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Key Points Urinary tract infections (UTIs) are some of the most common bacterial infections and are caused by both Gram-negative and Gram-positive species. UTIs are categorized into uncomplicated and complicated, and are a severe public health problem; this situation is being exacerbated by the rise in multidrug-resistant strains. Uropathogens carry multiple virulence factors involved in the pathophysiology of UTIs. These virulence factors are involved in invasion and colonization, as well as in mediating the subversion of host defences. Knowledge about the mechanism of action of these virulence factors is being used to develop new therapeutics against UTIs. Therapies that are currently in the initial stages of development include vaccines targeting bacterial factors that are essential for initial attachment and disease progression (such as adhesins, toxins, proteases and siderophores), and small-molecule inhibitors that prevent adhesin–receptor interactions. Urinary tract infections (UTIs) pose a severe public health problem and are caused by a range of pathogens. In this Review, Hultgren and colleagues discuss how basic science studies are elucidating the molecular mechanisms of UTI pathogenesis and how this knowledge is being used for the development of novel clinical treatments for UTIs. Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Enterococcus faecalis and Staphylococcus saprophyticus . High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the molecular details of the crosstalk that occurs at the host–pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs. We also describe current efforts to translate this knowledge into new clinical treatments for UTIs.

Catheter-associated urinary tract infections (CAUTIs), a common cause of healthcare-associated infections, are caused by a diverse array of pathogens that are increasingly becoming antibiotic resistant. We analyze the microbial occurrences in catheter and urine samples from 55 human long-term catheterized patients collected over one year. Although most of these patients were prescribed antibiotics over several collection periods, their catheter samples remain colonized by one or more bacterial species. Examination of a total of 366 catheter and urine samples identify 13 positive and 13 negative genus co-occurrences over 12 collection periods, representing associations that occur more or less frequently than expected by chance. We find that for many patients, the microbial species composition between collection periods is similar. In a subset of patients, we find that the most frequently sampled bacteria, Escherichia coli and Enterococcus faecalis , co-localize on catheter samples. Further, co-culture of paired isolates recovered from the same patients reveals that E. coli significantly augments E. faecalis growth in an artificial urine medium, where E. faecalis monoculture grows poorly. These findings suggest novel strategies to collapse polymicrobial CAUTI in long-term catheterized patients by targeting mechanisms that promote positive co-associations. The authors examine temporal polymicrobial community composition in patients with long-term urinary catheters to identify species co-occurrences and demonstrate uropathogenic Escherichia coli augments growth of a prevalent opportunistic uropathogen in urine.

Building on our finding that Streptococcus pyogenes pyruvate dehydrogenase (PDH) suppresses host disease tolerance (DT) via short-chain fatty acid (SCFA)-mediated modulation of host acetyl-CoA and IL-10 levels, we characterize the global transcriptomic and epigenetic mechanisms underlying this immunometabolic manipulation. Combining new histological and ultrastructural analyses with an in-depth re-analysis of single-cell and bulk RNA-seq datasets to more comprehensively characterize the DT response, we show that PDH deficiency is associated with broad immunologic rewiring, characterized by intracellular bacterial containment within phagocytes, expansion of pro-resolving myeloid cells, and altered cell–cell communication. Metabolic analysis of ΔPdh-infected tissues revealed a shift away from acetyl-CoA metabolism towards glycolysis and the coordinated activation of a multi-faceted DT program, encompassing hypoxia signaling, iron handling, and the NRF2-mediated antioxidant response. Crucially, a focused re-analysis of existing transcriptome datasets from Histone Deacetylase (HDAC)-inhibited macrophages suggested that Trichostatin A (TSA) abrogates the protective transcriptome in ΔPdh infection, indicating that acetylation-dependent repression functions as a key regulator of the host DT response. By integrating new experimental data with advanced computational analyses, our work reveals a bacterial strategy of metabolic-epigenetic crosstalk, suggesting acetylation as a critical control point for mitigating infection-associated tissue damage.

