A mucosal imprint left by prior Escherichia coli bladder infection sensitizes to recurrent disease

Abstract

Recurrent bacterial infections are a significant burden worldwide, and prior history of infection is often a significant risk factor for developing new infections. For urinary tract infection (UTI), a history of two or more episodes is an independent risk factor for acute infection. However, mechanistic knowledge of UTI pathogenesis has come almost exclusively from studies in naive mice. Here we show that, in mice, an initial Escherichia coli UTI, whether chronic or self-limiting, leaves a long-lasting molecular imprint on the bladder tissue that alters the pathophysiology of subsequent infections, affecting host susceptibility and disease outcome. In bladders of previously infected versus non-infected, antibiotic-treated mice, we found (1) an altered transcriptome and defects in cell maturation, (2) a remodelled epithelium that confers resistance to intracellular bacterial colonization, and (3) changes to cyclooxygenase-2-dependent inflammation. Furthermore, in mice with a history of chronic UTI, cyclooxygenase-2-dependent inflammation allowed a variety of clinical E. coli isolates to circumvent intracellular colonization resistance and cause severe recurrent UTI, which could be prevented by cyclooxygenase-2 inhibition or vaccination. This work provides mechanistic insight into how a history of infection can impact the risk for developing recurrent infection and has implications for the development of therapeutics for recurrent UTI.

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

“…4A). The decreased UpIII staining is indicative of exfoliation of the umbrella cells, which was previously shown to be accompanied by an expansion of the proliferative zone (43). Additionally, an increase in Fg coating the underlying cells was observed, which likely aids in healing the damaged epithelium, and MRSA primarily colocalized with the accumulating Fg.…”

Electrofulguration in the advanced management of antibiotic‐refractory recurrent urinary tract infections in women

“…Furthermore, exfoliated IBCs have been detected in the urine of women with acute cystitis, suggesting that the IBC/QIR cycle might occur in humans . Importantly, the strong pro‐inflammatory response prompted by bacterial infection and chronic bacterial antigen exposure can manifest as chronic cystitis and long‐standing physiological changes in urothelial cells . In support of this model, our group has studied human bladder wall biopsies of lesions of postmenopausal women with antibiotic‐refractory RUTIs, and confirmed the presence of intratissue bacteria…”

Bacterial virulence phenotypes of Escherichia coli and host susceptibility determine risk for urinary tract infections

“…Chronic cystitis and bladder inflammation result in large-scale remodeling of the bladder mucosa, which can last for weeks/months after antibiotic treatment to clear the infection (6, 7). This remodeling is evident in changes to the bladder itself and in host susceptibility to recurrent infection, exemplified by: (i) an altered transcriptional profile; (ii) an altered urothelial membrane proteome; (iii) defects in superficial cell maturation; (iv) changes to bacterial occupation of different habitats and; (v) differential host responses upon subsequent bacterial exposure (6, 7). To determine the effects of PUF carriage on the ability of UAEC to cause chronic cystitis, we examined three non-B2 strains: 41.4p (clade B1, PUF score=7), 9.1a (clade D, PUF score=13), and 9.2p (clade B1, PUF score=3) and three B2 UAEC strains: 20.1a (PUF score=16), 35.1a (PUF score=16), and 41.1a (PUF score=20) for their ability to cause persistent, high-titer bacteriuria (>10 4 CFU/mL urine), high-titer bladder colonization (>10 4 CFU/bladder) and chronic inflammation at 28 days post-infection in juvenile C3H/HeN mice.…”