Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection - PubMed (original) (raw)

Review

Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection

Thomas J Hannan et al. FEMS Microbiol Rev. 2012 May.

Abstract

Bladder infections affect millions of people yearly, and recurrent symptomatic infections (cystitis) are very common. The rapid increase in infections caused by multidrug-resistant uropathogens threatens to make recurrent cystitis an increasingly troubling public health concern. Uropathogenic Escherichia coli (UPEC) cause the vast majority of bladder infections. Upon entry into the lower urinary tract, UPEC face obstacles to colonization that constitute population bottlenecks, reducing diversity, and selecting for fit clones. A critical mucosal barrier to bladder infection is the epithelium (urothelium). UPEC bypass this barrier when they invade urothelial cells and form intracellular bacterial communities (IBCs), a process which requires type 1 pili. IBCs are transient in nature, occurring primarily during acute infection. Chronic bladder infection is common and can be either latent, in the form of the quiescent intracellular reservoir (QIR), or active, in the form of asymptomatic bacteriuria (ASB/ABU) or chronic cystitis. In mice, the fate of bladder infection, QIR, ASB, or chronic cystitis, is determined within the first 24 h of infection and constitutes a putative host-pathogen mucosal checkpoint that contributes to susceptibility to recurrent cystitis. Knowledge of these checkpoints and bottlenecks is critical for our understanding of bladder infection and efforts to devise novel therapeutic strategies.

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Figures

Figure 1. Hypothetical model for UPEC population bottlenecks in acute and chronic cystitis

This model depicts a hypothetical situation where two virulent and clonal UPEC populations, the Solids and the Pastels, are introduced into the urinary bladder. Individual bacteria within each clonal population are identical, but are represented by different Solid and Pastel tones to demonstrate the population bottleneck encountered during acute cystitis. Successful passage this acute bottleneck is linked to clonal expansion via the IBC cycle (Panels A-E) during acute cystitis (Schwartz, et al., 2011). If these clones are equally fit to proceed through the IBC cycle, the loss of “diversity” is purely stochastic, affecting both the Solids and Pastels equally. We postulate that the dominant role of type 1 pili in acute cystitis in naïve mice, including a critical role in IBC formation, explains why few UPEC genes have been demonstrated to contribute to acute virulence using isogenic knockout strains. Indeed, most genes identified so far directly impact upon type 1 pili production or the ability of the strain to process through the IBC cycle. Likewise, QIR formation during acute infection results in stochastic loss of diversity and in the latent QIRs that persist in the urothelium after acute infection resolves, the Solids and Pastels persist equally well (Mysorekar & Hultgren, 2006, Hannan, et al., 2010, Schwartz, et al., 2011). However, in chronic cystitis (Panel G), the urothelium is hyperplastic and cannot support IBC formation (Hannan, et al., 2010). Therefore, UPEC transitions to an extracellular niche, and either remains adherent to the urothelium or clustered with host cells in the bladder lumen. Therefore, loss of diversity is more gradual and will only occur if one clonal population is fitter for chronic persistence. In this example, the Pastels are more fit than the Solids in competing for limited resources and eventually take over the bladder.

Figure 2

IBC-like biofilms were found in the urines of women suffering from an episode of acute uncomplicated cystitis with UPEC. A-D, An E. coli strain was isolated from a human patient with recurrent cystitis. Urine cytology from this patient was positive for the presence of IBC-like structures and bacterial filaments, which are a hallmark of bacterial emergence from the IBC. A-B, this strain was inoculated into the bladders of C3H/HeN mice where it progressed through the IBC pathogenic cycle. Several IBCs were observed by Hematoxylin & Eosin staining in the mouse bladder at 30 hpi (A, arrow). IBCs could also be seen exfoliated into the bladder lumen (B, arrowhead). C-D, urine collected from mice at this time point were positive for IBCs (C). These IBCs were similar in morphology and size to those formed by the same E. coli isolate in the original human urine specimen (D). E-F, scanning Electron Microscopy analysis of cystitis urines deemed positive for IBCs and filaments captured large bacterial biofilm-like collections (E, inset shown in F) composed of bacteria with a smaller, more coccoid morphology than typical E. coli. Scale bars: 50 μm (A-D) and 5 μm (E–F). Figure modified from Rosen, et al., 2007.

Figure 3. Model of host-pathogen checkpoints in chronic and recurrent cystitis

We hypothesize that an acute host-pathogen mucosal checkpoint exists early in UPEC infection of the bladder that determines the outcome of infection. “Inputs” into this checkpoint (blue boxes) include bacterial virulence and host innate immune signaling, such as pattern recognition receptor (PRR) signaling (e.g. TLR4 signaling). The bladder mucosa integrates these signals (green box), which include the intensity and invasiveness of UPEC infection and the character of PRR signaling, and responds. These responses or “outputs” in naïve mice (green arrows) include the biomarkers of chronic infection, the severity of bladder inflammation, and the character and extent of urothelial cell death and exfoliation. These outputs correlate with disease outcome (brown boxes). Severe or weak mucosal responses can each lead to persistent bladder infection with (chronic cystitis in TLR4-responsive C3H mice) or without (“asymptomatic” bladder infection in C3H/HeJ mice) inflammation, respectively. In turn, the adaptive mucosal response that accompanies the development of chronic cystitis in C3H mice increases the sensitivity of the acute host-pathogen checkpoint, even after clearance of the infection with antibiotics, predisposing to severe recurrent and chronic cystitis after challenge infection (red arrows). QIRs, quiescent intracellular reservoirs; ASB/ABU, asymptomatic bacteriuria.

Figure 4. Mannosides successfully treat existing chronic infections

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Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection - PubMed (original) (raw)