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MIIM30011 Bacteriology > Bacterial Pathogenesis > Flashcards

Bacterial Pathogenesis Flashcards

1
Q

What is the main entry point for pathogens?

A

Mucosal Layers

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2
Q

What must pathogens overcome to colonise a host? What is required?

A
  • Overcome physical barriers, innate immunity
  • Establish self in host
  • Outcompete normal flora
  • Requires adherence
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3
Q

What can mediate adhesion?

A

o Pili/fimbriae
o Afimbrial adhesins
o Capsules

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4
Q

What allows bacteria to adhere?

A
  • Depends on bacterial factors, host receptor availability
  • Common host structure and accessible is glycocalyx
  • Bacteria need to pass mucin layer (goblet cells produce)
  • Target areas with reduced mucous (M cells e.g.)
  • Adhesins target common sugar structures (vary enough for some specificity)
  • Can target common protein receptors (β1 integrin)
  • Mimic natural ligand for receptor
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5
Q

What are fimbrial and afimbrial adhesins?

A

Fimbrial Adhesins
• Complex surface structures made up of repeating protein subunits
Afimbrial Adhesins
• Outer membrane proteins (G-)

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6
Q

What are the features of gram negative Type I/Pap fimbriae?

A

Type I/Pap pili
• Assembly requires usher/chaperone system
• Pilus = fibre of six strutrual proteins
• Thick rod, thin tip
• UPEC

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7
Q

What does type I pili bind?

A

mannose (glycoporteins)

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8
Q

What does Pap pili bind?

A

bind Gal α (1-4)Gal (glycolipids)

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9
Q

How is the biogenesis of type I and Pap pili regulated?

A
  • Switch mechanism for regulation: all on/off, all elements needed to form pilus
  • Pap gene cluster (regulation, major pilus subunit, rod terminator, outer membrane usher, periplasmic chaperone, adaptor/initiator as part of tip/adhesion, Gal α (1-4) binding adhesin)
  • Fim gene cluster (same with mannose binding adhesin)
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10
Q

What occurs during pili biogenesis?

A
  1. Subunits made in cytoplasm, transported to periplasm
  2. Pilin subunit must bind chaperone (or degraded)
  3. Ushered to outer membrane
  4. Subunits connected on cell surface
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11
Q

What are pilicides?

A

• Antibiotics, prevent pili construction (interrupt ushers, polygenesis on surface)

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12
Q

What are the features of type IV pili?

A
  • Different biogenesis (no usher, chaperone)
  • Polar location
  • Form bundles
  • Inter bacterial interactions, mucosal adherence, biofilms
  • Conserved features
  • Twitching motility
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13
Q

What type of pili does EPEC have? What is it essential for?

A

Type IV

For adherence/colonisation

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14
Q

What are the features of Bordetella pertussis?

A

o Whooping cough
o Pertussis toxin
o Fimbrial and afimbrial adhesins
o Acellular vaccine less powerful than whole cell (less adjuvants to make response last)
o Vaccine with inactivated toxin, afimbrial adhesins

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15
Q

What type of adhesins does Bordetella pertussis have?

A

o Fimbrial and afimbrial adhesins

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16
Q

What is FHA?

A

• Filamentous Haemagglutinin (FHA part of acellular vaccine for Brodetella pertussis)
o 250 kDa
o Adherence
o Binding domains (central RGD motif: mimics β1 integrin), Mimics extracellular matrix protein binding to integrin

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17
Q

What are the features of adhesins in Streptococcus and Staphylococcus?

A

o Bind extracellur matrix proteins
o Recognise ECM proteins: tissue tropism
o Fibronectin-binding proteins with similar organisation and several repeat regions

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18
Q

What is twitching motility? What organism has it?

A

o Pseudomonas aeruginosa
o Bacterial crawling
o Pili retract (Type IV)

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19
Q

What is LEE?

A
  • Pathogencity island
  • In all A/E pathogens, has all A/E genes
  • Genes for T3SS
  • Proteins for virulence:
  • Intimin
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20
Q

What is intimin?

A

o Outer membrane protein

o Afimbrial adhesin

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21
Q

What is TIR?

A

o Translocated intimin receptor
o Secreted by T3SS, put in host membrane
o Phosphorylated by host cell kinases
o Binds intimin

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22
Q

What are the functions of EspA, EspB and EspD?

A

• EspA, EspB, EspD (secreted proteins)
o EspA = pilus like surface organelle (hollow tube)
o EspB and EspD in host cell membrane, form pore

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23
Q

How do A/E lesions change cytoskeletal structure?

A
  • Intimate attachment causes cytoskeletal change
  • A/E pedestal body has lots of structural cytoskeletal proteins (F-actin, talin, ezrin, vilin)
  • Host proteins for recruitment: Arp2/3, N-WASP
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24
Q

What is the structure of actin? At which end does polymerisation occur?

A

o F-actin: polymerised monomers, two twisted linear protofilaments, dynamic
o Polymerisaition at + end (barbed)
o Depolymerisation at – end (pointed)
o Arp2/3 nucleates actin to begin filament

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25
Q

What does N-WASP do?