Microbial pathogens balance growth against tissue damage to achieve maximum fitness. Central carbon metabolism is connected to growth, but how it influences growth/damage balance is largely unknown. Here we examined how carbon flux through the exclusively fermentative metabolism of the pathogenic lactic acid bacterium Streptococcus pyogenes impacts patterns of growth and tissue damage. Using a murine model of soft tissue infection, we systematically examined single and pair-wise mutants that constrained carbon flux through the three major pathways that S . pyogenes employs for reduction of the glycolytic intermediate pyruvate, revealing distinct disease outcomes. Its canonical lactic acid pathway (via lactate dehydrogenase) made a minimal contribution to virulence. In contrast, its two parallel pathways for mixed-acid fermentation played important, but non-overlapping roles. Anaerobic mixed acid fermentation (via pyruvate formate lyase) was required for growth in tissue, while aerobic mixed-acid pathway (via pyruvate dehydrogenase) was not required for growth, but instead regulated levels of tissue damage. Infection of macrophages in vitro revealed that pyruvate dehydrogenase was required to prevent phagolysosomal acidification, which altered expression of the immunosuppressive cytokine IL-10. Infection of IL-10 deficient mice confirmed that the ability of aerobic metabolism to regulate levels of IL-10 plays a key role in the ability of S . pyogenes to modulate levels of tissue damage. Taken together, these results show critical non-overlapping roles for anaerobic and aerobic metabolism in soft tissue infection and provide a mechanism for how oxygen and carbon flux act coordinately to regulate growth/damage balance. Therapies targeting carbon flux could be developed to mitigate tissue damage during severe S . pyogenes infection.

Disease tolerance is a host response to infection that limits collateral damage to host tissues while having a neutral effect on pathogen fitness. Previously, we found that the pathogenic lactic acid bacterium Streptococcus pyogenes manipulates disease tolerance using its aerobic mixed-acid fermentation pathway via the enzyme pyruvate dehydrogenase, but the microbe-derived molecules that mediate communication with the host’s disease tolerance pathways remain elusive. Here we show in a murine model that aerobic mixed-acid fermentation inhibits the accumulation of inflammatory cells including neutrophils and macrophages, reduces the immunosuppressive cytokine interleukin-10, and delays bacterial clearance and wound healing. In infected macrophages, the aerobic mixed-acid fermentation end-products acetate and formate from streptococcal upregulate host acetyl-CoA metabolism and reduce interleukin-10 expression. Inhibiting aerobic mixed-acid fermentation using a bacterial-specific pyruvate dehydrogenase inhibitor reduces tissue damage during murine infection, correlating with increased interleukin-10 expression. Our results thus suggest that reprogramming carbon flow provides a therapeutic strategy to mitigate tissue damage during infection. Disease tolerance helps avoid inflammatory damages when immune system is trying to clear infection, but the mechanisms are still unclear. Here the authors show that the bacteria tap into disease tolerance by altering host cell acetyl-CoA metabolism to suppress innate cell function and cytokine production.

To achieve maximum fitness, pathogens must balance growth with tissue damage, coordinating metabolism and virulence factor expression. In the gram-positive bacterium Streptococcus pyogenes , the DNA-binding transcriptional regulator Carbon Catabolite Protein A (CcpA) is a master regulator of both carbon catabolite repression and virulence, suggesting it coordinates growth/damage balance. To examine this, two murine models were used to compare the virulence of a mutant lacking CcpA with a mutant expressing CcpA locked into its high-affinity DNA-binding conformation (CcpA T307Y ). In models of acute soft tissue infection and of long-term asymptomatic mucosal colonization, both CcpA mutants displayed altered virulence, albeit with distinct growth/damage profiles. Loss of CcpA resulted in a diminished ability to grow in tissue, leading to less damage and early clearance. In contrast, constitutive DNA-binding activity uncoupled the growth/damage relationship, such that high tissue burdens and extended time of carriage were achieved, despite reduced tissue damage. These data demonstrate that growth/damage balance can be actively controlled by the pathogen and implicate CcpA as a master regulator of this relationship. This suggests a model where the topology of the S. pyogenes virulence network has evolved to couple carbon source selection with growth/damage balance, which may differentially influence pathogenesis at distinct tissues.

