratory and gastrointestinal infections in the general population (3). The structure of adenovirus Adenovirus (Ad) virions are characterized by a nucleoprotein core containing a linear double-stranded DNA genome (~30–40 kb) surrounded by an icosahedral, non-enveloped capsid (~70 to 100 nm in diameter) (Fig 1). Human Adenovirus serotype 5, the most extensively studied Ad, contains ~36 kb genome that encodes genes that can be divided into 4 early genes (E1–E4) and five late genes (L1–L5). Early genes can be transcribed before DNA replication and they mainly express functional proteins to help virus complete the life cycle, while late genes transcribe after DNA replication and express viral structure proteins (4). Bovine Ad serotype 3, which is researched in our lab, has a 34,446 bp genome, and it can be divided into four early regions (E1-E4) and 7 late regions (L1-L7). In addition, to completing virion production, two other elements are essential. The Ad genome has inverted terminal repeats (ITR) and a packaging sequence, which are required for the replication and encapsidation of the viral DNA, respectively (5). Adenoviruses encode one or two non-encoded RNA called virus-associated RNA (VA-RNA), which can be synthesized by internal polymerase III and plays a very important role in viral replication (2). The adenoviruses (Ads) genome can encode more than 40 proteins, however only 13 proteins have been shown to be constituents of the virus particle (6), and they play a role in infection and stabilizing the viral particle. The structural proteins can be divided into three groups, major capsid proteins, minor capsid proteins and core proteins. In the major capsid proteins group, the most abundant one is hexon, 240 trimers of hexon (pII) proteins constitute the frame of the capsid. Then 12 pentons (pIII) are fixed on the 12 capsid vertices to form a whole icosahedral structure, and one fiber (pIV) protrudes from each penton base. The fiber consists of three parts, an N-terminal tail which binds on the penton base, a C-terminal knob domain which can attach to cells in the first step of infection, and a slender rod-like shaft which connects the N-terminal tail to the Cterminal knob (7). The minor capsid proteins group: IIIa, VI, VIII and IX are associated with the capsid (8), play a role to stabilize the structure of the capsid. In the core protein group, there are six other structural components which are located in the virus core, five of them bind the double stranded DNA genome [V, Mu, IVa2, VII and the terminal protein (TP)], pVII binds the viral DNA genome tightly and forms a nucleoprotein complex, pV links the viral DNA genome to the capsid, the last protein is the 23K virion protease which can cleave some viral proteins to make them mature proteins (4). The whole structure of adenovirus is shown in Figure 1. Application of adenoviruses With the development of recombinant DNA technology, genomics and immunology, adenovirus has been researched more and more thoroughly. Subsequently, adenovirus vectors were used for gene therapy, vaccination and treatment of tumors because of the inherent advantages of adenoviruses. Gene therapy is a technique for correcting defective genes responsible for disease development by introducing a new functional gene to complement or replace a defective gene in target cells. Gene therapy started by using retrovirus vector-mediated gene replacement, but the use of adenovirus for gene therapy becomes more and more prevalent because of several advantages. In 2008, the first case of gene therapy using an adenoviral vector succeeded (9). Adenovirus associated virus was used as a vector to treat Leber congential amaurosis, a monogenetic eye disease which causes the blindness of children. After adenovirus vector mediated gene therapy, vision was significantly improved (9). This method has the potential to maintain sight if patients are treated before onset of Leber congential amaurosis. Adenovirus associated virus vector can be used in gene therapy without adverse effects, especially for the neuronal and retinal gene, so it will be a promising method to treat nervous system diseases and eye diseases (10). Being used as a vaccine vector is another use for adenoviruses. Traditional viral vaccines are inactivated or attenuated viruses. Inactivated viral vaccines cannot express penton bases and extended fibres on the 12 fivefold apices. Other so-called ‘minor’ components: IIIa, VI, VIII and IX are also associated with the capsid (Vellinga et al., 2005). There are six other structural components situated in the virus core, five are associated with the double stranded DNA genome [V, VII, Mu, IVa2 and the terminal protein (TP)], the remaining component is the 23K virion protease which plays a vital role in the assembly of the virion (see below). Most of the detailed structural analyses have been carried out using human serotypes, although a recent study of canine adenovirus 2 has indicated that, while the basic features are retained, the capsid of the canine virus is much smoother and the fibre is more complex (Schoehn et al., 2008). A recent structural analysis of an atadenovirus by cryo-electron microscopy has indicated that there are some differences from mastadenoviruses in capsid topology, but the main char cteristic adenovirus morphology is retained (Pantelic et al., 2008). A more detailed description of these structural proteins is given below as a forerunner for consideration of their role in infection. Hexon The hexon capsomere is a pseudo-hexagonal trimer situated on the 20 facets of the icosahedral capsid created by threefold repetition of two b-barrels at the base of each hexon molecule. The pseudo-hexagonal base allows close alignment within the facets and there are three tower regions that are presented to the exterior. There are 240 hexons in the capsid. Because of their different environments there are four kinds of hexon – designated H1, H2, H3 and H4 (Burnett, 1985). Sixty H1 hexons associate with the pentons at the 12 apices and are also termed peripentonal hexons (Fig. 2a). The remaining hexons are designated ‘groups of nine’ or GONs on the 20 faces of the icosahedron and are further defined as H2 (on the twofold axes), H3 (on the threefold axes) and the remaining ones as