A

o Bind Arp 2/3 complex, induce actin polymerisation

o Tip of A/E lesion

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26
Q

What is the process that leads to actin recruitment?

A

Tir Has Tyr residue which is phosphorylated → recognised by Nick → binds N-WASP → N-WASP binds ARP 2/3 → Actin recruitment

  • N + C terminals of Tir interact with cytoskeletal components directly
  • Middle region of Tir binds intimin
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27
Q

How do the EPEC and EHEC actin pathways differ?

A
  • EPEC uses NICK (host protein) to recruit pro/N-WASP
  • EHEC: Tir not phosphorylates, use bacterial protein (TccP) and recruit GBD/N-WASP
  • Both lead to actin recruitment
28
Q

How does EPEC avoid the innate immune response?

A
  • Inhibits production of IL-8, prevent neutrophils
  • T3SS dependent (need secreted proteins)
  • NF-KB controls IL-8 production
29
Q

What is involved in the NF-KB signalling pathway?

A
  • TF’s p65 and p50 in cytoplasm sequestered by IkB proteins (mask nuclear localisation sequence)
  • External signal (TNF, IL-1, PAMPs) bind receptors on cell surface
  • Adapter proteins recruited
  • Downstream mediators TAB2/3 and TAK activated
  • IKK (inhibitor of NF-KB kinase) complex phosphorylated and activated
  • Ikk phosphorylates IKB
  • IKB ubiquitinated and degraded by proteasome
  • NF-KB proteins translocate to nucleus, bind DNA NF-KB consensus sites, transcription of IL-8
30
Q

How does luciferase indicate NF-KB activation?

A
  • More luciferase activity = more NF-KB activation

* Lack of activity suggests protein inhibits the pathway

31
Q

What is the action of NleE?

A
  • Cysteine methyltransferase (enzyme)

* Modifies TAB2/3

32
Q

What is the action of NleC?

A
  • Zinc metalloprotease (enzyme)

* Cleaves NF-KB p65 and p50 heterodimer

33
Q

What are the two invasion mechanisms?

A

Trigger and Zipper

34
Q

What is involved in the zipper mechanism?

A

• Exploit host cell adhesion pathway
• Cause receptor immobilisation and clustering
• High affinity binding bacteria ligand to host cell receptor
• RME
o Uptake mediated by host cell
o In endosome or escape endosome
• Tricks the cell

35
Q

What is involved in the trigger mechanism?

A

• Cell ruffling, growth factors and hormones
• Short contact, large scale actin polymerisation, ruffles form on host cell surface
• Ruffles fold over bacteria, engulfed
• Macropinocytosis
o Membrane ruffles trap membrane bound pockets of extracellular medium
o Mediate dby host cell
o In endosome or escape endosome

36
Q

What are the features of Listeria monocytogenes?

A
  • G+
  • Food borne
  • CNS, maternofetal infections, abortion
  • Invasive (Zipper)
37
Q

How does listeria invade? Which mechanism does it use?

A

• Internalised due to actin cytoskeleton
• Internalin protein (InIA) locks into host cell receptor (e-cadherin)
• α and β catenins have direct link to cytoskeleton
• Receptors cluster, invasion
Zipper mechanism

38
Q

What is the receptor of Internalin/InIA ?

A

E-cadherin

39
Q

What are the features of shigella flexneri?

A
  • G-
  • Water, person-person
  • Bacillary dysentery
  • Invasive (trigger)
40
Q

What did shigella evolve from? How does it differ to it’s relative?

A
  • From e.coli
  • Gene loss (flagella, anti-virulence genes) and acquisition (mobile virulence plasmid)
  • LNF and non-motile (unlike e.coli)
41
Q

What does shigella virulence plasmid encode? Which proteins are involved?

A
  • Encodes T3SS

* Secreted proteins (IpaB, IpaC, IpaD) form invasion complex

42
Q

What allows salmonella to invade?

A
  • Salmonella pathogenicity island 1 (SPI-1)
  • Encodes T3SS, Sip proteins, Ipa
  • Membrane ruffling
  • T3SS homologues of Shigella
  • Same function as Shigella proteins, target cytoskeleton and host GTPase
43
Q

Where does salmonella replicate? How?

A

Salmonella’s Second T3SS
• Allows replication in endosome
• SPI-2
• Ssa effector proteins

44
Q

How do SPI-1 and SPI-2 differ?

A 
SPI-1
•	Cytoskeletal rearrangements
•	Diarrhoea
•	Inflammation
•	Invasion
SPI-2
•	Avoidance of anti0microbial activities
•	Modification of vacuole trafficking
•	Intracellular survival, replication
45
Q

What are the main differences between the trigger and zipper mechanisms?

A 
Trigger	
Passive	 
Bacteria in cell vacuole	
One protein	
Listeria (Internalin)  
Ruffle
Active
Bacteria in cell vacuole 
Require several proteins
Shigella (Ipas), Salmonella (Sips)
46
Q

What are the benefits for pathogens to live intracellular?

