Mucosal bacterial infections are very common, accounting for over 42 million outpatient visits and a majority of the 270 million outpatient antibiotic prescriptions in the United States annually (Armstrong and Pinner, 1999; May et al., 2014; Outpatient antibiotic prescriptions, 2011). Of these, respiratory and urinary tract infections (UTI) can be highly recurrent, the latter leading to over $2 billion in direct and indirect costs annually in the United States (Foxman, 2010). Over 80% of community-acquired UTI are caused by uropathogenic Escherichia coli (UPEC) (Gupta and Bhadelia, 2014; Ronald, 2003), and the vast majority of these infections involve the lower urinary tract and specifically the urinary bladder, causing cystitis (bladder infection). Women are disproportionately affected: over 60% of women will experience at least one UTI during their lifetime (Foxman et al., 2000a), and of these women, 20–30% will experience a recurrence (rUTI) within 6 months (Foxman et al., 2000b). Some individuals experience recurrent UTI to such a high degree that they resort to taking daily suppressive antibiotic therapy to prevent further recurrence (Ikäheimo et al., 1996). In sexually active young women, one of the single biggest independent risk factors for developing an acute UTI is a history of two or more UTIs (Hooton et al., 1996). Furthermore, placebo studies of UTI patients show that the natural course of infection and symptoms can vary greatly: for some women, infections resolve spontaneously within a few days, while others may develop persistent bladder infections lasting for weeks (Ferry et al., 2004; Christiaens et al., 2002; Mabeck, 1972). Taken together, these data suggest that disease history may impact the nature of the future interaction of UPEC with the urinary tract mucosa of patients in a way that alters susceptibility to symptomatic rUTI.

In C3H/HeN mice, a dichotomy of self-resolving vs. chronic infection, similar to the natural course of UTI in women, occurs after experimental UPEC infection in an infectious dose-dependent manner (Hannan et al., 2010). Strikingly, the outcome of the initial infection polarizes future susceptibility to rUTI: mice that spontaneously resolve the initial infection are highly resistant to rUTI upon challenge, whereas those that develop an initial chronic infection (persistent high-titer bladder bacterial colonization and bladder mucosal inflammation) lasting two weeks or longer prior to antibiotic therapy are highly sensitive to rUTI (O'Brien et al., 2015). These studies revealed an early immune checkpoint that determines whether the host spontaneously resolves the infection or goes on to develop chronic cystitis (Hannan et al., 2010). Specifically, at 24 hours post-inoculation (hpi), elevated serum cytokines (IL-5, IL-6, G-CSF, CXCL1), severe bladder inflammation with mucosal wounding, and pyuria (neutrophils in urine) are the hallmarks of checkpoint activation, which indicates severe acute UTI that predisposes to chronic infection. In mice that trigger the checkpoint, robust cyclooxygenase-2 (COX-2) expression by bladder epithelial (urothelial) cells at 24 hpi promotes neutrophil transmigration through the urothelium, causing mucosal damage and ultimately the development of chronic cystitis (Hannan et al., 2014). If chronic cystitis is permitted to go on for two or more weeks prior to antibiotic therapy, affected mice then become highly susceptible to developing severe rUTI upon subsequent challenge in a COX-2 dependent manner (Hannan et al., 2010; Hannan et al., 2014; O'Brien et al., 2016). C57BL/6J mice, though inherently resistant to chronic cystitis upon a single bladder inoculation of UPEC, can be induced to develop chronic cystitis by repeated bacterial inoculation (Hannan et al., 2010; Schwartz et al., 2015), and those with a history of chronic infection become susceptible to severe rUTI upon challenge, similar to C3H/HeN mice, demonstrating that acquired factors related to a prior chronic infection can overcome genetic resistance (O'Brien et al., 2016). Translating these findings to humans, we found that serum cytokine biomarkers associated with more robust granulocytic responses, similar to those associated with the development of chronic cystitis in naive mice, were also predictive of susceptibility to rUTI in women (Hannan et al., 2014).

