HUMAN URINARY TRACT INFECTIONS AND THE GALACTOSE DETERMINANT FOR E'COLI

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HUMAN URINARY TRACT INFECTIONS ANDTHE GALACTOSE
DETERMINANT FOR E.COLI
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Introduction

• UTIs are defined by the presence of micro
  organisms within the urinary tract that may be
  difficult to distinguish between contamination,
  colonisation or infection
• 150 million people per year become infected

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• Importance of Urinary Tract Infections is
  demonstrated by the fact that 20 of women
  between ages 20-65 suffer one attack per year
• Approximately 50 of women develop a UTI during
  their lives and there is a prevalence rate of 5
  per year of asymptomatic or covert bacteriuria in
  non-pregnant women between ages 21 and 65

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• 1-6 of general practitioner visits are for
  UTIs.
• Amongst working women days lost from work as a
  result of UTIs account for about one tenth those
  due to respiratory infections.

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Bacteriology

• Urinary tract is normally sterile due to the
  fact that bacteria moving upwards are regularly
  washed out by urination
• Normal flora found in the urethra consist of
  lactobacillus and staphylococcus to name a few

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• UTIs mainly contain gram negative aerobic
  organisms originating from the gut flora
• Proteus, other Enterobactericiae, S.
  saprophyticus, enterococci, group B Strep and
  Chlamydiae cause 20 of uncomplicated UTIs

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• In complicated UTIs E. coli cause 20 of
  infections,
• Pseudomonas and Serratia cause 80 of
  infections.

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Depending on the location of infecting bacteria,
distinct diseases will arise

• Urethritis- painful urination and burning
• Cloudiness in urine
• Blood in urine
• Micro organism counts
• 100,000/ml (traditional)
• 1000/ml of one type
• 100/ml of E.coli

• Cystitis- inflammation of the bladder, but known
  to patients as any UTI.
• Infection caused by bacterial infection mainly E.
  coli.
• Symptoms include painful, burning, urgent
  urination and WBC in urine.
• Women mainly get this because of the shorter
  urethra, which puts it closer to the anus where
  E.coli is found.

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• Pyelonephritis- acute infection of the kidneys
  caused by progressively untreated cystitis
• Symptoms include fever, loin pain, increase in
  WBC, and bacteraemia
• Can compromise kidney function and require IV
  antibiotics

• Chronic pyelonephritis- caused by chronic
  inflammation of renal and tubular tissue with
  scarring and shrinkage secondary interstitial
  fibrosis.

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Virulence

• Infection is usually an interruptive aberration
  of the balance
• In order to exert damage, bacteria either invade
  normally sterile compartments of the body where
  they multiply, or they produce toxins with
  general or highly specific effects

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Virulence factors include

• Toxins
• Factors for adherence on surfaces such as
  epithelia
• Degrading enzymes for maceration of tissue
• Factors promoting endocytosis or preventing
  phagocytosis
• Factors to overcome or survive mechanisms of the
  host defense or combinations of factors of the
  five groups

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UTIs may occur either because of the
pathogenicity of the organism, the susceptibility
of the host or a combination of both factors

• Structures that are involved in pathogenicity
  Include

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• Fimbriae- a proteinaceous hair like
  extensions from bacterial cells. These recognize
  specific receptors usually carbohydrates,
  glycolipids or glycoproteins and can be
  characterized by their ability to agglutinate
  RBCs

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• glycocalyx- a capsule or layer composed of
  polysaccharides and glycoproteins which are
  exterior to the cell wall. They mediate adhesion
  to epithelial cells, reduce adhesion to
  phagocytes and reduce penetration of antibiotics.
  They contain high components of sialic acid
  which prevent activation of complement and are
  poorly immunogenic.

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• outer membrane constituents- the
  lipopolysaccharides of the outer membrane are
  able to prevent complement activation and inhibit
  adhesion to phagocytes

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Adhesion

• Adhesion to cell surfaces is important for the
  normal flora as well and appears to be mediated
  by a variety of factors
• Non specific factors include electrostatic forces
  and hydrophobic interactions
• Specific factors include interactions usually
  found between bacterial protiens and cell
  carbohydrates (receptors)
• There is a correlation between the severity of
  infection and adherence

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E.coli

• UTI-causing E.coli need to be able to adhere to
  the urinary tract epithelium in order to prevent
  being washed out.
• E.coli expresses adherence factors to prevent
  being washed out.

