Interaction of UPEC with the human host.
Urinary tract infections (UTIs) are among the most common infections encountered worldwide in clinical practice. Escherichia coli is by far the most frequent cause of infections responsible for nearly 80–90% of the infections. The strains of E. coli causing UTI are termed as uropathogenic E. coli. They vary from commensal strains as they have acquired virulence and resistant determinants through plasmids, bacteriophages, pathogenicity islands or DNA horizontal transfer of transposons which permits them to victoriously colonize the urinary tract and cause a broader spectrum of disease. For the fact, UPEC strains possess an abundance of both structural (as fimbriae, pili, flagella, capsule, lipopolysaccharide) and secreted (toxins, iron-acquisition systems, enzymes) virulence factors that play a crucial role in the pathogenesis. The pathogenesis of UPEC involves adherence, colonization, evading host defenses and damage to host tissue to achieve virulence. UTI is often treated empirically by broad-spectrum antibiotics in the absence of culture and susceptibility results. This over-use of antibiotics has resulted in the development of antibiotic resistance worldwide. Having a detailed understanding of the bacterium and its virulence factors can help us in developing new treatment options in presence of global antimicrobial resistance.
- virulence factors
- antimicrobial resistance
Urinary tract infections (UTIs) are among the most common infections encountered worldwide in clinical practice accounting for approximately 150 million cases annually causing heavy burden on health infrastructure . Women, undoubtedly are at greatest risk as compared to males and it is been observed that almost 50% of all women have experienced UTI at least once in their lifetime. The infection may result either due to the pathogenicity of the offending microorganism, host susceptibility or a combination of both. While many different microorganisms are known to cause UTI which includes bacteria, viruses and fungi, bacteria remain the main cause responsible for over 95% of cases. Among bacteria,
2. What is uropathogenic
E. coli? How it causes infection?
CFT073 is a prototypical strain of UPEC that was recovered from a woman having severe pyelonephritis infection, it belongs to phylogenetic group B2. It was noted to have increased hemolytic activity in comparison to other UPEC strains. On sequencing, its virulence genes were found to be grouped into five pathogenicity islands [7, 8].
2.2 Route of infection
For UPEC to cause infection, the ultimate origin of it is the intestinal tract of the human host which finally acts as a fecal reservoir. Principally apparent in women, the first step is the bacterial colonization of the vaginal introitus and periurethral meatus. Notably, colonization takes place in parallel with the loss of protective vaginal
3. Bladder defenses against UPEC
To cause infection, UPEC has to beat the natural urinary tract defenses that include physical and chemical defenses. Physical defenses include high urine flow, exfoliation of cells, high urine osmolality and low pH. Chemical defenses of the urinary tract comprise secreted proteins such as THP (Tamm-Horsfall protein), IgA (immunoglobulin), antimicrobial peptides and immune system activation (innate and adaptive). Table 1 summarizes the interaction of UPEC with the human host.
|Bacterial aim||Host barrier|
|Attachment to the host cell surface with the help of adhesins (P fimbriae, type 1 fimbriae)||Flow of urine, mucociliary blanket|
|Acquisition of nutrients by cellular lysis by hemolysin, iron acquisition by siderophores||Sequestration of nutrients (iron through intracellular storage)|
|Initial avoidance of bactericidal activity by the host—capsular polysaccharides and lipopolysaccharide||Phagocytic cells, complement, antimicrobial peptides|
|Late avoidance of bactericidal activity by the host—Antimicrobial resistance||Antimicrobial therapy, acquired immunity|
4. Virulence factors of UPEC
There are various virulence factors possessed by UPEC which enable its colonization and pathogenicity. These factors are inserted either in the genome (chromosome) by insertion elements or transposons or encoded on plasmids. The virulence factors are associated with the bacterial cell surface such as adhesins and factors that are secreted and carried to the site of action such as toxins .
For UPEC to colonize and cause infection, it needs to be equipped with some adhesive molecules which will promote attachment to the host cell surface. Adherence to host cell is regarded as the crucial step for colonization because in normal instances regular urinary flow does not permit colonization of the bacteria to the urinary tract. The adhesive factors found in UPEC are known to be adhesins which exists either in the form of filamentous surface organelles called pili or fimbriae or as non-filamentous proteins in the outer membrane.
