BIOSCI 349 > Pathogenicity > Flashcards

Pathogenicity Flashcards

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1
Q

Diseases caused by H.pylori

A

Peptic Ulcers
1. Duodenal ulcers
2. Gastric (stomach) ulcers

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2
Q

H.pylori

A
  1. Gram negative spiral shaped rod
  2. Microaerophillic
  3. Slow(ish) to grow: 3-5 days for primary culture from gastric biopsy
  4. Translucent white-grey colonies
  5. Urease +, Catalase +
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3
Q

Epidemiology of H.pylori infection

A
  1. Life long
  2. Most common chronic bacterial infection
  3. ~50% of the worlds population infected
  4. Generally contracted in early childhood (<10 years old)
  5. Largely restricted to humans & non-human primates
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4
Q

Risk factor for H.pylori

A

Over-crowded living conditions
Poor hygiene
Low socioeconomic status

High salt diet

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5
Q

Transmission of H.pylori

A

Hard to catch
Does not survive long outside the host
Requires close contact
Exact route of transmission unknown

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6
Q

Diagnosis of infection: invasive

A

Endoscopy
* visual inspection of tissue

Collection of tissue
* Culture: 1 week culture period on selective medium
* Biochemical testing: assay for urease production
* Histology: haematoxylin & eosi (H&E) for pathology, silver stain (e.g Warthin-Starry) to detect H.pylori bacteria

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7
Q

Diagnosis of infection: non-invasive

A

Urease breath test
* Highly accurate if used appropriately
* Based on radioactively labelled urea (13C or 14C)

ELISA based tests (considered less reliable)
* Serological tests - can only tell that you have developed a response to infection, not whether you are currently infected
* Stool antigen tests - most common nowadays
* * Monoclonal antibody-based
* * High diagnostic accuracy

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8
Q

Triple Treatment

A
  • 2 weeks on Amoxicillin/Carithromycin/Proton pump (reduce secretion of acid)
  • > 80% effective
  • Recurrence of infection after successful treatment is unusual (<1%), on top of that very unlikely to be exposed again
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9
Q

Adaptations that facilitate gastric colonisation: motility

A

Highly motile drills its way through the viscous gastric mucus, aided by:
* Spiral shape
* Polar flagella
* Mucinase (disrupts oligomeric structure of mucin)
* Non-motile mutants can’t establish infection in animal models
* H.pylori uses the pH gradient in the stomach for spatial orientation
* Occupy a niche ~ 0-25um above the tissue surface which is close to neutral in pH
* Require motility & spatial orientation to maintain position/ not get washed away by gastric mucus

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10
Q

Adaptations that facilitate gastric colonisation: urease

A
  • Urease enzyme is essential for survival at low pH, neutralises acid
  • Rapidly hydrolyses urea to CO2 and ammonia, which neutralises acid
  • H.pylori urease compromises ~ 5% of total cell protein
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11
Q

Model of urease synthase

A

Multimeric protein
Needs nickel to be fully functional

Urease-specific pore in the inner membrane
* opens at low pH
* closes at high pH

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12
Q

Immune evasion: LPS

A

H.pylori LPS is different vs other gram negative bacteria
* Lipid A component has an unusual acylation and phosphorlyation pattern
* 1000-fold less pyrogenic and mitogenic
* Simulates lower quantatites of pro-inflammatory cytokines IL-1 and TNF in in-vitro assays

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13
Q

Immune evasion: Molecular Mimcry

A

“We now report that LPS of H.pylori express Lewis y, Lewis x, and H type 1 blood group structures similar to those commonly occuring in gastric mucosa”

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14
Q

Immune evasion: flagellin

A
  • H.pylori flagella do not trigger the host flagellin receptor TLR5
  • 1000-fold less potent that Salmonella typhimurium flagellin at eliciting TLR5 mediated IL-8 production
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15
Q

