Uropathogen and host responses in pyelonephritis

Abstract

Urinary tract infections (UTIs) are among the most common bacterial infections seen in clinical practice. The ascent of UTI-causing pathogens to the kidneys results in pyelonephritis, which can trigger kidney injury, scarring and ultimately impair kidney function. Despite sizable efforts to understand how infections develop or are cleared in the bladder, our appreciation of the mechanisms by which infections develop, progress or are eradicated in the kidney is limited. The identification of virulence factors that are produced by uropathogenic Escherichia coli to promote pyelonephritis have begun to fill this knowledge gap, as have insights into the mechanisms by which kidney tubular epithelial cells oppose uropathogenic E. coli infection to prevent or eradicate UTIs. Emerging data also illustrate how specific cellular immune responses eradicate infection whereas other immune cell populations promote kidney injury. Insights into the mechanisms by which uropathogenic E. coli circumvent host immune defences or antibiotic therapy to cause pyelonephritis is paramount to the development of new prevention and treatment strategies to mitigate pyelonephritis and its associated complications.

Fig. 1 |. Antibiotic targets and antibiotic resistance strategies deployed by uropathogenic Escherichia coli.

a, Targets of antibiotics used to treat uropathogenic Escherichia coli and Gram-negative uropathogens. Polymyxin antibiotics target outer membrane phospholipids and lipopolysaccharides of Gram-negative bacterial cell membranes. Oxazolidinones inhibit bacterial protein synthesis by blocking the large ribosomal subunit. Similarly, aminoglycosides inhibit bacterial protein synthesis by blocking the small ribosomal subunit. Quinolones target enzymes involved in bacterial DNA synthesis. β-lactam antibiotics prevent bacterial cell wall synthesis. Sulphonamides prevent folic acid synthesis in bacteria by targeting dihydropteroate synthase. b, Antibiotic resistance strategies adapted by uropathogenic E. coli and Gram-negative uropathogens. Bacteria can resist β-lactam antibiotics through the expression of β-lactamases, which disrupt the structure of the antibiotic and render it ineffective. They can also increase the expression of efflux pumps, which facilitate the removal of antibiotics from the bacterial cell interior. Conversely, bacteria can suppress expression of porin channels, reducing access to the bacterial cell interior to antibiotics. Bacteria can adapt to the selective pressure of antibiotics by modifying lipid A so that polymyxins no longer recognize their substrate. They can mutate their DNA or protein synthesis machinery so that oxazolidinones and quinolones can no longer bind their targets, respectively. ESBL, extended-spectrum β-lactamase; MBL, metallo-β-lactamase. Figure adapted from ref. , Springer Nature Ltd.

Fig. 2 |. Antibacterial responses of the kidney collecting duct to uropathogenic Escherichia coli.

a, Collecting ducts are composed of principal cells (PCs) and three types of intercalated cells (A-IC; B-IC; and non-A, non-B IC) that express cell-specific transport proteins. A-IC express an apical H⁺-ATPase that interfaces with the urinary space and a Cl⁻/HCO₃⁻ exchanger AE1 along their basolateral surface. B-IC express pendrin, a Cl⁻/HCO₃⁻ exchanger, at their apical membrane and a basolateral H⁺-ATPase. In the connecting segment, non-A, non-B ICs express both H⁺-ATPase and pendrin at their apical surface. PCs express the epithelial sodium channel (ENaC), aquaporin 2 (AQP2) and an arginine vasopressin receptor (AVPR2). b, During pyelonephritis, uropathogenic Escherichia coli (UPEC) preferentially target the ICs in the collecting duct. UPEC are sensed by pattern recognition receptors, such as TLR4, on the surfaces of ICs. In addition, UPEC may access the interior of ICs via lipid rafts. ICs respond to uropathogens by releasing antimicrobial peptides (AMPs), cytokines and A-IC secrete protons into the urine. ICs also phagocytose UPEC. The role of PCs during pyelonephritis is less defined, but it is believed that activation of AVPR2 by vasopressin can induce secretion of cytokines by PCs and suppress endogenous dDAVP, ultimately reducing water reabsorption and increasing urine volume. c, (Top) In response to UPEC, the medullary sodium gradient orchestrates immune defences by stimulating NFAT5 in tubular epithelial cells to produce CCL2. CCL2 recruits human CD14⁺ mononuclear phagocytes (MNP) or mouse Ly6C⁺ macrophages (Macs) to the medulla where they differentiate into M1 macs and eliminate UPEC. Medullary epithelial cells and macs also secrete granulocyte-recruiting chemokines such as IL-8 (human), CXCL2 (mouse), or TNF to attract neutrophils to the source of infection. (Bottom) Neutrophil transepithelial migration into the urinary space combats UPEC by producing reactive oxygen species (ROS) and AMPs, phagocytosing UPEC and producing neutrophil extracellular traps (through NETosis).

Fig. 3 |. Emerging and potential antibiotic-conserving therapeutics for pyelonephritis.

a, Vaccines induce immunity against uropathogenic Escherichia coli (UPEC) bacterial antigens including adhesins and polysaccharide antigens, such as FimH and lipopolysaccharide (LPS), respectively. Vaccines can also induce immunity against iron receptors. Exogenous mannose or its derivatives, pilicides and cranberry extracts can reduce UPEC binding to host cells. Gepotidacin is a novel antibiotic with a dual-targeting mechanism of action, disrupting both DNA gyrase and topoisomerase IV in bacteria. Probiotics can prevent UPEC attachment to host cells by altering the microenvironment, including pH. Bacteriophages can inhibit biofilm formation and induce lysis of cells that they infect. Antimicrobial peptides (AMPs) are small, cationic peptides that can directly kill bacteria by disrupting their cell membranes or by sequestering metal ions that are required for bacterial enzyme activity. b, Host defences against urinary tract infections (UTIs) can be boosted in a number of ways. Cholesterol targeting drugs can prevent UPEC from utilizing lipid rafts to gain entry into host cells. Immunomodulation of pro-inflammatory factors including interferon regulatory factor 7 (Irf7) has been shown to reduce pyelonephritis in rodent models (dashed line). Additionally, hormones including oestrogen, insulin and vasopressin suppress the inflammatory responses that contribute to pyelonephritis and strengthen the epithelial barrier. These hormones may also boost expression of AMPs. Finally, histone deacetylase inhibitors (HDACi) increase AMP production and reduce UTIs in rodent and cell-culture models. siRNA, small interfering RNA.