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I&I year 3 > Bacterial pathogenesis and immune evasion > Flashcards

Bacterial pathogenesis and immune evasion Flashcards

1
Q

commensalism

A

a relationship that is beneficial to the bacteria but does not help or harm the host.

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2
Q

opportunistic pathogen

A

an infectious microorganism that is normally a commensal or does not harm its host but can cause disease when the host’s resistance is low

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3
Q

balanced pathogenicity - what is it meant by this term?

A

balanced pathogenicity is having a balance between microbe and host - based on the properties of both

e. g. microbe - adhesions, toxins, capsule, etc.
e. g. host - natural barriers, defensive cells, complement

Genetics can also tip the balance either way

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4
Q

name some general concepts of Bacterial Pathogenicity

A

Host defences and susceptibilities

  • innate/adaptive immunity (also antimicrobial peptides, turnover, iron binding proteins)
  • age
  • genetics

Genetic and Molecular Basis for Virulence

  • genes (chromosomes, plasmids)
  • bacteriophages, mobile genetic elements

Host-mediated Pathogenesis
-immunopathology – e.g. TB

Intracellular Growth
rickettsia, mycoplasm, chlamydia, TB, salmonella

e.g. if one is under the age of 1 then you have a very immature immune system that doesn’t respond to bacterial virulence factors very well

What’s unique that about that bacterial pathogen that causes them to cause that disease, what genes in that organism?

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5
Q

define immunopathology

A

E.g. in TB, granuloma formation

The host damage that occurs with TB infection is purely driven by our own immune response or (immunopathology) the organism cannot be killed by our innate or adaptive immune system so get granulomatous inflammation chronically

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6
Q

Virulence factors - 3 main roles

A
  1. Promote colonisation and adhesion
  2. Evade host defences
  3. Promote tissue damage
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7
Q

Why do we need virulence factors?

A

Bacteria need to be able to attach to the host and grow divide to cause disease

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8
Q

Examples of virulence factors

A
  1. Adherence factors, which colonise mucosal sites via pili
  2. Invasion factors, surface components that damage the tissue structure they adhere to
  3. Capsules, which prevent: antibodies binding, complement, phagocytosis and opsonisation
  4. Polysaccharides - protect from opsonisation and phagocytosis.
  5. Endotoxins - proteins that have an inhibitory effect on metabolic activity within host, damaging nerves/enterocytes/ciliated lung epithelial cells. Also lipopolysaccharides (g -ve) and lipteichoic acids (g +ve), cause fever, inflammation, lethal shock
  6. Exotoxins - produce toxins/enzymes, e.g. cytotoxins, neurotoxins
  7. Siderophores - proteins released by bacteria that bind to iron and take it back to bacteria, they need it for growth. iron-binding factors to compete with the host for iron
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9
Q

Types of Infection

A
  1. Local
    surface infection; wound
    skin or URT, but haven’t penetrated any deep tissue or gut infection such as cholera release toxins that cause disease without penetration
  2. Invasive
    penetrate barriers spread
    drive a specific response normally innate inflammatory – this means it’s made it into tissue and circulation
  3. Systemic
    via blood to other sites
    the damage that the immune response does to the host to contain the infection
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10
Q

Host defences - name some

A

Innate and adaptive immunity

Natural barriers - skin, gut, lungs, eyes, GU tract

Non-specific:
physical conditions (dry, acidic), sloughing, microflora, lysozyme,
toxic lipids, lactoferrin, lactoperoxidases, tight junctions, bile, mucin,
ciliated epithelia, bile, cryptdins, phagocytes, intraepithelial lymphocytes

Adaptive:
MALT, SALT, GALT, secretory IgA

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11
Q

Defences of tissue and blood

A

Usually involves tissue damage and controlled by feedback mechanisms

non-specific:
transferrin, complement, acute phase proteins (released by liver)
phagocytes- monocytes and macrophages, PMN’s -neutrophils

adaptive:
antibodies
macrophage activation
T cells

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12
Q

Stages of Infection

A
  1. Acquisition
  2. Colonisation – adherence
  3. Penetration – break down the barrier
  4. Multiplication and Spread –create a niche where it can get nutrients
  5. Immune avoidance
  6. Damage
  7. Transmission
  8. Resolution

NB - Not all microbes need all stages.

e.g. cholera does not need to worry about immune evasion, as it sits on the surface of the gut, only thing that is going to clear it is secretory IgA, but by the time there is enough IgA then it has already produced its toxin, caused watery diarrhoea, multiplied to infect a new individual

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13
Q

Mechanisms of microbial responses to immunity

A

Extracellular (eg pneumolysin, superantigens)
Capsule (inhibition C3 and Ig deposition, phagocytosis)
Surface structures (eg protein A, M protein, LPS)
Direct secretion into cells (eg type 3 secretion systems)