A
  • No access by complement or antibodies
  • No need for adherence
  • Nutrient access
  • Intracellular parasite
47
Q

What types of intracellular niches are there?

A
  • Intralysosome (low pH, hydrolytic, rare)
  • Intravacuolar (neutral pH)
  • Cytosolic (actin based motility)
48
Q

What kinds of intracellular niche do Shigella and Listeria use? How?

A 
Cytosolic
•	Invade cells
•	Escape vacuole and proliferate 
•	Recruit host cytoskeleton
•	Actin tail formation, propel to cells
49
Q

What is the process of cell to cell spread by Shigella?

A
  • Invade through ruffles via T3SS, Ipa
  • Phagocytosis → phagolysosome lysis → proliferation → actin based locomotion → cell to cell spread (double membrane dissolved)
  • Invade M cells, engulfed by macrophages, apoptosis, release pro inflammatory cytokines, recruit neutrophils
  • Can only invade enterocytes from basolateral surface
50
Q

What does IcsA do?

A

autotransporter, expressed at one end of bacterium ,polar, interacts directly with cytoskeletal machinery

51
Q

What are the interaction domains of N-WASP?

A

CDC42 (activates N-WASP), Nick, Actin, Arp2/3

52
Q

What is the role of ActA? Which bacteria express it?

A
  • ActA at pole
  • ActA binds VASP (not N-WASP) for actin polymerisation and Arp2/3

Listeria

53
Q

How does listeria spread from cell to cell?

A
  1. Bacteria adhere tightly, RME
  2. Internalised in vacuole
  3. Lyse vacuole
  4. Recruit actin all around bacteria
  5. Then actin mobilised to pole, actin tail allows movement through cytoplasm
54
Q

Why can it be beneficial to live in macrophages?

A
  • Professional phagocytes, easy to get in
  • Long lived cells
  • Migrate through body
  • Although they are APCs and can kill
55
Q

What occurs during phagocytosis?

A
  • Facilitated by opsonisation

* Killing after phagolysosome fusion, activation of oxygen independent and dependent pathway s

56
Q

What is oxygen dependent killing?

A

o Respiratory burst (NADPH oxidase)

o Reactive oxygen speices (ROS) O2, H202, OCl

57
Q

What is oxygen independent killing?

A 
o	Low pH (lysosome)
o	Proteolytic enzymes
o	Lysozyme
o	Lactoferrin
o	Membrane damaging proteins
58
Q

What is the process of phagosome maturation?

A
  • Phagosome
  • Fuse with early endosome
  • Fuse with late endosome
  • Fuse with lysosome
59
Q

What is coxiella burnetti? Why is it weird?

A
  • Vacuole has markers for late endosomal lysosomal compartments (LAMP1, LAMP2, cathepsin D)- looks like lysosome
  • Optimal growth at pH < 5
  • Obligate intracellular parasite
  • Related to legionella
  • Type IV secretion system (Dot/Icm)
60
Q

What are the features of Salmonella in terms of its intracellular niche?

A

• Tubular phagosome existence
• SCV: Salmonella containing vacuole
o Produce Sifs (salmonella induced filaments)
• Late endosomal, acidic, LAMP 1 marker present
• Prevents fusion of phagolysosome
• Phagosome has no CI-MPR (receptor) and lysosomal enzymes so is not a phagolysosome
SPI
• SPI-1 turned on for invasion, turned off after invasion and SPI-2 turned on

61
Q

How does SCV mature?

A
  • SPI-2 effectors responsible
  • Invasion (SPI-1)
  • Early SCV: EEA1, Rab
  • Intermediate SCV: Rab
  • Late SCV: LAMPs, vATPase, Rab7
  • Deviate from normal pathway to form SCV with protruding Sifs
62
Q

What is SifA?

A
  • Causes Sif formation and keeps integrity of SCV
  • Bacteria escape vacuole if it’s deleted
  • Host cell targets are Rab7 and SKIP- kinesin binding protein to recruit microtubule motors
63
Q

How does SPI-2 help salmonella form an intravacuolar niche?

A

• SPI-2 for inhibition of respiratory burst (prevent NADPH oxidase assembly on phagolysosomal membrane)

64
Q

How does legionella form an intravacuolar niche?

What are the features of LCV?

A

LCVs- legionella containing vacuoles
• Phagosomes don’t acidify and fuse lysosomes
• ER like
• Arf1, Rab1, Sec22b (t-SNARE), ER proteins (calnexin, sec61), ribosomes
• No association with markers of endocytic pathway
Dot/icm genes

65
Q

Why are dot/icm genes important?

A
  • Type IV SS- deliver virulence proteins
  • Mutants can’t prevent lysosome fusion, pathogen dies
  • Proteins have a lot of functional redundancy
  • Proteins cooperative or antagonistic (e.g. target Rab1 GTPase)
  • Some target Arf1 GTPase

MIIM30011 Bacteriology (5 decks)

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