Urinary tract infections (UTIs) are among the most common causes of infections across all genders and age groups worldwide
[1]. Over 404.6 million people across the planet were diagnosed with UTIs in 2019, which accounted for over 200,000 deaths
[2]. The financial burden of UTI-associated hospitalizations is substantial, with upwards of 2.8 billion dollars spent in the United States in 2011
[3]. Data collected from the Global Health Data Exchange from 1990 to 2019 revealed that the rate of infection, mortality, and disability-adjusted life-years has increased worldwide
[2]. Given the strain UTIs and their associated sequelae put on the health of individuals, hospital systems, and populations, continued efforts to understand and mitigate the occurrence remain vital. UTIs can be further classified as either uncomplicated or complicated. An uncomplicated or simple UTI is defined as an infection in the lower urinary tract system in either a male or non-pregnant female patient
[4]. Complicated UTIs are associated with atypical organisms, patients considered high risk (pregnancy, comorbidities, immunosuppression, etc.), or involve the upper urinary tract. The most common bacterial pathogen responsible for UTIs is
Escherichia (E.) coli, making up nearly 80% of infections. The other 20% are comprised mostly of
Klebsiella (K.) pneumonia,
Proteus (P.) mirabilis,
Enterococcus (E.) faecalis, and
Staphylococcus (S.) saprophyticus [4].
2. Pathogenicity
Of the known enterococcus species, the majority of urinary tract infections are due to
E. faecalis and
E. faecium, which have multiple mechanisms that increase their pathogenicity
[4][5]. These mechanisms include biofilm formation and virulence factors.
2.1. Biofilm
Biofilm formation by enterococcus has been observed and studied over the last 40 years. First described in the mid 1980s, there has since been robust investigation into how they develop and impact virulence and resistance patterns
[6]. We know that biofilm formation is a multifactorial process that enables evasion of the host defenses and enhances bacterial virulence and antibiotic tolerance
[6][7][8][9]. Ch’ng et al. described four stages of biofilm development by
E. faecalis: attachment, microcolony formation, biofilm maturation, and dispersal
[7]. Attachment is facilitated by surface adhesins (aggregation substance and enterococcal surface protein), proteases, and glycolipids. Once securely attached,
E. faecalis bacteria multiply and secrete a biofilm matrix that forms microcolony aggregates. This biofilm matrix then matures with the production of extracellular matrix components, such as extracellular DNA, polysaccharides, lipoteichoic acid, extracellular proteases, modified lipids, and glycoproteins. As the microcolony grows and matures, the colony endures local nutrient deficits, crowding, hypoxia, and waste accumulation, which creates environmental stress
[7][8]. The resultant stress response prompts a gene expression shift from maturation to dispersal, which is generally regarded as the final step of biofilm development. In dispersal, the core of the biofilm liquefies and the microcolony wall is disrupted, allowing individual bacteria to escape and form new colonies
[7][8]. While the process of biofilm formation of
E. faecium closely resembles that of
E. faecalis, it is not identical. Although both
E. faecalis and
E. faecium produce biofilm, their mechanism of protection is different.
E. faecalis produces a thick film that is difficult to penetrate, while the film
E. faecium produces contains antibiotic-resistant genes
[7]. Adherence and biofilm formation appear to be a hallmark of
Enterococcus spp., especially in urinary isolates
[6].
Biofilms pose further difficulty in treatment as they invite polymicrobial colonization with other species, namely
E. coli, which has been found in co-isolates with
E. faecalis in urinary tract infections
[7]. In this communalistic relationship,
E. Faecalis increases the virulence of
E. coli through immunomodulation and suppression. In a study by Tien et al., it was observed that
E. faecalis is able to subvert the recruitment and activation of immune cells such as macrophages, by preventing nuclear factor kappa B (NF-κB) signaling
[9]. Another method of immunomodulation is through the secretion of gelatinase, which works by cleaving complement components (C3, C3a, and C5a). In doing so,
E. faecalis is able to evade the innate immune system. Furthermore, Tien et al. investigated this communalistic relationship and its role in catheter-associated urinary tract infections (CAUTI). They found that multimicrobial CAUTI that contained both
E. faecalis and
E. coli showed a lower presence of macrophages than in CAUTI caused by only
E. coli.
2.2. Virulence Factors
Enterococcus also has a variety of other methods that increase its pathogenicity, known as virulence factors
[6][7]. Virulence factors are molecules that increase pathogenicity and assist in the survival and colonization of bacteria in the host environment
[10]. Some known virulence factors found in urinary isolates of
Enterococcus spp. include aggregation substances, enterococcal surface proteins, pilin gene clusters (PGCs), collagen binding protein, TcpF, and gelatinase
[6][9][11][12][13][14][15][16][17][18][19][20]. Enterococcal surface proteins (
Esp) are known facilitators of biofilm formation and have been shown to promote the primary adhesion.
Esp has been found in both
E. faecalis and
E. faecium [6][11][16]. A study by Shankar et al. further examined the role of
Esp in
E. faecalis-mediated UTIs and found that
Esp has a vital role in colonization
[11]. Aggregation substance (AS) is a necessary surface adhesion that mediates adhesion to host cells, is responsible for bacterial aggregation, and promotes cell conjugation with pheromone-responsive plasmids
[6][9][12][13]. Interestingly, some species of enterococci express a larger volume of one type of virulence factor compared with others. For example, in urinary isolates of
E. faecalis, a high frequency collagen-binding protein was observed
[12].
Table 1 lists common virulence factors and their role in increasing enterococcal pathogenicity.
Table 1. Known virulence factors of enterococcus.