This systematic review addresses the central research question, “what is known from the published, peer-reviewed literature about the impact of diabetes on the risk of bacterial urinary tract infections (UTI)?” We examine the results from laboratory studies where researchers have successfully adapted mouse models of diabetes to study the pathophysiology of ascending UTI. These studies have identified molecular and cellular effectors shaping immune defenses against infection of the diabetic urinary tract. In addition, we present evidence from clinical studies that in addition to diabetes, female gender, increased age, and diabetes-associated hyperglycemia, glycosuria, and immune impairment are important risk factors which further increase the risk of UTI in diabetic individuals. Clinical studies also show that the uropathogenic genera causing UTI are largely similar between diabetic and nondiabetic individuals, although diabetes significantly increases risk of UTI by drug-resistant uropathogenic bacteria.

Uropathogenic Escherichia coli (UPEC) is an important causative agent of urinary tract infections in diabetic humans. We examined the effects of in vitro exposure to glycosuria (presence of glucose in urine) on the virulence and gene expression by UPEC. Our results show that glycosuria rapidly (in 2 h) alters UPEC gene expression, induces biofilm formation, and suppresses type 1 piliation. These results offer novel insights into the pathogenesis of UPEC in the urinary tract.

Methicillin-resistant Staphylococcus aureus (MRSA) is an uncommon cause of urinary tract infections (UTI) in the general population. However, it is important to understand MRSA pathophysiology in the urinary tract because isolation of MRSA in urine samples often precedes potentially life-threatening MRSA bacteremia.

In contrast to typical membrane proteins that span the lipid bilayer via transmembrane α-helices, bacterial outer membrane proteins adopt a β-barrel architecture composed of antiparallel transmembrane β-strands. The topology of outer membrane proteins is difficult to predict accurately using computer algorithms, and topology mapping protocols commonly used for α-helical membrane proteins do not work for β-barrel proteins. We present here the topology of the PapC usher, an outer membrane protein required for assembly and secretion of P pili by the chaperone/usher pathway in uropathogenic Escherichia coli. An initial attempt to map PapC topology by insertion of protease cleavage sites was largely unsuccessful due to lack of cleavage at most sites and the requirement to disrupt the outer membrane to identify periplasmic sites. We therefore adapted a site-directed fluorescence labeling technique to permit topology mapping of outer membrane proteins using small molecule probes in intact bacteria. Using this method, we demonstrated that PapC has the potential to encode up to 32 transmembrane β-strands. Based on experimental evidence, we propose that the usher consists of an N-terminal β-barrel domain comprised of 26 β-strands and that a distinct C-terminal domain is not inserted into the membrane but is located instead within the lumen of the N-terminal β-barrel similar to the plug domains encoded by the outer membrane iron-siderophore uptake proteins.

The effects of electronic cigarette (e-cigarette) vapor (EV) exposure on the physiology of respiratory microflora are not fully defined. We analyzed the effects of exposure to vapor from nicotine-containing and nicotine-free e-liquid formulations on the virulence and transcriptome of Streptococcus pneumoniae strain TIGR4, a pathogen that asymptomatically colonizes the human nasopharyngeal mucosa. TIGR4 was preexposed for 2 h to nicotine-containing EV extract (EVE^+NIC), nicotine-free EV extract (EVE^−NIC), cigarette smoke extract (CSE), or nutrient-rich tryptic soy (TS) broth (control). The differences between the treatment and control strains were explored using transcriptome sequencing (RNA sequencing [RNA-Seq]), in vitro virulence assays, and an in vivo mouse model of acute pneumonia. The analysis of RNA-Seq profiles revealed modest changes in the expression of 14 genes involved in sugar transport and metabolism in EVE^−NIC-preexposed TIGR4 compared to the control, while EVE^+NIC or CSE exposure altered expression of 264 and 982 genes, respectively, most of which were involved in metabolism and stress response. Infection in a mouse model of acute pneumonia with control TIGR4 or with TIGR4 preexposed to EVE^+NIC, EVE^−NIC, or CSE did not show significant differences in disease parameters, such as bacterial organ burden and respiratory cytokine response. Interestingly, TIGR4 exposed to CSE or EVE^+NIC (but not EVE^−NIC) exhibited moderate induction of biofilm formation. However, none of the treatment groups showed significant alterations in pneumococcal hydrophobicity or epithelial cell adherence. In summary, our study reports that exposure to EV significantly alters the S. pneumoniae transcriptome in a nicotine-dependent manner without affecting pneumococcal virulence. IMPORTANCE With the increasing popularity of e-cigarettes among cigarette smoking and nonsmoking adults and children and the recent reports of vaping-related lung illness and deaths, further analysis of the adverse health effects of e-cigarette vapor (EV) exposure is warranted. Since pathogenic bacteria such as Streptococcus pneumoniae can colonize the human nasopharynx as commensals, they may be affected by exposure to bioactive chemicals in EV. Hence, in this study we examined the effects of EV exposure on the physiology of S. pneumoniae strain TIGR4. In order to differentiate between the effects of nicotine and nonnicotine components, we specifically compared the RNA-Seq profiles and virulence of TIGR4 exposed to vapor from nicotine-containing and nicotine-free e-liquid formulations. We observed that nicotine-containing EV augmented TIGR4 biofilms and altered expression of TIGR4 genes predominantly involved in metabolism and stress response. However, neither nicotine-containing nor nicotine-free EV affected TIGR4 virulence in a mouse model.

To explore whether glycosuria induces virulence of uropathogens, in turn facilitating urinary tract infection (UTI), we exposed group B Streptococcus (GBS) strain 10/84 to human urine plain or with 300 mg/dL glucose (mimicking moderate glycosuria). Exposure to moderate glycosuria significantly augmented bacterial growth, kidney bacterial burden in a mouse model of ascending UTI, and virulence characteristics and expression of corresponding genes. Exposure to glycosuria increased GBS adherence to human bladder epithelial cell line and expression of corresponding PI2a fimbrial gene, antimicrobial peptide LL-37 resistance and bacterial surface charge modulating dltA, and GBS hemolytic ability and expression of genes encoding pore-forming toxins.