This review provides a comprehensive and technically rich synthesis of the multifactorial pathogenesis of urinary tract infections (UTIs), host susceptibility mechanisms, and the emerging landscape of antibiotic-sparing therapeutic strategies. The strength of this paper lies in its detailed integration of molecular microbiology, immunology, and translational perspectives. Nonetheless, several critical points merit further scholarly consideration:
1. While UPEC serves as a valuable paradigm, the predominance of UPEC-focused findings may limit generalizability across other clinically significant uropathogens (e.g., P. aeruginosa, Enterococcus spp., K. pneumoniae). Greater comparative analysis would help contextualize the unique and shared virulence strategies across species.
2. The review presents promising preclinical and early-phase human data on mannosides, vaccines, and catheter modifications. However, clinical efficacy and long-term safety in diverse patient populations remain unaddressed. A critical discussion of scalability, regulatory hurdles, and cost-effectiveness would enhance translational relevance.
3. The paper acknowledges that adaptive responses often fail in rUTIs, but this area remains underexplored. While tissue-resident memory T cells are highlighted, the roles of B cell-mediated humoral memory and local IgA responses are largely overlooked and warrant deeper investigation.
4. The preclinical support for COX2 inhibition is promising, but the inflammatory duality of this axis (i.e., its role in both resolution and damage) highlights the need for precision-targeted immunomodulation. Potential off-target effects and long-term impact of such interventions in human subjects deserve more critical discussion.