Sepsis is the most common cause of acute kidney injury in the intensive care unit and is coupled with very high mortality. It is a highly dynamic pathological state in which a wide array of pro- and anti-inflammatory pathways are aberrantly activated, resulting in a complex syndrome that evolves rapidly over hours. Therefore, determining the timeline of sepsis and developing timeline-specific therapies are essential for successful interventions. Recently, we examined temporal changes in the translatome of the kidney in animal models of bacterial sepsis. We showed that 1) initial outburst of inflammation is accompanied by significant increases in RNA transcription and translation, 2) the initial inflammatory phase is followed by activation of antiviral programs, and 3) the activation of antiviral programs leads to translation shutdown?a hallmark of late phase sepsis. Crucially missing from this recent work is the nature and source of the antiviral program activators in the absence of an actual viral infection. We hypothesize that induction of the initial inflammatory cascades results in a state of self-RNA overburden, which provokes a milieu resembling that of a viral infection. In this proposal, we will investigate the role of endogenous RNA stress as the determinant of antiviral program activation and resultant sepsis-induced organ failure. This work will provide an important framework for understanding the link between the early phase inflammation and late phase total organ shutdown, and could lead to novel diagnostic and therapeutic applications in sepsis-induced kidney failure.
Sepsis-induced acute kidney injury is associated with high mortality. This deadly disease lacks effective therapeutics due in large part to poorly understood pathophysiological mechanisms. The proposed research is highly relevant to the NIH's mission as well as to public health because the discovery of pathophysiological mechanisms involved in sepsis-induced kidney injury will lead to the development of rational therapeutic and preventative interventions at the bedside.
