Pathogenicity of Enterococcal Urinary Tract Infections: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Alia Jazmin Codelia-Anjum.

A brief overview of biofilm formation and virulence factors contributing to enterococcus's pathogenicity in urinary tract infections. 

  • enterococcus
  • urinary tract infection
  • resistance

1. Introduction

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][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][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][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][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][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][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][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][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.
Virulence Factor Function
Aggregation substance [6,9,12,13][6][9][12][13]
-
Responsible for bacterial aggregation and helps facilitate conjugation
-
Mediates adhesion to host cells and extracellular matrix
Collagen binding protein [12]
-
Facilitates adhesion to extracellular matrix and type 1 collagen
Cytolysin [14,15][14][15]
-
Toxin that is able to lyse various cell types through pore formation
-
Encoded through plasmids
Enterococcal surface protein [7,16][7][16]
-
Promotes initial adherence to surfaces and biofilm formation
-
Associated with bacterial colonization and persistence
Gelatinase [9,17][9][17]
-
Able to break down various substrates including complement proteins and collagen
-
Assists with biofilm formation
Hyaluronidase [18]
-
Breaks down hyaluronic acid to increase permeability of connective tissues
Pilin gene clusters (PGCs) [6,19][6][19]
-
Encodes gene for pili formation, which assists with biofilm formation and adhesion to host cells
-
E. faecalis and E. faecium express different PCGs, however, they perform similar roles in adherence and biofilm formation
TcpF [9,20,21][9][20][21]
-
Suppresses Toll-like receptors (TLR) from producing cytokines by interfering with the signaling pathway