Immune evasion: Heterogeneity

A

Mechanism to maintain diversity
* Lack of mismatch DNA repair
* Repititive DNA for intra-genomic recombination (high frequency deletion and duplication) to change phenotypes
* Natural competence for DNA uptake
* * Many start with one strain and change over time
* Not uncommon to be infected with more than one strain - provides an opportunity to obtain new genetic sequences & recombination events which occur commonly
This plasticity and adaptability of H.pylori enables:
* Ready adaptation to changing conditions within the host stomach
* Allows rapid adaptation to the gastric environment of new hosts, will change environment of stomach, can increase or decrease pH

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16
Q

H.pylori - Virulence factors: Adhesins

A
  • Resist removal by host
  • Close interaction with gastric epithelium/effective delivery of cytotoxins
  • Cell surface as a site of replication
  • ~20% of H.pylori in the stomach are found adhered to the surfaces of mucus epitheliated cells
  • 4% of the Hp genome (>30 genes): predicted to encode for adhesins
  • Redundancy: H.pylori has many adheisns, none of which are essential
  • Variability: between & within strains over time
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17
Q

Virulence factors: BabA/SabA

A

Colonisation - H.pylori expresses BabA (Blood group antigen-binding adhesin)
Basal state - Gastric epithelial cells express, Lewis B blood group antigen

Chronic infection - H.pylori expresses SabA (Sialic acid-binding adhesin) - associated with development of gastric cancer
Inflamed gastric epithelium: decreased lewis B, decreased Lewis X, sLex also on neutrophils

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18
Q

H.pylori - Virulence factors: VacA

A

Vacuolating Cytotoxin A, a multifunctional toxin
* 88 kDa protein with aa sequence with little homology to other bacterial or eukaryotic proteins - unique to H.pylori
* Universally expressed in H.pylori but only ~50% of strains express functional VacA
* Active form of VacA associated with increased severity of disease
* Gene structure - see diagram in lecture slides

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19
Q

Virulence factors: cag PAI

A

Pathogenicity island (PAI)
* characterized by different nucleotide composition to host bacterial genome
* flanked by transposable elements
* usually acquired by horizontal transfer

Cag = cytotoxin associated gene A
* PAI has ~30 genes encoding for Type IV secretion system + CagA

Increased transmission
Stimulates pro-inflammatory cytokines (IL-8)
Shifts H.pylori from commensal to pathogen, strongly associated with the development of gastric cancer

Delivery of: Cytotoxin-associated gene A (CagA), 121-145kDa immunodominant protein, peptidogylcan

Flow chart see lecture slides

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20
Q

Gonorrhoea - NZ specific information

A
  • Notifiable since January 2017
  • ~150 cases/100,000
  • Peak incidence 15-24 year olds
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21
Q

Long term conseqeunces of gonorrhea

A

Can often by asymptomatic,
leading to infertility, ectopic pregnancy, increased HIV risk (due to inflammation of gastric mucosa)

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22
Q

Neisseria gonorrhea: general info

A

Gram negative diplococcus
Variably piliated
Located extracellularly or intracellulary
Fasitidious to culture - 48hrs to get visible colonies
Microaerophillic

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23
Q

Neisseria gonorrhea: Laboratory testing - traditional method

A

Urine or swab -> transferred to culture medium, CO2 -> Checked for growth (24-48hrs) -> Gram stain

