(9) A Dysregulated Inflammatory Response Explains Differences in Experimental Pyelonephritis Susceptibility Among Inbred Mouse Strains with Vesicoureteral Reflux

Background: Urinary Tract Infection (UTI) is a common and serious bacterial infection in young children and is most frequently due to uropathogenic Escherichia coli (UPEC). Vesicoureteral reflux (VUR) is an established risk factor for ascending infection, which can result in tubulointerstitial injury due to pyelonephritis (PN) and renal scarring (RS), but the incidence of these complications is variable and mechanisms underlying differences in susceptibility are poorly understood. Previous studies have identified inbred mouse strains that vary in their susceptibility to PN and RS following UPEC challenge despite similar incidence of VUR. Comprehensive transcriptomic profiling provides the opportunity to unveil key factors that govern PN susceptibility in these strains.

Objectives: Using mouse models of VUR and ascending UTI, we hypothesized that differences in the inflammatory response contribute to PN and RS susceptibility.

Design/Methods: Adult female C3H/HeOuJ (PN-susceptible) and C3H/HeN (PN-resistant) mice were transurethrally inoculated with 10^8 Colony-Forming Units (CFU) of CFT073, a strain of UPEC isolated from a female patient with pyelonephritis. CFU were enumerated and histopathological scoring was performed up to 28 days post infection (dpi). Kidneys from each strain underwent bulk transcriptome analysis at baseline, 1, 3, and 7 dpi, to identify differential expression of immune-related genes during PN.

Results: C3H/HeOuJ exhibited sustained kidney UPEC burden over the experimental time-course, while C3H/HeN mice displayed comparable burden at 1, 3, and 7 dpi and subsequently cleared their infection. Histological analysis of C3H/HeOuJ kidneys substantiated the presence of wedge-shaped cortical abscessation, acute tubular necrosis, and venous thrombosis. In contrast, UPEC infected C3H/HeN kidneys exhibited pyelitis and healthy parenchyma. Bulk transcriptomics revealed an enrichment of neutrophil chemotaxis and macrophage activation pathways at 7 dpi in the C3H/HeOuJ, along with pathways mediating fibrosis and injury repair. The C3H/HeN kidneys exhibited a more robust initial immune response at 1 dpi, suggesting differences in the efficiency of host defense between the two strains.

Conclusions: Alterations in the kinetics and magnitude of the innate immune response in C3H/HeOuJ kidneys are associated with this strain’s unique susceptibility to tubulointerstitial injury and RS compared to their C3H/HeN counterparts. These findings warrant further investigation into specific immune and parenchymal cell populations that contribute to divergent host responses and disease outcomes following UTI.