Ross, T. L. | bioRxiv Science

bioRxiv2026

Tracking Inflammation and Fibroblast Activation in Hypertensive Heart Failure Across the Cardio-Renal Axis

Hypertension and heart failure are associated with increased risk of chronic kidney disease. Cardiorenal syndrome is characterized by excessive systemic inflammation and progressive fibrosis. We hypothesized that transient hypertension in mice due to infusion of angiotensin II and phenylephrine (Ang/Phe) would induce parallel immune cell and fibroblast activation in both the heart and kidney, where the intensity of inflammation and fibroblast activity would predict decline in function of both organs. Adult male C57Bl/6N mice were randomized to receive 7d infusion of either Ang/Phe (n=41) or vehicle (n=27) by subcutaneous osmotic minipump. Despite removal of minipumps at 7d, Ang/Phe mice displayed persistent myocyte hypertrophy, interstitial fibrosis, and modestly reduced systolic function to 6 weeks. Molecular imaging of chemokine receptor CXCR4 using 68Ga-pentixafor at 3d of Ang/Phe infusion revealed transient inflammation in the left ventricle. Imaging of fibroblast activation protein (FAP) revealed diffuse fibroblast activity in the left ventricle. Both imaging signals predicted subsequent functional decline. Magnetic resonance imaging of the kidney revealed transient prolongation of T1 relaxation in at 2 weeks after Ang/Phe infusion that returned to normal by 6wk, despite a progressive reduction in renal perfusion. CXCR4 and FAP PET displayed no change in kidney inflammation or fibroblast activation. Comparison of imaging data described a direct correlation between cardiac and renal CXCR4 PET signal at 3d and FAP PET signal at 7d. The intensity of cardiac inflammation correlated with subchronic fibrosis in the kidney cortex. Total body molecular imaging enables simultaneous evaluation of the immune-fibrosis network in heart-kidney crosstalk after short term hypertension and may provide valuable guidance of novel therapies.

physiology↗

bioRxiv2023

Mapping Niche-specific Two-Component System Requirements in Uropathogenic Escherichia coli

Sensory systems allow pathogens to differentiate between different niches and respond to stimuli within them. A major mechanism through which bacteria sense and respond to stimuli in their surroundings is two-component systems (TCSs). TCSs allow for the detection of multiple stimuli to lead to a highly controlled and rapid change in gene expression. Here, we provide a comprehensive list of TCSs important for the pathogenesis of uropathogenic Escherichia coli (UPEC). UPEC accounts for >75% of urinary tract infections (UTIs) worldwide. UTIs are most prevalent among people assigned female at birth, with the vagina becoming colonized by UPEC in addition to the gut and the bladder. In the bladder, adherence to the urothelium triggers E. coli invasion of bladder cells and an intracellular pathogenic cascade. Intracellular E. coli are safely hidden from host neutrophils, competition from the microbiota, and antibiotics that kill extracellular E. coli. To survive in these intimately connected, yet physiologically diverse niches E. coli must rapidly coordinate metabolic and virulence systems in response to the distinct stimuli encountered in each environment. We hypothesized that specific TCSs allow UPEC to sense these diverse environments encountered during infection with built-in redundant safeguards. Here, we created a library of isogenic TCS deletion mutants that we leveraged to map distinct TCS contributions to infection. We identify - for the first time - a comprehensive panel of UPEC TCSs that are critical for infection of the genitourinary tract and report that the TCSs mediating colonization of the bladder, kidneys, or vagina are distinct. IMPORTANCEWhile two-component system (TCS) signaling has been investigated at depth in model strains of E. coli, there have been no studies to elucidate - at a systems level - which TCSs are important during infection by pathogenic Escherichia coli. Here, we report the generation of a markerless TCS deletion library in a uropathogenic E. coli (UPEC) isolate that can be leveraged for dissecting the role of TCS signaling in different aspects of pathogenesis. We use this library to demonstrate, for the first time in UPEC, that niche-specific colonization is guided by distinct TCS groups.

microbiology↗