The diverging susceptibilities of mice to rUTI as a consequence of the outcome of a prior infection were found to be due in part to bladder remodeling that alters the pathophysiology of acute cystitis upon the second infection (Hannan et al., 2014; O'Brien et al., 2016). However, the molecular mechanisms by which this bladder remodeling impacted susceptibility to rUTI were unclear. Here, we leveraged the power of bladder transcriptomics and the C3H/HeN mouse model of rUTI to interrogate the molecular basis for the impact of UTI history on host susceptibility to rUTI. We discovered that tumor necrosis factor-alpha (TNFɑ) signaling was a hallmark of bladder inflammation during acute UTI in mice. However, the temporal nature of the TNFɑ response differed according to UTI history and impacted the outcome of recurrent infection. Antibody-mediated depletion experiments showed that the polarizing rUTI susceptibility phenotypes (i.e. mice with a history of chronic UTI were susceptible to rUTI, whereas mice with a history of self-resolving UTI were resistant to rUTI) were each mediated by TNFɑ signaling, but with divergent dynamics and effects. Thus, these findings demonstrate the central role of TNFɑ in directing acute bladder inflammation and provide mechanistic insight into how UTI history affects host susceptibility to recurrent infection by modulating TNFɑ signaling dynamics.

The mucosal response to pathogens is influenced by both the virulence of the infecting organism and the propensity for a given mucosa to respond to bacterial colonization, the latter being determined by both inherited and acquired host traits. In immunocompetent individuals, an initial infectious disease episode—particularly one that can lead to chronic inflammation, such as upper respiratory infections (sinusitis, tonsillitis, and nasopharyngitis) and urinary tract infections—can act as a potent effector of tissue remodeling that predisposes to recurrent infection (Hooton et al., 1996; Nuhoglu et al., 2003; Toews, 2005). In this work, we sought to understand the molecular basis for how the character of an initial mucosal infection may affect susceptibility to recurrent infection using an inbred immunocompetent mouse model of recurrent UTI. Based on our prior investigations of this model (Hannan et al., 2010; Hannan et al., 2014; O'Brien et al., 2016; Schwartz et al., 2015; O'Brien et al., 2018), we hypothesized that early host-pathogen interactions at the bladder mucosa trigger time-sensitive checkpoints that determine the outcome of infection, but that the character of a prior bladder infection can alter the kinetics and downstream effects of these disease checkpoints. By investigating the nature of acute inflammation during the first 24 hr of UPEC infection in isogenic mice that differed only in their disease histories, we identified distinct patterns of bladder inflammation that dictated the severity of recurrent cystitis (Figure 8). The nature of an initial bladder infection – self-resolving vs. long-lasting – imparts upon the bladder different capacities for TNFɑ signaling in response to recurrent infection, which in turn lead to different host outcomes: i) a history of a self-resolving infection corresponds with robust, but transient, early-onset TNFɑ signaling that leads to resistance to severe recurrent infection; whereas ii) a history of a long-lasting infection corresponds with robust early-onset TNFɑ signaling that is sustained though 24 hpi and leads to susceptibility to severe recurrent infection. Others have shown that TNFɑ plays a role in the bladder’s response to UPEC infection in naive mice (Engel et al., 2006; Schiwon et al., 2014; Gur et al., 2013). However, our study demonstrates the centrality of this response and surprisingly shows that both the kinetics and the effects of this response can vary substantially based upon host infection history. These results have significance not only for our understanding of rUTI, but also of other recurrent mucosal infections.

Figure 8

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Our RNA-seq and pathway analysis indicated that both TNFR1 and TNFR2 signaling pathways were activated in UPEC-infected bladders. TNFɑ binds to TNFR1 (expressed in most tissues, including urothelial cells) and/or TNFR2 (typically expressed by immune cells) and can activate distinct signaling cascades based on the receptors it binds to and the local microenvironment (Wajant et al., 2003; Wang et al., 2018; Wang and Bjorling, 2011). To add further complexity, both TNFɑ and the TNFRs can exist in either membrane bound or soluble forms. Both forms of TNFɑ can activate TNFR1, which leads either to NF-κB activation, cell survival, and cytokine production on the one hand, or cell death by apoptosis or necroptosis on the other (Wang et al., 2018). The balance between cell survival and cell death, as well as the inflammatory nature of the cell death in response to stimuli such as pathogen-associated molecular patterns (e.g. LPS), is influenced by many factors (Geppert et al., 1994). In contrast, only membrane-bound TNFɑ can activate TNFR2, thereby stimulating cell-mediated immunity, including activation of monocytes and lymphocytes, production of cytokines, and mediation of cytotoxic activity to promote host defense (Horiuchi et al., 2010). Although the pathway analysis employed in this study cannot distinguish between the two TNFR signaling pathways because of substantial overlap in the downstream regulated gene sets, it is likely that both TNFR1 and TNFR2 signaling are occurring in the bladder. Our use of whole bladder RNA-seq precludes us from identifying the cell types producing and responding to TNFɑ at this time.

