We propose to study the set of immune modulating proteins made by the smallpox virus as a source for treatments for human inflammation. Recent molecular studies on poxviruses have established that an important key to their pathogenic success are immunomodulatory proteins they secrete during infection, which blunt the inflammatory response to infection. In a remarkable twist, these anti-inflammatory proteins are now finding success in treatment models of disease, in which inflammation plays a significant role. Since smallpox is the deadliest human virus the world has seen, and since its primary host is human, its human specific immunomodulatory proteins may form an optimised cocktail that is ideal for blocking human inflammation. We will explore these proteins alone and in combination and determine the molecular basis of their activity. This is a radical idea, but the results obtained could serve as the basis for the development of a transformational virus-based anti-inflammatory treatment.