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14
Q

PAMPs and PRRs - example

A

LPS and TLR4 Cells

Links innate immunity recognition to adaptive immunity via signalling
Importantly – cells respond to signals, TLR4 respnds to lipopolysaccharide
There are intracellular receptors NOD4 drive signalling cascade that lead to changes in transcription that will induce a procytokine response

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15
Q

Immune response to some important bacteria

A

look at table

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16
Q

‘discuss virulence factors in relation to bacterial infections’

A

Neisseria meningitides – its nasopharyngeal carriage rather than infection, infection occurs when natural barrier has been compromised or maybe they had a cold before damage mucousal surface, or some phase variations may switch on genes that allow penetration to randomly become a more virulent strain than before

TB is an intracellular organism , antibodies don’t really have much affect on it, need the right cytokine profile from the right T cell population to engage with macrophages activating them to kill the intracellular bacteria – this does not work on TB, once infected you cant really get rid of it

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17
Q

gram +ve envelope

A

Large peptidoglycan layer on the outside on which teichoic and lipoteichoic acid sits in it – potent immune-stimulatory molecules

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18
Q

gram -ve envelope

A

Outermembrane is complex full of these LPS chains

Also proteins on the surface that interact with host immunity, to evade immunity

When it lives in the host for a long time then it can change those outer membrane proteins

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19
Q

name some bacterial structures involved in mobility and attachment

A

Flagella, fimbriae and pili on the outside of some bacteria (vibrio cholera, salmonella, e.coli)

They may be associated with movement such as in the gut with flagella

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20
Q

what are Bacterial Adhesins

A

Cell-surface components that facilitate adhesion to other cells or surfaces (Skin, Urogenital, GI & respiratory tracts)

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21
Q

Bacterial Adhesin receptors

A

glycolipids, glycoproteins, transmembrane proteins, mucins, CD’s
extracellular matrix – elastin, laminin, fibronectin, vitronectin, hyaluronan, heparin, collagen

22
Q

examples of bacterial adhesins

A 
Fimbriae or pili
Capsular polysaccharides
LPS
Lipoteichoic acid
Outer membrane proteins
Flagella
Curli
  • E coli “P” fimbriae (pili) bind P blood group on uroepithelial cells
  • Neisseria gonorrhoeae pili attach to mucosal cells – non-piliated mutants are less pathogenic.
  • Vibrio cholera fimbriae bind intestinal epithelial cell receptors.
  • Strep pyogenes lipoteichoic acid binds to epithelial cell.
23
Q

Host-pathogen interactions - Strep pyogenes

A

Strep pyogenes group A strep – engulfed by polymorphonucleosome

it is not being engulfed such that the host is in control, rather some bacteria influence the way a phagocyte will phagocytose to the advantage of the bacteria

they can express proteins or carbohydrate meaning they will be engulfed through a different receptor mechanism pathway that doesn’t stimulate the respiratory burst

M protein of Streptococcus pyogenes acts as adhesin and structural component of cell wall

24
Q

Host-pathogen interactions - E coli

A

E.Coli in the gut

-causes the cell to exude out a pedestal upon which the bacteria sits, so has a close interaction with this cell type to the extent that it can live on the surface without damage to the bacteria

25
Q

Host-pathogen interactions - N gonorrhoeae

A

Fimbriae of Neisseria gonorrhoeae allow the bacterium to adhere to tissues

Fimbrae about 2/3 times the size of the bacteria so can easily attach to target

Once it has penetrated:
it will switch of some of the genes that it needed to adhere to evade the immunity
small number of phase variants are the ones that will survive and take over, then will enter cell and express tight adhesins allowing it to survive inside the cell

26
Q

what is e coli

A

Commensal gut organism

but can become a pathogen, causing: diarrhoea, dysentery, Haemolytic uraemic syndrome (HUS), Urinary tract and kidney infections, Septicaemia, Pneumoniae and meningitis

Different strains of E. coli – different repertoire of genes

e.g. entero-haemorrhagic E. coli – cause haemolytic uraemic syndrome -> life threatening – they probably have 300 genes different from simple enterotoxigenic E. coli

Enteropathogenic Escherichia coli (EPEC) cause the pedestal – it damages the villi, so it can no longer regulate fluid, so get diarrhoea – repair -> acute secretory

Enteroinvasive Escherichia coli (EIEC) have mechanisms that allow them to enter by damaging surface – then will express proteins that allows them to survive inside the cell and spread through epithelial layer, dysentery -> blood and puss in faeces due to tissue destruction + shigella like toxin leads to systemic effects on endothelial cells on kidney, haemolytic uraemic syndrome

27
Q

Bacterial host cell attachment – Mechanism summary

A

Pili or fibrillae protruding from the bacterial surface.