Process quite time consuming

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24
Q

Neisseria gonorrhea: Laboratory testing - new method

A
  • Urine or swab
  • Nucleic acid amplification testing (NAATs)
  • Advantages
  • *Rapid
  • *Specimens can be stored
    • Technically straight forward
  • Disadvantages
  • *No strain types
  • *No antimicrobial resistance profiling
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25
Neisseria gonorrhea: Standard Treatment - Antibiotics
Dual therapy: injectable cephalosporin cefriaxone + oral azithromycin Prior infection does not necessarily prevent re-infection/immunity to infection very slow to develop
26
Neisseria: General information
Only 2 pathogenic species Naturally competent for DNA transformation Capable of conjugation Human DNA fragment found in Ng
27
Neisseria gonorrhea: Transmission and Asymptomatic
* Transmitted during vaginal, oral and anal sex * Can be passed to baby during childbirth * >50% women asymptomatic * >5% men asymptomatic
28
Neisseria gonorrhea: Symptoms
* Pain and inflammation/burning during urination * If untreated can lead to system disseminiation Skin pustules Septic Arthritis Meningitis Endocarditis Pelvic inflammtory disease Infertility Septic Abortion
29
Neisseria gonorrhea: Mechanism of Infection
See lecture slides
30
Neisseria gonorrhea: Adherence - Type IV pilli
* Attachment to host epithelial cells * Enable twitching motility * Undergo phase/antigenic variation * Uptake of DNA
31
Neisseria gonorrhea: Attachment - Opacity A (OpA) protein
Initiates cellular invasion: binds to CD66 found on epithelial cells and neutrophils * Most abundant adhesin * Multiple variants * Many strains have >1 variant * Undergoes phase & antigenic variation
32
Neisseria gonorrhea: Internalisation/Engulfment: LOS & Sialylation
LOS * Major component of cell wall * Lipid A, no O antigens * Variable composition * Mimics host glycosphingolipids - so not recognised by host Sialyation * LOS can become sialylated (coating itself in host sugars) * Gonocci cannt synthesise sialic acids * BUT can acquire from host fluids * Evade host immune response * *Inhibits opsonisation-mediated phagocytosis * *Prevents detection/killing of bacteria by complement cascade
33
Neisseria gonorrhea: Transcytosis - IgA protease
Transcytosis * Cleaves LAMP1 (Lysosome associated membrane protein) * Lysosome modification > subsequent bacterial survival * IgA protease -/- strains cannot transcytose - prevents maturation of lysosome and therefore prevents acidification * IgA cleavage : cleaves human IgA1
34
Neisseria gonorrhea: survival in neutrophils
OpA: required for entry into neutrophils IgA protease: facilitates survival in lysosomes Porin: allow transport of ions & nutrients across the cell membrane. Neutrophils become vector for infection
35
Neisseria gonorrhea: Porin - immuno-dominant antigen
* ~60% of total protein * Highly variable: * *basis for serological typing of N.gonorrhoea * Two major classes: * *Por1A: more serious disease * *Por1B: uncomplicated mucosal infections * Role in adherence to host cells
36
Neisseria gonorrhea: Porin - a multifunctional virulence factor
See lecture slides
37
Neisseria gonorrhea: Porin - blocks activation of complement pathways
See lecture slides
38
Neisseria gonorrhea: Enter blood stream
* Gonorrhoea infection can become systemic * Sialylation of LOS confers serum resistance -> bacterial survival * *Inhibits opsonisation-mediated phagocytosis * * Prevents detection of bacteria by complement
39
Neisseria gonorrhea: a pro-inflammatory infection
Attachment (Opa-CD66) Contact with epithelium (type IV pili) Engulfment/internalisation (LOS) Transcytosis to basolateral side of epithelium (IgA protease -> cleaves LAMP1) Enter bloodstream serum resistant (LOS) Survival residence in Neutrophils (OpA, porins, IgA protease) - Facilitates transmission
40
Neisseria gonorrhea: Antimicrobial resistance
Sulfonamides Penicillin Tetracycline Fluoroquinolones Cefixime
41
Neisseria gonorrhea: Mechanism of antimicrobibal resistance
Multiple Transferable Resistance (Mtr) Efflux Pump: Expels toxic materials, including antibiotics PorB: some variants associated with increased resistance PBP2: Mutations to pen2 gene, prevent antibiotic binding
42
Neisseria gonorrhea: Why don't we have a vaccine?
"A signature property of the gonococcus is the ability to modulate their surface antigenic make up with remarkable speed" = basis of success as a human pathogen Constant surface modulation Point mutations
43
Neisseria gonorrhea: Vaccine used for a period
