Toxoplasma remains an important cause of congenital infection and a common opportunistic infection in patients with primary and acquired defects in T cell function. This parasite can also cause significant disease in immune competent individuals and has been classified as a category B agent of bioterrorism. Consequently, there has been a long standing interest in defining the immune mechanisms that control this organism. Studies using mouse and human cells have led to a model in which the innate immune system directs the development of protective T cells, characterized by the production of IFN-? which limits parasite replication. However, while T cells are required for the long-term control of T. gondii this same response can contribute to immune-pathology. Consequently, there are numerous regulatory networks that limit the pathological response and early studies identified IL-10 as a key cytokine to prevent immune hyper-reactivity. More recently, this laboratory identified a similar role for the heterodimeric cytokine IL-27 in limiting T cell responses during toxoplasmosis and defined a role for IL-27 in inhibiting multiple T helper cell responses during other parasitic infections. Subsequently we also showed that IL-27 induced the production of IL-10. This latter finding has led to competing models for how T cell sources of IL-10 are regulated. In addition, there remains a poor understanding of the cellular sources of IL-27, the stimuli that control its production during infection and whether it is a negative regulator of innate immunity to T. gondii. Moreover, our preliminary data indicate that different components of IL-27 have unique biological functions and this has raised questions about the role of the cytokine sub-units in promoting protective anti-parasite responses versus limiting infection-induced pathology. Based on these findings, complimentary SA have been developed with the overall goal of understanding the role o IL-27 in innate and adaptive responses to T. gondii.
Toxoplasma is a common opportunistic infection in patients with defects in T cell function and can cause significant disease in immune competent individuals. Under certain circumstances the immune response to this microbe can be extremely violent and cause severe tissue damage. The overall goal of this proposal is to understand how the molecule IL-27 prevents the immune system from over reacting to this infection.
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