The role of Amyloid-Beta in pyelonephritis and urosepsis
Urinary tract infections (UTI) are the second leading infectious disease worldwide. This ascending infection is caused largely by pathogenic bacteria that spread from the bladder to the kidneys. The most severe cases develop into urosepsis, which is the leading cause of nosocomial sepsis with up to 40% mortality. It is therefore critical to understand the mechanisms contributing to UTI pathogenesis, disease progression, and kidney injury. Strikingly, it was recently discovered that intensive care unit patients with sepsis have elevated levels of the aggregative peptide, amyloid-ß (Aß), in their plasma. Until now, Aß has almost exclusively been studied in the context of neurocognitive disorders and neuroinflammation where Aß aggregation into large, insoluble plaques is a hallmark of disease. However, Aß has newly emerged as an antimicrobial peptide that can transition from host-protective to deleterious responses during bacterial infection. Our innovative study design will address an unexplored avenue for Aß-derived plaque formation in the kidney as a driver of UTI pathophysiology. We will test the novel hypothesis that infection elicits the production of Aß peptides that aggregate into plaques and disrupt organ function. The breakthrough discoveries in this proposal will be to demonstrate that elevated levels of Aß are detectable in the urine of patients with active UTI and to determine the kinetics of this acute organ injury in a mouse model of pyelonephritis. This high-risk/high-reward proposal has the potential to shift the current paradigm of pyelonephritis- and urosepsis-induced kidney damage. This proposed mechanism of acute kidney injury in response to bacterial infection will significantly alter the field of pyelonephritis research. In fact, because there are known treatments to enhance the clearance of Aß in other diseases, our discovery may ultimately lead to a reconsideration of UTI treatments, especially in the cases that progress to pyelonephritis.
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