4.1.1 P fimbriae
Edén and his colleagues discovered in the year 1976 when they identified that
P fimbriae are said to increase UPEC virulence at various stages of infection. They help the bacteria to persist longer in the intestinal tract and expand more strongly in the urinary tract with the plan of colonization and going ahead with ascending infection [12, 13]. So, when they reach the urinary tract,
4.1.2 Type I fimbriae
Type I fimbriae are considered as a crucial virulent factor in UTI but their exact individual role is challenging to understand as they are expressed by pathogenic as well as commensal strains of
Type I fimbriae bind to uroplakin Ia and IIIa (urothelial mannosylated glycoprotein) through the
Besides, playing a role in attachment to bladder epithelium, it is also found to directly trigger invasion by UPEC into epithelial cells of the bladder (BECs) where they induce formation of IBCs and remain as reservoirs to act as a source of clinical relapse [16, 17]. Some studies have given an insight to the fact that type I fimbriae enhance the infectious potential of UPEC [18, 19] but the accurate timing of expression of fimbria during urinary tract infection remains blurred. It was also seen that UPEC isolates obtained from clinical samples (urine) during infection expressed little to no type I fimbriae . In addition, fimbrial expression was more or less absent in UPEC strains from the urine of women with cystitis .
The expression of these fimbriae is finely regulated attending to environmental signals and is under the control of phase variation that determines the percentage of fimbriated cells in the population.
Hultgren and colleagues, in the experimental murine model of UTI, found out that
4.1.3 Dr adhesins
The Dr adhesin family consists of both fimbrial and afimbrial adhesins on
4.1.4 S and F1C fimbriae
S and F1C fimbriae are also involved in the urinary tract infection process. Both fimbriae are shown to have very related biogenesis genes however they have different adhesin alleles. They exhibit binding to epithelial and endothelial cells from the lower urinary tract and kidneys in humans [25, 26]. S fimbriae binds to sialic acid epitopes which are present in renal sialylated lipoproteins. Also, they particularly are also responsible for other extraintestinal infections such as sepsis, meningitis apart from UTI because they may promote the dissemination of bacteria within the host tissues. As per various pooled studies, F1C fimbriae are more usually seen in strains from pyelonephritis and cystitis patients than fecal strains used as controls . Furthermore, experiments conducted in a try to know their exact role in UTI have not been reported clearly but in strain CFT073, in which type 1 and P fimbriae encoding genes have been inactivated, F1C fimbriae were expressed at elevated levels demonstrating a synchronize fimbrial expression in UPEC .
4.1.5 Other adhesins
Adhesins belonging to the Afa family are also involved in urinary tract infections. The UPEC strains expressing them have distinctive renal tissue tropism. Further findings suggest that these adhesins have properties that supports the development of chronic or/and recurrent infections . Other adhesins identified in vivo among UPEC strains are type 1c, G, M, X adhesins which vary in molecular binding specificities and serologic properties. Table 2 summarizes various UPEC adhesins contributing to virulence.
|Type of adhesin||Corresponding receptor||Encoding genes||Special points|
|Type 1 fimbriae||PMNs and epithelial cells with mannose proteins||—|
|Type 1c fimbriae||Unknown||—|
|Type 3 fimbriae||M blood group||mrkABCDF||Mediate formation of biofilm|
|P fimbriae||P blood group antigen: Gal-α 1–4||Associated with bacteremia, cystitis and pyelonephritis|
|S/F1C fimbriae||Sialyl-α-2-3 galactoside||THP inhibits the adherence|
|G fimbriae||Terminal N-acety-D-glucosamine||—||—|
|Dr family||Type 4 collagen & Dr blood group antigen||—|
There are three main types of toxins that are secreted by UPEC. These are:
Cytotoxic necrotizing factor 1 (CNF)
Apart from these, there are other toxins identified which are secreted by UPEC strains and have cytotoxic activity. Toxins production by UPEC leads to inflammatory response causing UTI symptoms.
In 1921, Dudgeon
At low concentrations, it can cause apoptosis of target host cells which involves neutrophils, T-lymphocytes and renal cells and also stimulate the exfoliation of epithelial cells of the bladder .
At high concentrations, HlyA can lyse erythrocytes and nucleated host cells including uroepithelial cells. This may enable UPEC to cross mucosal barriers effectively, destroy effector immune cells and gain advanced access to nutrients and iron stores of the host.
