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A novel immunomodulatory function for E3/49K the first secreted adenovirus protein

Reference	BB/D002877/1
Principal Investigator / Supervisor	Dr Hans-Gerhard Burgert
Co-Investigators / Co-Supervisors
Institution	University of Warwick
Department	Biological Sciences
Funding type	Research
Value (£)	253,190
Status	Completed
Type	Research Grant
Start date	03/01/2006
End date	02/10/2009
Duration	45 months

Abstract

The early transcription unit 3 (E3) of human adenoviruses (Ads) of subgroup C encodes immunomodulatory proteins that subvert host defense mechanisms. Interestingly, the E3 coding capacity differs considerably among different Ad subgroups, suggesting that specific immunomodulatory E3 functions may contribute to the different disease pattern. Thus far, functional studies have only been carried out for subgroup C Ads. Here, we concentrate on subgroup D Ads, which represent the largest subgroup, are often isolated from AIDS patients and have the propensity to cause eye infections. We previously showed that subgenus D Ads encode a unique E3 protein, named E3/49K. E3/49K is an unusually large, highly glycosylated type I transmembrane protein that localizes to the Golgi/TGN, early endosomes and the plasma membrane. We now have discovered a novel processing pathway for E3 proteins. We demonstrate that E3/49K is proteolytically cleaved close to the C-terminus and that the large N-terminal fragment (sec49K) is secreted. Thus, 49K represents the first E3 protein (and the first Ad protein) to be secreted. Unlike all other known E3 proteins which act on infected cells, 49K is likely to affect surrounding cells. We hypothesize that sec49K modifies functions of infiltrating cells of the immune system. To test this hypothesis and to investigate the function of this novel E3 protein, we have generated mAbs against 49K. Using one of these mAbs we have been able to purify sec49K to homogeneity (on a small scale). Thus, we have now everything in hand to investigate the function of this viral protein. We will introduce purified sec49K into various immunological assays to test its effect on T cell proliferation-, CTL- and NK cell activities. In addition, we will examine whether sec49K has any cytokine- or chemokine activity, or binds to such factors. Furthermore, the preliminary data on the binding activity of sec49K to lymphocytes suggest that we will almost certainly characterize its function and identify its cellular target receptor. Thus, we are confident that we will establish a novel mechanism of Ad-mediated immunomodulation that bears relevance for our general understanding of viral immune evasion and lymphocyte activation/regulation.

Summary

Human adenoviruses cause acute and persistent infections of the respiratory- and gastrointestinal tract, and the eye. On the other hand, adenoviruses are also used therapeutically as vectors for gene- and cancer therapy. We are interested in the different strategies adenoviruses use to evade the host immune system and cause persistent infections and differential disease. By investigating the molecular interactions between adenovirus E3 proteins and immunologically important host molecules we previously demonstrated that E3 proteins exhibit a variety of immunomodulatory functions that facilitate immune evasion. Thus far, only E3 proteins from two Ads (both from subgroup C) of the 51 human Ads have been functionally characterized. Here, we focus on E3/49K, an E3 protein unique to Ads of the largest subgroup D. Our previous studies together with the new data presented below identify E3/49K as the first secreted E3 protein, and suggest a novel, fundamentally different immunomodulatory E3 activity that is not directed to infected cells, as expected, but rather to uninfected lymphocytes. Our major aim is to characterize the E3/49K function and identify its cellular target molecules.

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	Immunology, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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