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Urinary tract infection - Coggle Diagram
Urinary tract infection
Definitions
Upper UTI
-Kidney infections -> Pyelonephritis
-Ureters infections -> Ureteritis
Pain in lower back, genitals; Fever; Shiver/chills; Weakness; Loss of appetite; Diarrhea
Low UTI
-Bladder infections -> Cystitis
-Urethra infections -> Urethritis
-Prostate -> Prostatitis
Painful micturition; Urge to pee; Pain low abdomen
Uncomplicated UTI
Infection that occurs in an otherwise healthy individual with a normal urinary tract and has not spread beyond the bladder.
Complicated UTI
Infection that occurs in the urinary tract and is associated with factors that increase the risk of treatment failure, recurrence, or more severe complications.
- Anatomic anormalities
- Pregnant women
- Male UTI
- Immune suppression
- Recurrent/Chronic infections
Epidemiology
- ~150 million cases/year
- 85% of all diagnosed UTIs are in women
50% of women will suffer at least one episode
- Highly recurrent
- AMR strains
Sex difference
- 50% female in their lifetime
- 10-15% male in their lifetime
- female more high recurrence
- male more chronicity
- pregnant women: 18%
- institionalized elderly: >30% (both sexes)
Uropathogens
Causative agents
Uropathogens:
- Bacteria
- Uropathogenic E. coli (UPEC)
- Other Gram negative
- Gram positive: E. faecalis, S. saprophyticus
- Fungi (e.g. C. albicans)
- Virus (e.g. BK virus, adenovirus, and cytomegalovirus) only in immunocompromised individuals.
Uropathogenic E.coli (UPEC)
E. coli
- Gram-negative
- Part of the commensal microbiota Pathogenic E. coli
- Virulent factors: adherence, colonization, invasion, cell surface molecules, secretion, transport, and siderophores
- Intestinal infection (IPEC)
- Extraintestinal pathogenic (ExPEC) - UPEC: uropathogenic E. coli
- NMEC: neonatal meningitis E. coli - SEPEC: septicemia E. coli
- MPEC: mammary pathogenic E. coli
Infection route
1) colonization of the vaginal and periurethral areas with uropathogens, such as uropathogenic Escherichia coli (UPEC), which usually reside in the gut, occurs.
2) these uropathogens migrate to the bladder
3) UPEC type 1 pili adhere to uroplakins on superficial umbrella cells, leading to bacterial internalization
4) UPEC multiply to form intracellular bacterial communities (IBCs)
5) efflux of UPEC from IBCs results in reinvasion of neighbouring cells and the formation of quiescent intracellular reservoirs in transitional cells, which can remain viable for months
-
Recurrent UTI
A recurrent urinary tract infection is defined as three episodes of a UTI in the previous 12 months or two episodes within the previous 6 months
Reinfection
Reinfection refers to an infection where the pathogen is eradicated by treatment, then the same or a different pathogen ascends the urinary tract to cause a new infection.
Persistence
Persistence means the pathogen that caused the UTI is not completely cleared from the bladder by treatment and after treatment returns to a level that once again causes symptoms of infection. This cycle of persistence can repeat indefinitely, feeling like a new infection each time.
Treatment options
- “Natural” treatments
- Cranberry juice/extract (proanthocyanidins→ antiadhesives for UPEC)
- Plant extracts (e.g. Uva-ursis)
- Mannose
- Probiotics
- NSAIDs (e.g. Ibuprofen)
- Antibiotics
- Vaccines
Microbiota
- The origin of the “urine is sterile” dogma dates to the mid-1800s: Louis Pasteur, Joseph Lister and William Roberts showed that a vial of urine in a sealed container did not turn cloudy, in contrast to a vial of urine exposed to air or with added
- results suggest that rUTI susceptibility is in part mediated through the gut–bladder axis, comprising gut dysbiosis and differential immune response to bacterial bladder colonization, manifesting in symptoms
- study suggest that dysbiosis of the bladder microbiome may show different colonization and different symptoms.
Probiotics
Lactobacillus spp
- Oral or vaginal suppositories
- Protect vaginal mucosa (UPEC reservoir)
- Effective lactobacilli for controlling UTI are L. rhamnosus GR-1 and L. reuteri B-54 and RC-14
NSAIDs
- ~50% can resolve infection with NSAIDs instead of AB
- Cox-2/PTGS2 upregulation upon infection
- Mediates inflammation in the bladder
- Link with chronic infection
Antibiotics
- Trimethoprim and sulfamethoxazole
- Fosfomycin
- Nitrofurantoin
- Cephalexin
- Ceftriaxone
Vaccines
- Uro-Vaxom®: 18 dif. strains of E. coli
- Uromune®: whole-cell inactivated bacteria (E. coli, K. pneumoniae, E. faecalis, and P. vulgaris)
- Strovac®: 10 strains of inactivated uropathogens: six of E. coli with different serotypes and one of K. pneumoniae, P. mirabilis, Morganella morganii and Enterococcus faecalis.