The involvement of TNFɑ in both tissue damage and tissue regeneration represents an interesting functional duality (Wajant et al., 2003), and consequently, the host must tightly regulate TNFɑ activation to prevent damaging inflammation. We found that a major distinction between the responses of Sensitized and Resolved mice to bacterial challenge was the duration of TNFɑ signaling. Whereas Resolved mice had largely shut down TNFɑ signaling and bladder inflammation by 24 hpi, effectively nipping the infection in the bud, Sensitized mice had sustained TNFɑ signaling pathway activation in the bladder at 24 hpi, which contributed to the development of more severe infection. Adult Naive mice also had evidence of sustained bladder TNFɑ signaling pathway activation, though it was slower to develop and not as robust as in Sensitized mice at 24 hpi. The dynamics of bladder inflammation in Resolved mice—that is, robust early phase that is rapidly quenched by 24 hpi—has also been reported in juvenile naive C57BL/6 mice, which are naturally resistant to severe acute and chronic cystitis with UPEC (Hannan et al., 2010; Chan et al., 2013; Duell et al., 2012; Mulvey et al., 1998; Ingersoll et al., 2008; Liu et al., 2015). However, in contrast to our findings in Resolved mice, a prior study found no effect on overall neutrophil recruitment to the bladder in juvenile naive TNFR-/- vs WT C57BL/6J mice at 6 hpi, though transmigration of neutrophils across the bladder epithelium and exfoliation of infected bladder cells was impaired (Schiwon et al., 2014). While genotype can dictate these differences in the dynamics of host response in naive mice, our studies show that these dynamics are plastic and can be reshaped by non-germline factors such as prior infections and inflammation. Indeed, we previously demonstrated that superinfection of C57BL/6 mice can result in chronic cystitis, which subsequently sensitizes these mice to severe rUTI upon challenge (O'Brien et al., 2016).

We elucidated that previously infected C3H/HeN mice, regardless of disease outcome, shared an accelerated pattern of robust TNFɑ signaling and bladder inflammation relative to age-matched naive mice in the first 6 hours of infection (Figure 8). In naive mice, a critical event in bladder disease pathogenesis in the acute stages of E. coli infection is the formation of intracellular bacterial communities (IBCs), which allow the bacteria to rapidly increase in number while avoiding host defenses. However, previously infected C3H/HeN mice harbor very few, if any, IBCs at 6 hpi, a phenomenon we have termed ‘intracellular colonization resistance’ (O'Brien et al., 2016). We found that in Resolved mice, abrogation of TNFɑ signaling disrupted intracellular colonization resistance by reducing the recruitment of neutrophils to the bladder and exfoliation of IBC-containing cells, thus resulting in abundant IBCs detected in the bladder epithelium at 6 hpi. TNFɑ induces downstream targets (e.g. neutrophil chemokines such as CXCL1) that stimulate neutrophil recruitment to the site of infection, supporting our observations of decreased neutrophil recruitment to the bladder and pyuria in TNFɑ-depleted Resolved mice. In contrast, Sensitized mice were unable to harbor IBCs in the presence or absence of TNFɑ signaling, likely due to the significantly smaller size of the superficial umbrella cells (average surface area approximately one eighth that of Adult Naive umbrella cells four weeks after the initiation of antibiotics), which likely restricts IBC formation (O'Brien et al., 2016; O'Brien et al., 2018). Thus, we found that the mechanism of intracellular colonization resistance differs between Sensitized and Resolved mice.

We found that the kinetics of TNFɑ expression and pathway activation mirrored the kinetics of Ptgs2 (COX-2) expression regardless of disease history, suggesting that TNFɑ signaling may be associated with Ptgs2 expression during bladder infection. COX-2 signaling is known to affect susceptibility to chronic and recurrent UTI in C3H/HeN mice, as COX-2-dependent severe inflammation and neutrophil transmigration through the bladder was shown to cause mucosal wounding leading to chronic cystitis (Hannan et al., 2014). Experimental suppression of COX-2-mediated acute inflammation with COX-2 inhibitors prevents chronic cystitis in naive mice and is a potent suppressor of recurrent UTI in Sensitized mice (Hannan et al., 2014; O'Brien et al., 2016). TNFɑ is capable of inducing COX-2 expression in some systems (Chen et al., 2000; Mark et al., 2001). However, whether COX-2 acts downstream of TNFɑ or both are activated by a common mechanism in mice during UPEC infection remains to be elucidated. While TNFɑ depletion in Sensitized mice phenocopied COX-2 inhibition in certain ways (e.g. reduced edema and reduced bacterial titers), unlike COX-2 inhibition, it did not affect pyuria, suggesting that neutrophil transmigration across the urothelium is independent of TNFɑ signaling in Sensitized mice. Taken together, these prior studies and our findings here elucidate an interesting dichotomy: whereas in Resolved mice, moderate, TNFɑ-mediated neutrophil recruitment to the bladder and subsequent exfoliation of IBC-containing urothelial cells allows for the clearance of infection, in Sensitized mice prolonged TNFɑ-signaling, coupled with COX-2 mediated transmigration of neutrophils across the bladder epithelium, exacerbates inflammation and mucosal wounding to promote severe acute cystitis. These different effects of TNFɑ signaling on the severity of recurrent cystitis may be a consequence of differences in epithelial remodeling that we previously demonstrated by quantitative proteomics (Hannan et al., 2014), and/or could be due to differences in bladder resident immune cell populations.

