Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm Urinary tract infection: Pathogenicity, antibiotic resistance and development of effective vaccines against Uropathogenic Escherichia coli Mohammad Reza Asadi Karam, Mehri Habibi ⁎ , Saeid Bouzari ⁎⁎ Department of Molecular Biology, Pasteur Institute of Iran, Pasteur Ave., Tehran, 13164, Iran ARTICLE INFO Keywords: Urinary tract infection Uropathogenic Escherichia coli Virulence factors Immune responses Antibiotic resistance Vaccine ABSTRACT Urinary tract infections (UTIs) are recognized as one of the most common infectious diseases in the world that can be divided to different types. Uropathogenic Escherichia coli (UPEC) strains are the most prevalent causative agent of UTIs that applied different virulence factors such as fimbriae, capsule, iron scavenger receptors, flagella, toxins, and lipopolysaccharide for their pathogenicity in the urinary tract. Despite the high pathogenicity of UPEC strains, host utilizes different immune systems such as innate and adaptive immunity for eradication of them from the urinary tract. The routine therapy of UTIs is based on the use of antibiotics such as β-lactams, trimethoprim, nitrofurantoin and quinolones in many countries. Unfortunately, the widespread and misuse of these antibiotics resulted in the increasing rate of resistance to them in the societies. Increasing antibiotic re- sistance and their side effects on human body show the need to develop alternative strategies such as vaccine against UTIs. Developing a vaccine against UTI pathogens will have an important role in reduction the mortality rate as well as reducing economic costs. Different vaccines based on the whole cells (killed or live-attenuated vaccines) and antigens (subunits, toxins and conjugatedvaccines) have been evaluated against UTIs pathogens. Furthermore, other therapeutic strategies such as the use of probiotics and antimicrobial peptides are considered against UTIs. Despite the extensive efforts, limited success has been achieved and more studies are needed to reach an alternative of antibiotics for treatment of UTIs. 1. Urinary tract infection 1.1. Definition of urinary tract infection The urinary tract infection (UTI) occurs when the pathogen is able to enter the urinary tract system and reach more than 10 5 colony/ml in urine (Smelov et al., 2016). UTI is known as the second common cause of infectious diseases (Klumpp et al., 2006). According to the previous studies, UTI accounts for approximately 40% of all infections acquired in the hospitals and 50% of bacteremia that can prolong the hospita- lization and increase the morbidity and mortality rate of patients (Mathai et al., 2001; Saint et al., 2008). In the United States, about 11 million people causing to UTI have been annually referred to the healthcare centers, and approximately 470,000 have been hospitalized, which annually costs was about $6 billion (Mann et al., 2017; Subashchandrabose and Mobley, 2015). In general, it is estimated that nearly half of women and 12% of men will experience at least one UTI during their lifetimes, and a quarter of these people will have the re- currence form of disease in the future (Brumbaugh et al., 2013). 1.2. Classification of urinary tract infections Urinary tract infections have the ability to develop disease in var- ious types, including asymptomatic bacteriuria, acute, chronic, and recurrent infection (Smelov et al., 2016). The incidence of three or more UTIs per year, as well as 2 or more UTIs in less than 6 months is considered as the recurrent UTI, which are the major challenge in treatment of UTI patients (Nuutinen and Uhari, 2001; Terlizzi et al., https://doi.org/10.1016/j.molimm.2019.02.007 Received 4 August 2018; Received in revised form 2 February 2019; Accepted 12 February 2019 Abbreviations: UTI, urinary tract infection; UPEC, Uropathogenic Escherichia coli; E. coli, Escherichia coli; IBC, Intracellular bacterial communities; LPS, Lipopolysaccharide; DAF, Decay-accelerating factor; RBC, Red Blood Cell; HlyA, alpha-hemolysin; CNF1, Cytotoxic necrotizing factor 1; Ag43, Antigen 43; Vat, Vacuolating autotransporter cytotoxin (Vat); Sat, Secreted autotransporter toxin; TLR, Toll like receptor; NK, Natural killer; PAMP, Pathogen-Associated Molecular Pattern; IFN-γ, Interferon gamma; CLSI, Clinical and Laboratory Standards Institute; Mar, Multiple antibiotic resistance locus; ESBL, Extended Spectrum β-Lactamase; PMQR, plasmid-mediated quinolone resistance; CT, Cholera toxin; MPL, Monophosphoryl Lipid A ⁎ Corresponding author at: Department of Molecular Biology, Pasteur Institute of Iran, Tehran, Iran. No. 69, Pasteur Ave, Tehran, 1316943551, Iran. ⁎⁎ Corresponding author. E-mail addresses: m_habibi@pasteur.ac.ir (M. Habibi), bouzari@pasteur.ac.ir (S. Bouzari). Molecular Immunology 108 (2019) 56–67 0161-5890/ © 2019 Elsevier Ltd. All rights reserved. T