- More being developed …
Pathogenesis
Adhesines
- Fim
- Ucl
- Fml
- Pap
static conditions -> multivalent binding; moderate affinity
flow -> catch-bond; high affinity
Invasion and vacuole escape
- UPEC PldA promotes bacterial escape from fusiform vesicles in superficial BECs
- UPEC infection triggers upregulation of host PIT1 in superficial BECs
- PIT1 transports phosphate out of fusiform vesicles, resulting in UPEC pldA expression
- Silencing PIT1 prevents and reduces acute UPEC infection in mouse bladders
- host innate immunity to UPEC infection causes phosphate reduction in UPEC-containing vesicles
- UPEC senses this cue to express a phospholipase disrupting the vesicle membrane and escapes into the cytosol to form intracellular bacterial communities.
Biofilm formation
IBC resemble biofilm
- Different transcriptomic program
- Smaller coccoid bacteria
- Increased bladder fitness
- Antimicrobial tolerance
- Type I pili
- Curli fibres & Phosphoethanolamine cellulose
Toxins
HlyA -> cell death; immune modulation
CNF1 -> cytoskeleton rearrangements
sat -> vacuolation and tissue damage
Two component system
α- Hemolysin (HlyA)
- Pore forming toxin that perforates the outer membrane of host cells
- Activation of host inflammasome
- Regulated by CpxR-CpxA system
YdpA–YdpB and BtsS–BtsR system
- upregulate transporter genes in acute and chronic mouse models
QseB–QseC system
- regulate UPEC virulence factors in response to high levels of ferric iron
QseB–QseC and the PmrA–PmrB systems
- antimicrobial resistance - OrhK/OrhR system
- Resistence to ROS
Metal uptake
Iron uptake: siderophores (eg. Yersiniabactin and salmochelin)
- The UT is a iron-limiting environment
- Iron is necessary for a successful UTI
- higher expression than gastrointestinal isolates
- Host counteract: Production of lactoferrin and lipocalins
Research
Cell lines
- Immortalized cells
- Lack tissue complexity
- Only short-term infection
Small mammals
- Differences between human and animal physiology
- Do not mimic fully the human infection
Organoid-based model
- Contain stem cells and differentiated cells
- Primary non- transformed cells
- Exhibit key functions of the in vivo organ
- Patient-specific
Organoid-based model is a promising tool to study UTIs
- Our model mimic the epithelial compartment of the bladder urothelium
- Cell types (including umbrella cells)
- Differential bacteria replication
Host response
- Urine composition
- Metal sequestration
- Bacterial expulsion (TLR4)
- Exfoliation of cells
- Inflammation
- Neutrophils & macrophages - Adaptive immune response
Urine composition
Uromodulin protein→ saturates mannose-binding sites
- High osmolality and low pH
- Lactoferrin (iron sequestration)
- UPEC virulence factors are regulated by these cues
1) UPEC enters bladder
2) infection is initiated/sustained
3) intracellular bacteria haboring in fusiform vesicled are retained even after bladder voiding
4) once urine collects, bacteria reemerge and mutiply -> 2)
Bacterial expulsion (TLR4)
- Toll-like receptor 4
1) UPEC expelled into urinary lumen via FVs
2) escape FV into the cytosol and establish intracellular bacterial communities (IBCs); fluxing out of the cell to reinitate the infection cycle
3) directed to lysosome for degradation yet still escape by neutralizing lysosomal pH resulting in bacterial expulsion
OR
4) be recognized by autophagy pathway proteins via intracellular NOD-like receptors and enter autophagosomes which can cause recurrent UTIs
Exfoliation of infected umbrella cells
- HylA-toxin mediated
- Inflammation-mediated (neutrophils and macrophages)
Infection outcome depends on host response
- 50% of women resolve infection without AB treatment
- The innate immune response to female mice is characterized by robust cytokine expression and immune cell infiltration
- which is notably absent in male mice (bottom, transparent immune cells and missing cytokines) - both sexes have two subtypes of resident macrophages, however, whether they behave similarly in defense against infection is unknown
- both sexes mount a non-sterilizing adaptive immune response to infection, although whether this response is mediated by similar mechanisms in female and male mice is unclear