GDF-15 as a mediator of immune-regulated sickness response during infection

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Abstract: The cytokine IFN-γ controls both protective and pathogenic host responses during Toxoplasma gondii infection. By activating hemopoietic and non-hemopoietic cell autonomous resistance mechanisms, this cytokine mediates toxoplasmastatic and toxoplasmacidal activities that control pathogen replication. Much less is known about how the same cytokine regulates host sickness responses. We have recently obtained data indicating that IFN-γ regulates the systemic levels of the stress hormone GDF-15, without affecting tissue levels of the hormone. GDF-15 is produced by a variety of immune and tissue cell types in response to a broad range of stressors and acts through the GFRAL-receptor expressed in the hindbrain to suppress appetite and induce weight loss. Circulating GDF15 levels are elevated in a wide range of human diseases states including infections and cancer and is often associated with poor clinical outcomes. GDF-15 has been reported to have immunomodulatory effects on macrophages and lymphocytes. Consistent with its systemic regulation by IFN-γ, IL-10 deficient animals infected with T. gondii exhibit higher levels of circulating GDF-15. Thus we hypothesize that GDF-15 may be a principal mediator of the pathogenic effects of IFN-γ that promote sickness responses during T. gondii infection. Our experimental aims utilize a combination of genetic and immunological approaches to rigorously evaluate our hypothesis that GDF- 15 mediates the effects of IFN-γ to promote sickness responses during Toxoplasma infection. Our discovery that an immune cytokine controls of the systemic availability of the stress hormone GDF-15 is an novel finding and may have implications for the management of disease conditions associated with “cytokine storms”. Specific Aim 1 will interrogate the role of specific proinflammatory cytokines in inducing elevations in tissue GDF-15 levels during infection. Specific Aim 2 will test the hypothesis that IFNγ triggers the release of GDF-15 from tissue stores by promoting its maturation and release, putatively through a TRANS-cellular mechanism. Specific Aim 3 will interrogate the role and function of endogenous GDF-15 in regulating the immune and sickness responses in wildtype and IL-10-deficient mice during T. gondii infection. Completion of this project will provide fundamental insights into how immune cytokines control the host sickness response during infection. These insights may provide avenues to promote health by decreasing disease sequelae that result from hyperactivation of immune response.