Viruses have evolved to infect a host, propagate and be transmitted to another host as efficiently as possible. In contrast, an infected host has evolved to try to survive infection, irrespective of transmission of the virus. Viruses take many different approaches to survival in a host prior to transmission, such as manipulating the host immune response to reduce or prevent recognition or clearance of the virus. The task of the host immune response is to clear the pathogen as quickly as possible to prevent virus-induced disease. However, an over exuberant immune response can cause immunopathology, potentially leading to death of the host, an evolutionary dead end. Therefore it is the aim of both the virus (to allow sufficient opportunity for transmission) and the host (to prevent immunopathology) to moderate the immune response and often virus and host use similar approaches to achieve this goal. In this proposal we will examine the role of pro-resolving lipids that are products of 15-lipoxygenase action of omega-3 fatty acids, and which have a profound anti-inflammatory action. We have made the unprecedented finding that mice lacking 15-lipoxygenase are susceptible to lethal challenge with ectromelia virus, a poxvirus that is a natural pathogen of mice and is the cause of mousepox. Poxviruses are a unique family of viruses that, despite the eradication of smallpox, constitute an ever- increasing risk of human infection worldwide via the action of monkeypoxvirus, camelpox and buffalopox transmission to humans. Therefore these studies have broad implications for human health, both for these infections, for the design of effective viral vacine vectors, and for lipid moderation of virus infections as a whole. Poxviruses are also known to encode many modulatory proteins that alter immune function, among them the serpin SPI-2, that has been shown to alter production of lipids in infected cells.
In Aim 1 we will examine the changes in the production of pro-resolving lipids is changed by ectromelia infection, both in vitro in different cell types and in vivo over te course of infection. In addition, we will examine the effect of the immunomodulatory protein SPI-2 upon the changes observed in vitro and in vivo.
In Aim 2 we will examine the changes in the innate and adaptive immune response to ECTV in the absence of 15-lipoxygenase, and how this is changed by the action of SPI-2. We expect the results produced to be a comprehensive characterization of how poxvirus infection changes the production of pro-resolving lipids both in vitro and in vivo. We anticipate that the results gained from these studies will form the basis of future RO1 or PO1 proposal in which the mechanisms by which pro-resolving lipids confer survival from lethal viral challenge are examined.
The study of poxvirus biology, the immune response to poxviruses, and the modulation of that immune response by the virus is relevant for emerging poxvirus infections, such as monkeypox, and as a model of molluscum contagiosum infection which infects the skin of over 130 million people worldwide. This study focuses on the novel area of changes in the production of pro-resolving lipids that are induced by virus infection. Pro-resolving lipids reduce immune activation and promote tissue function and are vital for survival following challenge with ectromelia, the virus used for these studies.
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