α-Hemolysin can also result in the elevated elaboration of IL-6 and IL-8 by inducing Ca2+ oscillations in renal epithelial cells. In addition, this toxin is associated with renal complications in 50% of cases of pyelonephritis and also causes endothelial damage and renal vasoconstriction. To add up permanent renal scarring is a usual complication that follows infection by HlyA
CNF-1 is frequently detected in
Autotransporters toxins also named as type V secretion toxins consists of SAT (secreted autotransporter toxin) and VAT (vacuolating autotransporter toxin) encoded by UPEC . SAT is demonstrated more commonly among
VAT was originally discovered in avian pathogenic
Moreover, recent studies have identified other proteins which are secreted by UPEC and known to have cytotoxic activity. These are NRPS (nonribosomal peptide synthases) and PKS (polyketide synthases) which are produced by B2
4.3 Iron acquisition by UPEC
Iron, a necessary cofactor for enzymes found in all organisms, remains concealed by iron-binding proteins in humans. Iron is very crucial for the growth of the bacteria. Therefore, bacteria colonizing and causing infections in humans should have some systems to obtain it. Iron is present at a very low concentration at the infection site of the urinary tract and UPEC is known to have multiple systems for iron scavenging. One such potent way to hunt iron is the possession of siderophores by bacteria as it has got a very high affinity for Fe3+ that enables
4.4 Extracellular polysaccharides
There are a variety of extracellular polysaccharides produced by
The capsule is known to provide protection against phagocytosis and complement-mediated bactericidal effect in the host. In addition, it has been found that the K2 capsule and not the K54 capsule acts to be confirmed urovirulence factor [3, 37].
Proteases are enzymes that leads to the cleavage of peptide bonds. They are generally found in mobile genetic elements like transposons, plasmids or prophages . Although, they are not needed for the survival and replication of bacteria, they may be vital for virulence.
Omptins are considered outer-membrane proteases seen in various members of the Enterobacteriaceae family.
Flagella is an organelle that accounts for the motility in bacteria and flagellated UPEC is responsible for nearly about 70–90% of all UTIs. Genes for synthesis of flagella form a well-regulated and directed cascade of three 3 classes. The benefits of having flagella mediated motility by
Chemotaxis is generally a behavior that is used by the bacteria to sense and then respond to external chemical signals. There are mainly four chemotaxis protein receptors that are necessary for chemotaxis in
5. Antimicrobial resistance in UPEC
Antimicrobial therapy is generally recommended for all symptomatic UTI cases including uncomplicated and complicated cases. The choice of an antibiotic should be led by spectrum and susceptibility patterns of the causative agent, its efficacy for the particular indication, tolerability and adverse events, costs and availability, etc. The most commonly used antimicrobials for treating uncomplicated cases include nitrofurantoin, cotrimoxazole (first line), fosfomycin and pivmecillinam (alternative), fluoroquinolones (second line). Ceftriaxone, cefepime, piperacillin-tazobactam, aminoglycosides and carbapenams are used for complicated cases . The international guidelines recommend the use of nitrofurantoin, fosfomycin trometamol and trimethoprim-sulfamethoxazole for the treatment of uncomplicated UTI. Fluoroquinolones in such situations should be kept in reserved as they are used to treat complicated UTI and mild to moderate pyelonephritis .
UTIs and especially recurrent UTIs are associated with significant use of antibiotics that promotes resistance. Antimicrobial resistance in UPEC and the spreading of multidrug resistant (MDR) UPEC is a concerning clinical problem, particularly in women with recurrent UTIs. Increasing ineffectiveness of the antimicrobials has led to the emergence of MDR UPEC (resistance to at least one antibiotic in three or more classes) and XDR UPEC (resistance to at least one in all but at least two or fewer classes) .
The various mechanisms responsible for resistance include:
Target site inactivation
Presence of β-lactamases enzyme
Efflux pumps mechanism
Through mobile genetic elements such as transposons, gene cassettes, insertions sequences, integrons, etc.
Antibiotic consumption without bacterial characterization of the UTI pathogen.
Over the counter availability of antimicrobials, thus leading to its overuse.
