Final Report Summary - DAMAGECONTROL (Tissue Damage Control Regulates The Pathogenesis of Immune Mediated Inflammatory Diseases)
Resistance to infection is an evolutionarily conserved defense strategy that is central to preserve host homeostasis in face of infection. Resistance to infection relies on a series of immune-based mechanisms that exert a negative impact on infectious agents, i.e. the pathogens. DAMAGECONTROL explored the hypothesis that disease tolerance is a distinct but yet equally essential evolutionarily conserved defense strategy against infection. However, while indispensable to preserve host homeostasis, disease tolerance does not exert a direct negative impact on pathogens. Instead, it relies on a number of stress and damage-responses, conferring tissue damage control in parenchyma tissues, which are essential to preserve host homeostasis. DAMAGECONTROL was structured to identify and characterize mechanisms that are essential to establish disease tolerance to different types of infection. The central hypothesis being that disease tolerance relies on stress and damage-responses that fall under the control of a restricted number of transcription factors. Presumably, these transcriptional “master regulators” control the expression of a number of effector genes that confer metabolic adaptation, cytoprotection and/or tissue regeneration in response to different forms of stress and damage associated with infection. This hypothesis was confirmed for a number of effector genes and for some of the transcriptional “master regulators” tested. As an example DAMAGECONTROL established that some of these transcriptional regulators are essential to establish disease tolerance to bloodborne infections. These type of infections are normally associated with the development of hypoferremia, that is, systemic reduction of circulating iron levels and concomitant iron accumulation in macrophages and parenchyma cells. While critical to limit iron availability to pathogens and regulate immune-driven resistance mechanisms, hypoferremia carries a trade off. Namely it favors iron-catalyzed oxidative stress to host parenchyma tissues. Some of the transcriptional programs studied under DAMAGECONTROL control the expression of iron regulatory genes that prevent iron-catalyzed oxidative stress. This was found to provide metabolic adaptation to oxidative stress and prevent oxidative driven programmed cell death, establishing disease tolerance to bloodborne infections. Overall, we believe that DAMAGECONTROL played an important role in the initial identification of mechanisms underlying the establishment of disease tolerance to infection.