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• The best receptors are those associate with the
  fimbriae or pili. They anchor to the cell
  envelope.)
• Strains of E.coli that express pili for adhesion
  on human uro-epithelia are known as uropathogenic
  E.coli (UPEC)

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• There are two types of pili that cause two
  different types of diseases. This is because the
  two types of pili each bind to specific receptors
  on the epithelia
• Type I accounts for cystitis and P pili account
  for pyelonephritis.

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Structure of Pili

• Pili are helical polymerization products of one
  peptide subunit
• Sometimes pili are bent or damaged, however they
  still serve their purpose of attaching the
  bacterium to the host cell
• Present researchers are looking for vaccines
  against or specific blockage of pilus-binding to
  host cells http//www.bumc.bu.edu/www/Busm/By/bull
  itt/newwebsite/Avg10-2.gif

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• P pili that bind the alpha-D-galactopryanosyl-(1-gt
  4)-beta-D-galactopyranoside or (Gala (1-gt4)Gal)
  moiety are present in the globoseries of
  glycolipids on cells lining the upper urinary
  tract
• UPEC isolates express pap-encoded adhesions

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Paper (

• Isolated and purified SGG (sialosyl galactosyl
  globoside) and DSGG (disialosyl galactosyl
  globoside) from the kidneys were assessed in
  vitro for binding of Pap-expressing E.coli
• In addition, possible mechanisms through which
  the selective expression of one or both of these
  molecules in the vaginal or urogential epithelium
  of nonsecretors might influence their risk of UTI
  was looked at.

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Secretor verses non-secretor

• Secretor is defined as a person who secretes
  their blood type antigens into body fluids and
  secretions like the saliva in your mouth, the
  mucus in your digestive tract and respiratory
  cavities, etc. Basically what this means is that
  a secretor puts their blood type into these body
  fluids. A Non-secretor on the other hand puts
  little to none of their blood type into these
  same fluids. As a general rule, in the U.S. about
  20 of the population are Non-secretors (with the
  remaining 80 being Secretors).

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• What they found was SGG and DSGG were expressed
  in the tissue of the kidneys and these compounds,
  purified from this source, bind cloned and
  wild-type UPEC isolates expressed pap-encoded
  adhesions.
• These strains represent three known classes of P
  fimbrial adhesins

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• Using PCR, they demonstrated that the binding of
  SGG and DSGG was by IA2(wild-type isolate
  expressing P fimbriae carrying a class II
  pap-encoded adhesion, as well as a cloned isolate
  PapG)
• Class I papG-encoded adhension and class III
  papG-encoded adhesion were also represented.
  http//iai.asm.org/cgi/content/full/66/8/3856

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• Demonstrating that SGG and DSGG are relevant
  bacterial binding moieties for UPEC isolates was
  done by expression of P fimbriae carrying all
  three members of the family of pap-encoded
  adhesion molecules.

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Biological implications

• Assessed the relative binding of these E.coli
  isolates expressing pap-encoded adhesion to the
  GSLs other than SGG and DSGG.
• These studies demonstrated relatively little
  difference between GSL binding to globoside and
  binding to Gb3 for those E.coli isolates
  expressing P fimbriae carrying pap-encoded
  adhesions of class I and II.
• .

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• Isolates expressing P fimbriae carrying class III
  pap-encoded adhesion demonstrated a preference
  for binding to extended GSLs.
• What was found was E.coli isolates bound more
  strongly to SGG rather than other GSLs like DSGG.
  This demonstrates that, at least in the
  urogenital epithelia of nonsecretors, SGG may be
  a preferred ligand for UPEC isolates.

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Conclusion

• These studies have demonstrated the presence of
  SGG and DSGG in the human kidneys and have
  defined SGG as a GSL to which was of three
  classes of pap-encoded adhesion binds avidly.
• Biological significance of these findings
  requires further study, but since E.coli isolates
  bearing P fimbrial adhesions are very strongly
  associated with renal infections, SGG may well
  play a role in pathogenesis of acute
  pyelonephritis.

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• It has been reported that an association between
  nonsecretor status and an increased likelihood of
  clinically defined inflammatory responses
  suggestive of pyelonephritis, such as fever,
  leukocytosis, and elevated C-reactive protein.
• Currently studies of GSL composition of normal
  human bladder epithelium are being done

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• Data from these studies will increase our
  knowledge of bladder glycobiology and may
  eventually lead to novel preventive strategies
  for UTI through the use of carbohydrate-based
  compounds that competitively inhibit bacterial
  attachment.