5.1 Drug resistance mechanisms in different classes of antibiotics
5.1.1 Beta lactam drugs
They are cell wall synthesis inhibitors. One of the main mechanisms of resistance in UPEC is the production of the β-lactamase enzyme which is encoded by the
They are bactericidal drugs. It functions by inhibiting the enzymes topoisomerase II (DNA gyrase, which is encoded by gyr A and gyr B genes) and topoisomerase IV (parC and parE) involved in winding—unwinding of the DNA. It is one of the most widely prescribed drugs due to easily available oral formulations. Fluoroquinolone resistance may be due to chromosomal mutations, plasmid mutations, alteration of outer membrane proteins causing decreased antibiotic uptake and presence of efflux pump systems.
Chromosomal mutation in DNA sequences of gyr A QRDRs i.e., quinolone resistance determining region is predominantly responsible for fluoroquinolone resistance. Resistance is also mediated via PMQR (plasmid-mediated quinolone resistance) genes which include qnr genes such as qnrA, qnr B and qnr C.
It is also a bactericidal drug that blocks cell wall synthesis at early stages. It’s a widely used drug as a single dose of 3 g is used for the treatment of uncomplicated UTI, and also because of its activity against ESBL and MBL (metallo-β-lactamases). Resistance to fosfomycin is not widespread till date, however, if present may be conferred by:
Presence of efflux pumps
Enzymatic cleavage by Fos A, Fos X
It works by inhibiting the folate synthesis pathway thus inhibiting the DNA synthesis in the susceptible organism. Though widely used as a first-line therapy for uncomplicated cystitis, the use of trimethoprim-sulfamethoxazole has been stopped for empirical use because of its resistance. Over 20% of the UPEC isolates are resistant to trimethoprim-sulfamethoxazole. Resistance to the drug is mediated by
Efflux pump mechanism
Target enzyme modification
Mutational changes in target enzymes
Reactive intermediates are formed from nitrofurantoin by the action of flavoproteins as a result of which the bacterial ribosomal proteins are inactivated. Resistance to nitrofurantoin till date is much lesser in comparison to the other drugs available, this is attributed to the fact that it acts on multiple targets in the bacterial cell. Resistance may develop due to gene mutations such as nsfA and nfsB genes .
6. New therapeutic options, what is in pipeline?
Emerging drug resistance has led to decreased therapeutic options. Therefore, it is imperative to find alternative treatment options. The options are in pipeline for preventing and treating infections caused by UPEC includes antibiotic recarbrio (FDA approved), vaccines, anti-adhesives etc. Table 3 highlights newer therapeutics options in the pipeline for the treatment of urinary tract infections caused by UPEC .
|Newer therapeutic and disease target||Target in UPEC||Available evidence|
|Mannosides for acute cystitis||Type 1 pili (FimH)||In a mouse model, the reduced bacterial burden was observed following treatment and also as a prophylactic agent in mouse models [46, 47]|
|Galactosides for chronic cystitis and/or pyelonephritis||Fim-like (Fml) pili||In experimental mouse model infected with chronic UTI, reduced bacterial burden in the bladder and kidney |
|FimCH against acute and chronic cystitis||UPEC expressing type 1 pili||Phase 1 clinical trial showing no safety concerns and a reduction in total UTI recurrence in treatment cohort; approved for compassionate use as an investigational intervention|
|Uro-vaxom||Contains a lyophilized mix of membrane proteins from 18 different strains of ||Licensed in 30 countries, represents a safe and effective treatment option for prophylaxis of recurrent UTIs |
|Urovac||Recurrent UTI |
|Non-steroidal anti-inflammatory drugs (NSAIDS)—chronic and recurrent cystitis||UPEC|
|HIF-1α inhibition (AKB-4924)||UPEC||Decreased adherence and invasion of UPEC of cultured human uroepithelial cells, decreased inflammation and bacterial load in mouse models of infection |
|Probiotics—recurrent UTI||UPEC||Reduced frequency of infection in various patient populations having rUTI |
|Lactoferrin—cystitis||UPEC||Reduced adherence to human bladder epithelial cell lines and reduced mouse bladder bacterial burdens following treatment with exogenous lactoferrin |
|Antibiotic—recarbrio (Imipenem, cilastatin and relebactam)||Approved by FDA (U.S. Food and Drug Administration) for the treatment of complicated UTI|
Urinary tract infections, community and hospital-associated affects millions of people especially women worldwide each year. As UPEC is the most common microorganism behind these infections, so adequate knowledge and understanding of UPEC, its virulence factors and antimicrobial resistance pattern is vital for adequate treatment and prevent recurrences. In addition, this can help in developing new therapeutics options in the era of widespread antimicrobial resistance.
Conflict of interest
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