Catheter-associated urinary tract infections (CAUTIs) are the most prevalent healthcare-associated infection globally, with Enterococcus faecalis posing a significant threat due to widespread antibiotic resistance. This study identifies host cysteine proteases—particularly cathepsin L and caspase-1—as unrecognized drivers of CAUTI pathogenesis and renal fibrosis. Pharmacologic inhibition of these proteases using E64 reduces bladder inflammation, epithelial disruption, and kidney abscesses, while restoring fibrinogen and collagen homeostasis. Strikingly, E64 treatment unmasks a protective eosinophil response via CCR3 signaling that enhances bacterial clearance. Genetic deletion of cathepsin L recapitulates these protective effects, establishing it as a key host factor in E. faecalis persistence. These findings reveal host cysteine proteases as viable therapeutic targets for CAUTI and provide proof-of-concept for host-directed strategies that bypass antibiotic resistance.

Summary Streptococcus pyogenes uses the cytolysin streptolysin O (SLO) to translocate an enzyme, the S.pyogenesNAD+ glycohydrolase (SPN), into the host cell cytosol. However, the function of SPN in this compartment is not known. As a complication, many S.pyogenes strains express a SPN variant lacking NAD+ glycohydrolase (NADase) activity. Here, we show that SPN modifies several SLO- and NAD+-dependent host cell responses in patterns that correlate with NADase activity. SLO pore formation results in hyperactivation of the cellular enzyme poly-ADP-ribose polymerase-1 (PARP-1) and production of polymers of poly-ADP-ribose (PAR). However, while SPN NADase activity moderates PARP-1 activation and blocks accumulation of PAR, these processes continued unabated in the presence of NADase-inactive SPN. Temporal analyses revealed that while PAR production is initially independent of NADase activity, PAR rapidly disappears in the presence of NADase-active SPN, host cell ATP is depleted and the pro-inflammatory mediator high-mobility group box-1 (HMGB1) protein is released from the nucleus by a PARP-1-dependent mechanism. In contrast, HMGB1 is not released in response to NADase-inactive SPN and instead the cells release elevated levels of interleukin-8 and tumour necrosis factor-[alpha]. Thus, SPN and SLO combine to induce cellular responses subsequently influenced by the presence or absence of NADase activity.

Catheter-associated urinary tract infections (CAUTIs) are amongst the most common nosocomial infections worldwide and are difficult to treat partly due to development of multidrug-resistance from CAUTI-related pathogens. Importantly, CAUTI often leads to secondary bloodstream infections and death. A major challenge is to predict when patients will develop CAUTIs and which populations are at-risk for bloodstream infections. Catheter-induced inflammation promotes fibrinogen (Fg) and fibrin accumulation in the bladder which are exploited as a biofilm formation platform by CAUTI pathogens. Using our established mouse model of CAUTI, here we identified that host populations exhibiting either genetic or acquired fibrinolytic-deficiencies, inducing fibrin deposition in the catheterized bladder, are predisposed to severe CAUTI and septicemia by diverse uropathogens in mono- and poly-microbial infections. Furthermore, here we found that Enterococcus faecalis , a prevalent CAUTI pathogen, uses the secreted protease, SprE, to induce fibrin accumulation and create a niche ideal for growth, biofilm formation, and persistence during CAUTI. Catheter-associated urinary tract infections can often lead to secondary bloodstream infections, and catheter-induced bladder inflammation. In this work, authors utilise murine models to probe defective fibrinolysis drives extravascular fibrin formation, potentially predisposing hosts to severe CAUTI.

Diabetic patients experience disproportionately severe bacterial infections, yet the microbial mechanisms that exacerbate disease in this immunocompromised context remain incompletely understood. This study demonstrates that the Streptococcus pyogenes ClpX-dependent regulatory pathway, a central regulator of virulence, amplifies tissue damage and inflammatory dysfunction during diabetic skin infection. ClpX-dependent regulation exacerbates disease by intensifying neutrophil dysregulation, excessive NET accumulation, and impaired resolution of infection in an already compromised host environment. These findings underscore the importance of host-pathogen interactions in shaping infection severity and suggest that targeting pathogen regulatory pathways may be particularly effective in settings of immune dysfunction such as diabetes.