A question that this study was unable to answer is how the acute bladder inflammatory response is dampened so rapidly in Resolved mice. Although the RNA-seq pathway analysis gave some indication of activation of anti-inflammatory pathways in Resolved mice at 24 hpi, there was not a strong anti-inflammatory transcriptional signature that was also entirely absent in Sensitized mice. It may be that a unique, transient transcriptional signature arises in Resolved mice between the 6 and 24 hpi time points sampled, or alternatively, it may be that Resolved mouse bladders have additional inherent differences that are not evidenced by transcriptional changes. Previous ex vivo proteomics studies of urothelial cells isolated from convalescent mice suggested that the Sensitized urothelium is more susceptible to inflammatory cell death, neutrophil mediated damage, wounding, and oxidative stress (Hannan et al., 2014). Therefore, it is possible that the rapid elimination of intracellular bacterial communities in Resolved bladders, coupled with an inherent increased propensity for the Resolved urothelium to heal relative to the Sensitized urothelium, may explain the differences seen at 24 hpi. Understanding the specific mechanisms that allow Resolved mice to quickly quench bladder inflammation is an avenue of research that requires further investigation.

In summary, we show here that the nature and pattern of the bladder mucosal inflammatory response to UPEC infection, and particularly the dynamics of TNFɑ signaling, can be shaped by a prior infection in a way that dramatically alters host resistance to rUTI (Figure 8). Our studies indicate that TNFɑ signaling is a critical central mediator of bladder mucosal immune response to UPEC but can have different effects on acute disease outcome in previously infected mice depending upon the character of the prior infection. This central role is supported by clinical data indicating that prolonged use of anti-TNFɑ therapy in patients increases the risk of UTI (Tong et al., 2015). Understanding the underlying host mechanisms that dictate patient susceptibility to recurrent infections is critical for developing effective new therapies that target the host inflammatory response as an alternative strategy to combat rapidly increasing antimicrobial resistance.

Sequencing data were deposited in GEO database under accession number GSE117532.

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Author details

1. Lu Yu

   Department of Molecular Microbiology and Center for Women’s Infectious Disease Research, Washington University School of Medicine, St Louis, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Contributed equally with

   Valerie P O'Brien

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2361-2347

2. Valerie P O'Brien

   Department of Molecular Microbiology and Center for Women’s Infectious Disease Research, Washington University School of Medicine, St Louis, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Contributed equally with

   Lu Yu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0502-2690

3. Jonathan Livny

   The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States

   Contribution

   Conceptualization, Resources, Formal analysis, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

4. Denise Dorsey

   Department of Molecular Microbiology and Center for Women’s Infectious Disease Research, Washington University School of Medicine, St Louis, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Nirmalya Bandyopadhyay

   The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States

   Contribution

   Software, Formal analysis, Investigation

   Competing interests

   No competing interests declared

6. Marco Colonna

   Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States

   Contribution

   Conceptualization, Resources, Funding acquisition

   Competing interests

   No competing interests declared

7. Michael G Caparon

   Department of Molecular Microbiology and Center for Women’s Infectious Disease Research, Washington University School of Medicine, St Louis, United States

   Contribution

   Supervision, Writing—review and editing

   Competing interests

   No competing interests declared

8. Elisha DO Roberson

   1. Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St Louis, United States
   2. Department of Genetics, Washington University School of Medicine, St Louis, United States

   Contribution

   Resources, Formal analysis, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5921-2399

9. Scott J Hultgren

   Department of Molecular Microbiology and Center for Women’s Infectious Disease Research, Washington University School of Medicine, St Louis, United States

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Writing—review and editing

   For correspondence

   hultgren@wustl.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8785-564X

10. Thomas J Hannan

    1. Department of Molecular Microbiology and Center for Women’s Infectious Disease Research, Washington University School of Medicine, St Louis, United States
    2. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States

    Contribution

    Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Writing—review and editing

    For correspondence

    thannan@wustl.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-0498-8231

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