Strengths and Limitations of Model Systems for the Study of Urinary Tract Infections and Related Pathologies

Abstract

Urinary tract infections (UTIs) are some of the most common bacterial infections worldwide and are a source of substantial morbidity among otherwise healthy women. UTIs can be caused by a variety of microbes, but the predominant etiologic agent of these infections is uropathogenic Escherichia coli (UPEC). An especially troubling feature of UPEC-associated UTIs is their high rate of recurrence. This problem is compounded by the drastic increase in the global incidence of antibiotic-resistant UPEC strains over the past 15 years. The need for more-effective treatments for UTIs is driving research aimed at bettering our understanding of the virulence mechanisms and host-pathogen interactions that occur during the course of these infections. Surrogate models of human infection, including cell culture systems and the use of murine, porcine, avian, teleost (zebrafish), and nematode hosts, are being employed to define host and bacterial factors that modulate the pathogenesis of UTIs. These model systems are revealing how UPEC strains can avoid or overcome host defenses and acquire scarce nutrients while also providing insight into the virulence mechanisms used by UPEC within compromised individuals, such as catheterized patients. Here, we summarize our current understanding of UTI pathogenesis while also giving an overview of the model systems used to study the initiation, persistence, and recurrence of UTIs and life-threatening sequelae like urosepsis. Although we focus on UPEC, the experimental systems described here can also provide valuable insight into the disease processes associated with other bacterial pathogens both within the urinary tract and elsewhere within the host.

FIG 1

UPEC-associated fitness and virulence determinants. Shown is a sampling of the many different factors that can promote the survival and virulence of UPEC strains within the host. (Left) These factors include iron acquisition systems like enterobactin and salmochelin. Enterobactin is a broadly conserved, high-affinity siderophore that can be inhibited by the host protein lipocalin. To sidestep this host factor, some UPEC isolates produce salmochelin, a glucosylated version of enterobactin that is not recognized by lipocalin. (Right) UPEC strains can secrete a variety of toxins that can disrupt normal host proteolytic cascades, membrane trafficking, cytoskeletal rearrangements, inflammatory responses, and survival pathways. Indicated here are some of the effects of host cell intoxication by alpha-hemolysin (HlyA), secreted autotransporter toxin (Sat), and cytotoxic necrotizing factor 1 (CNF-1). (Bottom) UPEC can bind host cells and tissues via multiple adhesins. These include Afa/Dr adhesins (which bind integrins, collagens, or CD55), S pili (which bind α-sialyl-2,3-β galactoside-containing receptors), F1C pili (which bind lactosylceramide-containing receptors), type 1 pili (T1) (which bind numerous factors, including α₃β₁ integrins and UP1a), and P pili [which bind Galα(1-4)Galβ moieties of glycosphingolipids].

FIG 2

Multiple fates for UPEC in association with the urothelium. Interactions between the type 1 pilus-associated adhesin FimH and the sugar side chains of receptors like UP1a or α3/β1 integrins can stimulate actin cytoskeletal rearrangements leading to the internalization of UPEC. Bacteria are then either trafficked back out of host cells or taken into membrane-bound compartments that are similar to late endosomes or early lysosomes. Within bladder cells, UPEC can remain in a nonreplicating state, forming quiescent reservoirs that are protected from host defenses and antibiotics. Intravacuolar growth of UPEC is restricted in part by the host actin cytoskeleton, which is dense within the immature epithelial cells of the bladder. Within terminally differentiated umbrella cells, where F-actin is localized primarily at basolateral surfaces, UPEC can break into the host cytosol and subsequently multiply to form IBCs. These bacterial communities are not long-lived and are most apparent during the acute phase of a UTI. The disruption or exfoliation of IBC-containing umbrella cells, as well as the transient formation of filamentous bacteria, can facilitate the efflux and dissemination of UPEC. Bacteria released from within IBCs can infect neighboring host cells, including the immature urothelial cells that appear to serve as the primary home for persistent UPEC reservoirs within the bladder. Released bacteria and exfoliated bladder cells that are flushed from the urinary tract with the flow of urine likely facilitate the spread of UPEC between hosts.

FIG 3

Model systems for investigating the pathogenesis of UPEC and related pathogens. Some of the key pros and cons for each system are indicated.