Identification of functional links between redox homeostasis and immunity

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The recognition of invasive microorganisms by the immune system requires their uptake by specialized antigen presenting cells (APCs) which expose pathogen-derived immunogenic peptides to T helper cells. The latter provide the "tools" to eradicate the intruder, and the quality and efficacy of their responses is strongly controlled by the APC. There is cumulating evidence that the "oxidative state" of the APC plays an important role in determining the type of T helper cell to become activated as well as the type of immune response to be developed. The mechanisms involved in these interactions are presently unknown and may rely on the effect that oxidants have on messengers communicating APCs with T helper cells. The present research program aims to characterize the effects induced by oxidants on the communication signals between APC and T helper cells. The murine Plasmodium chabaudi adami malaria model has been chosen for this study since infections with this pathogen exert a strong oxidative stress on APCs, which seems dependent on iron-containing compounds present in infected red blood cells that are avidly taken up by APCs. In addition, the immunity against P. c. adami parasites is well characterized, and comprises a pattern of contrasting responses governed by T helper cells which may result from the effect of oxidants on the regulation of T helper cell function. By means of standard techniques in molecular biology, biochemistry and immunology, the oxidative stress generated by iron-containing compounds present in infected red blood cells such as hemoglobin and its degradation products on APCs will be analyzed, and key signaling molecules affected by these compounds will be studied. As a long-term perspective, our studies will help to characterize the effect of other oxidants such control mechanisms that have been naturally selected to preserve homeostasis.