Friday, May 9, 2025
5/9/2025
Role of Transposable Elements in Septic Immune Aging - Project Summary Sepsis is an overwhelming, maladaptive, and lethal dysregulation of the immune response to infection. Annually, approximately 50 million people suffer from sepsis with 11 million resulting deaths worldwide. Age is one of the strongest risk factors for mortality from sepsis. Aging correlates with an overall reduction in the quality of immune response. The reasons behind age related immune decline are poorly understood, however, de-repression of transposable elements may play a role. Transposable elements (TEs) are repetitive, mobile, genetic elements that translocate, and amplify, themselves across a genome. Usually, they exist in a repressed state. However, their de-repression has been shown to result in accelerated aging phenotypes in mice and flies. Furthermore, we show de-repression of TEs in human immune cells can result from a genetic mutation in the AGO2 gene. This TEs de-repression results in activation of innate immune defenses in the form of interferon signaling. This phenomenon, known as viral mimicry, ultimately causes resting immune cells to exit quiescence in the absence of pathologic stimuli. TEs-mediated sterile activation of the interferon pathway is associated with immune aging. Notably, TEs located within immune genes are highly differentially expressed in sepsis. Furthermore, de-repressed TEs have been shown to affect human immune responses to infection. However, the relation between TEs expression and sepsis severity is poorly understood. We hypothesize that immune cell TEs de-repression in sepsis correlates with immune system aging, and with increased morbidity and mortality. Specifically, in Aim 1 we will investigate the dynamics of TEs de-repression as a function of age and sepsis. In Aim 2 we will employ machine learning to quantify immune aging and identify specific TEs, or families of TEs, that can predict immune aging or ICU outcomes such as mortality and secondary infections. In Aim 3 we will conduct whole exome sequencing on septic patient samples to identify mutations associated with high TEs expression. We will use CRISPR for reverse genetic experiments, in immortalized immune cells, to determine if mutations from septic patients, and candidate mutations such as AGO2 and SIRT6, lead to TEs de-repression. Finally, we will compare gene expression levels in cells with mutations giving TEs de-repression (ie: AGO2) to sepsis with high TEs expression using RNA-seq. Overall, these studies will investigate what role transposable elements may play in sepsis pathogenesis and maintenance. Results from this work could potentially shed light on genomic mechanisms underlying sepsis progression. Such mechanisms, should they exist, could suggest novel and personalized therapies similar to what is seen in cancer.
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