References

  1. McLellan, L.K.; Hunstad, D.A. Urinary Tract Infection: Pathogenesis and Outlook. Trends Mol. Med. 2016, 22, 946–957.
  2. Zilberberg, M.D.; Nathanson, B.H.; Sulham, K.; Shorr, A.F. Descriptive Epidemiology and Outcomes of Hospitalizations with Complicated Urinary Tract Infections in the United States, 2018. Open Forum Infect. Dis. 2022, 9, ofab591.
  3. Zeng, Z.; Zhan, J.; Zhang, K.; Chen, H.; Cheng, S. Global, regional, and national burden of urinary tract infections from 1990 to 2019: An analysis of the global burden of disease study 2019. World J. Urol. 2022, 40, 755–763.
  4. Flores-Mireles, A.L.; Walker, J.N.; Caparon, M.; Hultgren, S.J. Urinary Tract infections: Epidemiology, Mechanisms of Infection and Treatment Options. Nat. Rev. Microbiol. 2015, 13, 269–284.
  5. Dunny, G.M.; Hancock, L.E.; Shankar, N. Enterococcal Biofilm Structure and Role in Colonization and Disease. In Enterococci: From Commensals to Leading Causes of Drug Resistant Infection; Gilmore, M.S., Clewell, D.B., Ike, Y., Eds.; Eye and Ear Infirmary: Boston, MA, USA, 2014. Available online: https://www.ncbi.nlm.nih.gov/books/NBK190433/ (accessed on 22 March 2023).
  6. García-Solache, M.; Rice, L.B. The Enterococcus: A Model of Adaptability to Its Environment. Clin. Microbiol. Rev. 2019, 32, e00058-18.
  7. Ch’ng, J.H.; Chong, K.K.L.; Lam, L.N.; Wong, J.J.; Kline, K.A. Biofilm-associated infection by enterococci. Nat. Rev. Microbiol. 2018, 17, 82–94.
  8. Delcaru, C.; Alexandru, I.; Podgoreanu, P.; Grosu, M.; Stavropoulos, E.; Chifiriuc, M.C.; Lazar, V. Microbial Biofilms in Urinary Tract Infections and Prostatitis: Etiology, Pathogenicity, and Combating strategies. Pathogens 2016, 5, 65.
  9. Tien, B.Y.Q.; Goh, H.M.S.; Chong, K.K.L.; Bhaduri-Tagore, S.; Holec, S.; Dress, R.; Ginhoux, F.; Ingersoll, M.A.; Williams, R.B.H.; Kline, K.A. Enterococcus faecalis Promotes Innate Immune Suppression and Polymicrobial Catheter-Associated Urinary Tract Infection. Infect. Immun. 2017, 85, e00378-17.
  10. Sharma, A.K.; Dhasmana, N.; Dubey, N.; Kumar, N.; Gangwal, A.; Gupta, M. Bacterial Virulence Factors: Secreted for Survival. Indian J. Microbiol. 2016, 57, 1–10.
  11. Shankar, N.; Lockatell, C.V.; Baghdayan, A.S.; Drachenberg, C.; Gilmore, M.S.; Johnson, D.E. Role of Enterococcus faecalis Surface Protein Esp in the Pathogenesis of Ascending Urinary Tract Infection. Infect. Immun. 2001, 69, 4366–4372.
  12. Hashem, Y.A.; Abdelrahman, K.A.; Aziz, R.K. Phenotype–Genotype Correlations and Distribution of Key Virulence Factors in Enterococcus faecalis Isolated from Patients with Urinary Tract Infections. Infect. Drug Resist. 2021, 14, 1713–1723.
  13. Süßmuth, S.D.; Muscholl-Silberhorn, A.; Wirth, R.; Susa, M.; Marre, R.; Rozdzinski, E. Aggregation Substance Promotes Adherence, Phagocytosis, and Intracellular Survival of Enterococcus faecalis within Human Macrophages and Suppresses Respiratory Burst. Infect. Immun. 2000, 68, 4900–4906.
  14. Coburn, P.S.; Gilmore, M.S. The Enterococcus faecalis cytolysin: A novel toxin active against eukaryotic and prokaryotic cells. Cell. Microbiol. 2003, 5, 661–669.
  15. Nallapareddy, S.R.; Qin, X.; Weinstock, G.M.; Höök, M.; Murray, B.E. Enterococcus faecalis Adhesin, Ace, Mediates Attachment to Extracellular Matrix Proteins Collagen Type IV and Laminin as well as Collagen Type I. Infect. Immun. 2000, 68, 5218–5224. Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC101781/ (accessed on 22 March 2023).
  16. Toledo-Arana, A.; Valle, J.; Solano, C.; Arrizubieta, M.J.; Cucarella, C.; Lamata, M.; Amorena, B.; Leiva, J.; Penade, R.; Lasa, I. The Enterococcal Surface Protein, Esp, Is Involved in Enterococcus faecalis Biofilm Formation. Appl. Environ. Microbiol. 2001, 67, 4538–4545.
  17. Vergis, E.N.; Shankar, N.; Chow, J.W.; Hayden, M.K.; Snydman, D.R.; Zervos, M.J.; Linden, P.K.; Wagener, M.M.; Muder, R.R. Association between the Presence of Enterococcal Virulence Factors Gelatinase, Hemolysin, and Enterococcal Surface Protein and Mortality among Patients with Bacteremia Due to Enterococcus faecalis. Clin. Infect. Dis. 2002, 35, 570–575.
  18. Louis, B.R.; Carias, L.; Rudin, S.; Vael, C.; Goossens, H.; Konstabel, C.; Klare, I.; Nallapareddy, S.R.; Huang, W.; Murray, B.E. A Potential Virulence Gene, hylEfm, Predominates in Enterococcus faecium of Clinical Origin. J. Infect. Dis. 2003, 187, 508–512.
  19. Sava, I.G.; Heikens, E.; Huebner, J. Pathogenesis and immunity in enterococcal infections. Clin. Microbiol. Infect. 2010, 16, 533–540.
  20. Zou, J.; Baghdayan, A.S.; Payne, S.J.; Shankar, N. A TIR Domain Protein from E. faecalis Attenuates MyD88-Mediated Signaling and NF-κB Activation. PLoS ONE 2014, 9, e112010.
  21. Kraemer, T.D.; Quintanar Haro, O.D.; Domann, E.; Chakraborty, T.; Tchatalbachev, S. The TIR Domain Containing Locus of Enterococcus faecalis Is Predominant among Urinary Tract Infection Isolates and Downregulates Host Inflammatory Response. Int. J. Microbiol. 2014, 2014, 918143.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback