Erythrocytes, immuno-modulation and G6PD deficiency

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DESCRIPTION (provided by applicant): It is becoming well appreciated that genetic polymorphism has a major impact on the inflammatory response. Glucose-6-phophate dehydrogenase (G6PD) deficiency is the most common known human genetic polymorphism. G6PD deficiency has a major impact on the host response to trauma and infections and protects against malaria infection. The cellular and biochemical mechanisms responsible for the immuno-modulatory effects of G6PD deficiency are not known. Our general hypothesis is that a compromised antioxidant defense in G6PD deficient erythrocytes and in activated white blood cells alters macrophage activation and subsequent T-cell responses during infections. The studies will employ a septic rodent model (cecal ligation and puncture) in the G6PD deficient mouse. In the context of the most common forms of human G6PD deficiencies, the proposed mouse line is relevant because the residual cellular G6PD activity in the deficient mice is similar to that of the human African, type A- G6PD deficiencies. The proposed hypotheses will test (in general) whether (1) macrophage activation and T lymphocyte polarization are different between G6PD deficient and non-deficient animals. These will be tested in vitro as well as in vivo using the cecal ligation and puncture model. (2) We will also investigate wether the sepsis induced erythrocyte damage is more pronounced in G6PD deficiency. The effects of G6PD deficiency on the sepsis-induced organ inflammatory responses and damage, as well as, mortality will also be tested. Additionally, we will investigate (3) whether antioxidant and anti nitric oxide therapies will be beneficial in G6PD deficiency during sepsis. In view of the well-known early oxidative stress and erythrocyte damage during infections and the importance of macrophage and T-cell responses in the inflammatory response the investigated questions are novel and important and may benefit all trauma patients. Elucidating these questions in the context of G6PD deficiency brings in a highly relevant clinical aspect; furthermore, this also provides a unique opportunity to test the relationship between erythrocyte dysfunction and the modulation of the innate immune response. Elucidation of macrophage and T-cell cytokine responses to infection in G6PD deficiency may also be important in providing a mechanism of malaria protection alternative to currently accepted notions.