HOST-MICROBE INTERACTIONS: HARNESSING CO-EVOLUTION TO TREAT DISEASE

AbstractA new perspective for treating disease. There is a disconnect between our methods for treating diseasesand our understanding of the mechanisms that keep us healthy; this needs to change. The past fifty years ofbiological research have done an excellent job of understanding disease pathogenesis by reducing theorganism to its component parts, in order to understand the intricate details of how dysfunction of these partsleads to disease. A significant limitation to this approach, however, is that physiologies do not exist inisolation; when one system becomes dysfunctional, the whole body is affected. A second issue thatcomplicates this approach is that current methods for treating disease primarily involve blocking pathogenicresponses rather than inducing pathways that work to maintain health. The reason for this is two-fold: 1)scientists study disease, not health, and therefore do not understand the mechanisms that promote health;and 2) It is commonly assumed that blocking a pathogenic response will bring the patient back to a healthystate, which is not necessarily true. Therefore, rather than asking how we should treat disease, the questionthat should be asked is, ?How is health maintained?? To understand and ultimately manipulate the complex multi-directional interactions that occur between allof our physiologies, a novel approach is proposed in this application. This approach is based onunderstanding that the body and its resident microbiota have co-evolved to rely on communication between allphysiologies in order to maintain proper physiological function. The overall hypothesis of this proposal is thathealth is an active process that includes the induction of physiological mechanisms coordinated by microbes.By understanding the physiological mechanisms our bodies encode and how microbes coordinate theseprocesses to maintain health, treatments that work to extend health-span and lifespan by overridingphysiological decline can be developed, enabling patients to stay healthy despite infection. This applicationproposes a new paradigm for studying disease, where whole animal models, evolutionary principles and host-microbe interactions are used to define the properties and fundamental principles governing health. The workresulting from this application will establish a new conceptual framework and approaches in which tomechanistically understand what it means to be healthy and how this can be applied to treat diseases.