MeNZB vaccine: made using membrane vesicles. High cost of production.
44
Streptococcus pyogenes: General information
* Gram positive, thick peptidoglycan layer * B-hemolytic, break down red blood cells when grown in blood agar * Group A, Lancefield classification based on cell wall carbohydrate * Forms chains that resemble a 'string of pearls' when viewed under the microscope
45
GAS: which strains are associated with disease?
High encapsulated strains
46
GAS: virulence
See diagram in lecture slides
47
GAS: general disease info
* Obligate human pathogen * Colonizes the throat or skin * Causes a broad spectrum of disease
48
GAS: Diagnosis
* Bacterial swab, and labaratory culture remain gold standard, results take 48-72hrs * Rapid tests are now available but are less commonly used. ... high false positive?
49
GAS: Transmission
1. Human to human by direct contact * Droplet spread from pharyngeal colonisation (sneezing, coughing) * Touching infected skin 2. Contaminated fomites * Biofilm formation may enhance survival outside the host Rarely food source Household crowding facilitates transmission
50
GAS: Carriage
The GAS carriage is poorly understood * GAS can be carried in a benign state in the pharynx * Carriage rates estimated to be as high as 15% in children * Carriage rates are lower in adults, less than 5% Carriage results in positive throat swab * Antibiotic treatment can be prescribed for treatmnet of viral sore throat with 'co-incidental carriage' * GAS carriers maybe resistant to antibiotic therapy, throat swab after penicillin treatment is still positive * UNKNOWN if GAS carriage can lead to post-infectious immune sequel (ARF and APSGN)
51
GAS: Penicillin
GAS is susceptible to penicillin BUT controlling disease in high burden area remains challenging. 1. Not realising they need treatment 2. Barriers to accessibility 3. Not having full antibiotic course 4. Antibiotic treatment fails in severe infections
52
GAS: M protein - general information
* Encoded by the emm gene * Has a hypervariable N-terminus which provides the basis for emm typing * Comprised of a series of repeated regions * Conservation between GAS strains increase as you move down the protein * C-repeat and D-repeat are highly conserved * Extends from cell surface as coiled-coil (dimer) * Repeat regions vary depending of emm type * Multifunctional protein - roles in adhesion by binding fibronectin in ECM, assist in immune evasion by binding fibrinogen, factor H and immunoglobulin
53
GAS: Emm-typing
* Developed by the CDC in the USA * Relies upon the use of the two highly conserved primers to amplify a large portion of the emm-gene * The hypervariable sequence lies adjacent to one of the amplifying primer sequences, allowing for direct sequencing
54
GAS: emm type distribution
* emm types differ in space (geographical variation) * Globally, emm1 is the most common emm-type in resource rich setting * Diversity of emm-type is greater in resource poor setting * No single dominating strain-type is associated with disease in LMIC * emm types differ in type (temporal variation)
55
GAS: Emm-pattern type
Three main pattern types, A-C, D and E
56
GAS: Emm-pattern type - tissue tropism marker
A-C pharyngeal strains dominate in temporate climates D pattern 'skin' isolates dominate in warm tropical climates E = throat or skin
57
GAS: WGS
* >200 emm-types, but this doesn't capture all the diversity in GAS * Strains of the same emm-type can have different phenotype driven by differences in other important virulence factors * Emm81 outbreak in NZ aged care in winter, 2014 WGS proved useful. * WGS not used a lot due to genome being so large and large cost
58
GAS: ARF symptoms
Elevated antibody titers to GAS antigens
59
GAS: ARF symptoms
Elevated antibody titers to GAS antigens
60
GAS: Pathogenesis
Poorly understood - see diagram in lecture slides
61
GAS: Pathogenesis
Poorly understood - see diagram in lecture slides
62
GAS: ARF Autoimmunity Hypothesis I
* Mimicry between M protein and human proteins found in heart tissue (myosin, collagen) - but myosin is intracellular so antibodies cannot access * Laboratory studies only, clinical data are lacking * Still a concern for M-protein based vaccine.
63
GAS: ARF Autoimmunity Hypothesis 2
Streptococcal infection disrupts ECM which exposes collagen CD3 domains that normally isn't seen, cryptic epitopes. Immune system develops collagen antibodies (not cross reactive with M-proteins) Damage to overlying epithelium. Endothealialitis heals ubiquitously, with no residual damage; only heart valves heal with scarring.
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