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Marek's disease virus (MDV), an avian alphaherpesvirus, is one of the most potent oncogenic herpesviruses. It is very stable in the environment and is capable of eliciting malignant T-cell lymphomas in chickens within several weeks after infection. Three serotypes of MDVs are recognized based on recognition of monoclonal antibodies. All pathogenic strains of MDV that induce disease in chicken belong to serotype <br>1. Naturally avirulent strains that infect chicken and turkey, belong to serotypes 2 and 3 respectively. Marek's disease (MD) has been successfully controlled by vaccination since the 1960's using attenuated strains of serotype 1 and naturally occurring non-oncogenic strains of serotypes 2 and 3 individually or in combination. The vaccination of chickens is carried out by inoculation of live virus either in-ovo or at hatch, when the immune system is not fully developed. It is believed that the vaccinated chickens under commercial rearing conditions are exposed to wild-type pathogenic strains within the first few days of life. The mechanism of protection by MDV vaccines is not fully understood. Since the commercial vaccines are 99% effective, even though there are exposure to wild-type pathogenic strains happens within days after vaccination, we speculate that natural killer (NK) play a critical role in pathogenesis and protection. The NK cells constitute the first line of defense to kill target cells without prior sensitization. These cells are a type of lymphocyte than does not undergo genetic recombination to increase their affinity to antigens, and are thus considered components of innate immune responses. <p>Because of devastating consequence of NK cell activation, normal cells must have adequate inhibitory signals to escape from NK cell lysis. The NK cell receptors interact with HLA class I antigens and thus modulate NK cell mediated cytotoxicity. There are various other inhibitory receptors expressed on NK cells, including killer inhibitory receptors (KIR), immunoglobulin-like inhibitory receptors (ILT), and the C-type lectin like heterodimer (CD94-NKG2A). Since viruses have co-evolved along with their hosts, it is plausible that they interact with the host's immune system. It is especially important for viruses like herpesviruses, which establish lifelong infection, to use host immune machinery to gain survival advantage. MDV infected cells show dramatic down regulation of MHC class I on the cell surface, however in the adjacent cells there is dramatic increase in class I expression. <p>This down-regulation of MHC class I was observed in all serotypes of MDV including vaccine strains. Cell surface down regulation of MHC class I in infected cells will result in lysis of infected cells, however MDV is able to overcome NK cell lysis to establish lifelong infection. This led us to believe that MDV gene products may regulate NK cell activity.
NON-TECHNICAL SUMMARY: <p>Marek's disease virus causes a cancer-like disease in chickens. This disease is widespread and is controlled by vaccination. The purpose of this project is to understand the mechanism how this virus causes disease and how the vaccines protect against the disease. <p>
APPROACH: <p>We analyzed the putative open reading frames of MDV to scan for gene products that have homology to the NK inhibitory receptors. Surprisingly, MDV058 gene product showed significant homology to a human C-type (calcium-dependent) lectin domain containing NK cell receptor proteins. The C-type lectins have a carbohydrate recognition domain and four conserved cysteine residues (8). <p>Preliminary analysis of MDV058 showed that all four cysteine residues were positionally conserved and the overall length of the proteins was similar, leading us to believe that MDV058 may play a critical role in NK activity by binding to its receptors. The long-term goals of this project are to understand the mechanisms of protection by MDV vaccines. It is well established that MD vaccines are able to confer protection even when exposed to virulent MDV within days after vaccination. This suggested that innate immunity might play an important role in protection. By manipulating the MDV genes involved in NK activity, we could not only understand the role they play in pathogenesis (immune evasion and protection) but also aid in the design of better vaccines that are capable of protecting chickens against highly virulent field strains. The specific objectives of this research project are: <br>1. Structural analysis of MD058 and comparison of NK activity among vaccine and pathogenic strains of MDV. <br>2. Construction of a MDV deletion mutant in which the MDV058 gene is disrupted from a very virulent strain of MDV using overlapping cosmid technology. <br>3. Study the role of MDV058 on pathogenesis with respect to NK activity.