Pathogen-Induced Amyloid-ß Drives Inflammation in UTI

About This Grant

PROJECT SUMMARY/ABSTRACT Urinary tract infections (UTIs) are the second most common infectious disease worldwide, primarily caused by pathogenic bacteria that ascend from the bladder to the kidneys. In severe cases, UTIs can progress to urosepsis, the leading cause of hospital-acquired sepsis, with mortality rates as high as 40%. Understanding the mechanisms that drive UTI pathogenesis, disease progression, and resulting kidney injury is therefore critical. This R21 is based on the emerging role for amyloid-β (Aβ) as a novel innate immune effector that drives deleterious inflammation in the context of bacterial infection. Aβ has been studied almost exclusively in the context of neurocognitive disorders and neuroinflammation, where its aggregation into insoluble plaques is a hallmark of disease. However, a growing body of evidence highlights a role for Aβ as an antimicrobial peptide and pro-inflammatory signal molecule. Our recent findings have shown that intensive care unit (ICU) patients with sepsis have elevated levels of Aβ in their plasma, and that Aβ correlates with outcome severity. Strikingly, a control ICU cohort with no suspicion of infection did not display elevated plasma Aβ levels, indicating a requirement for infection. Moreover, we present new preliminary data indicating that Aβ accumulates in the kidney in a mouse UTI model and is directly correlated with bacterial burden. While published and preliminary data support the idea that Aβ is an antimicrobial peptide, it is unknown as to whether Aβ is capable of transitioning from a host-protective role to a detrimental one during bacterial infection. Our innovative study aims to explore the novel hypothesis that bacterial infection triggers the accumulation of Aβ peptides in the kidney to drive deleterious inflammation and UTI pathophysiology. This is an early conceptual stage project that may lead to a breakthrough in the current understanding of kidney damage in pyelonephritis and urosepsis. Given that treatments to enhance Aβ clearance are already in use for other diseases, our findings may pave the way for novel therapeutic approaches to UTIs, especially in cases that progress to severe kidney involvement. Our discovery that Aβ is elevated in the context of infection and is a potential driver of deleterious inflammation in the kidney is a highly significant conceptual advance with broad impact across the fields of infectious disease and renal biology. Gram-negative cystitis and pyelonephritis are highly prevalent in hospital and community settings, and the most severe cases progress to sepsis, and multi-organ failure. Importantly, survivors often suffer long-term sequelae such as post-intensive care syndrome that reduce overall quality of life. Thus, future studies stemming from the work proposed herein may reveal potentially transformative links between a pathogen-mediated dysfunctional Aβ response and organ dysfunction.