A - Pili or fibrillar protruding from bacterial surface. These proteinaceous appendages bind to host cell surface molecules, usually carbohydrates, by adhesin proteins located at the distal tip of the pilus/fibrillar organelle.

B - Bacterial/epithelial cell interactions mediated by afimbrial adhesin proteins.

C - Some bacteria establish intimate associations with eukaryotic cells by intimin proteins, resulting in cytoskeletal rearrangements, host cell signalling, possible internalisation of the bacteria, and in many cases systemic disease.

D - Some bacteria secrete their own receptor protein, which is internalised by the target host cell, phosphorylated, and embedded in the eukaryotic cell as a new receptor for tight binding by the bacterium.

28
Q

Bacteria interfere with cellular functions

- examples

A
  1. adhesion to receptors (adhesins/integrins)
  2. block phagocytosis (yersinia)
  3. membrane disruptions (pore forming toxins)
  4. -ve protein synthesis
  5. manipulation of lysosomal function (e.g. S typhi)
  6. endosomal trafficking
  7. manipulation of cytoskeleton
29
Q

how do bacteria interfere with innate immunity?

A
  1. influence phagocytosis! (macrophages and PMN’s)
  2. complement (diff flashcard)
  • kill cell via leucocidins - staphs
  • prevent opsonisation via protein A, which binds to the Fc portion of IgG - staphs
  • block contact via capsules - meningococcus, HibB

intracellular pathogens:

  • promote uptake via C3R, Fc receptors (no ROI)
  • prepares cell for invasion- class III secretion, Shigella
  • down regulates P-L fusion - M. tuberculosis
  • escape P-L to cytoplasm - Listeria
  • resist oxidative killing via catalase/peroxidase production - blocks MHC, IFN receptors, TNF release
30
Q

how do bacteria survive inside the cell?

A
  1. Directs phagocytosis via CR3 – no ROI
  2. Actin rearrangement - +ve engulfmant
  3. Type 3 secretion systems – prepares cell
  4. Resists digestion and ROIs, in PLs - SOD, catalase
  5. Escape into cytoplasm, e.g. Listeria; Legionella
  6. Inhibits PL fusion, maintains early endosome and blocks acidification
    e. g. mycobacteria
  7. Controls antigen presentation - stops CTLs or Pφ activation
31
Q

what is listeria?

A

Listeria monocytogenes (listeria) is a bacterium that causes an illness called listeriosis.

32
Q

how does listeria invade?

A

cell-cell invasion, involves a pore forming toxin called listeriolysin

Listeria reorganises actin filaments within the cell – allows it to travel through the cell and from cell to cell

33
Q

Stages – attachment and effacing lesions by EPEC

A

bfp – bundle forming pili – mediate initial attachment

Activation of Type 111 secretion systems –
secretion of bacterial translocated intimin receptor Tir. Receptor for the adhesion protein, intimin.

Cytoskeletal rearrangements – pedestal formation

This strain can secrete its own receptor when it comes into contact with the cell.

It activates a secretion process, the protein secreted is a receptor which goes into the target cell then becomes expressed on the surface of the target cell, to allow the bacteria to adhere, forms a tight intimin interaction between receptor and the ligand

34
Q

explain how class III secretory systems work further

A

There are about 8 different ways that bacteria can secrete proteins and into the target cell.

This image shows bacteria with loose attachment to cell, it makes a hypodermic needle called a secretory apparatus, that responds to the environment, allows upregulation of some genes to make this bridging structure

It then injects proteins or Yops into the cell some which are receptors to be presented, other effector proteins affect the cell in different ways

Yop E - actin rearrangement via GTPases, cell rounding, anti-phagocytic

YopH - Tyrosine phosphatase, -ve phagocytosis

YopT - Actin rearrangement

35
Q

Gram negative bacteria secretion systems

A

• ‘injects’ effectors into host cell: MOLECULAR SYRINGES

• examples:
Salmonella gut epithelium invasion

modification macrophage phagosome 

Yersinia inhibition neutrophil and macrophage function 

Shigella macrophage invasion and escape from phagosome

cell-to-cell spread 

E. coli EHEC and EPEC adhesion to gut epithelium 

Legionella inhibition phagolysosomal fusion
36
Q

how do bacteria interfere with innate immunity?

A
  1. complement
    - failure to trigger - LPS/capsules
    - downregulation of binding - coating with non-fixing with IgA
    - block MAC - C5a proteases
37
Q

roles of complement?

A 
induces inflammatory response
	promotes chemotaxis
	↑ phagocytosis by opsonisation
	↑vascular permeability
	mast cell degranualtion
	lysis of cell membranes
38
Q

complement pathways

A

look at table

39
Q

what is MBL?

A

part of complement pathway

Mannose-binding lectin - an acute phase protein
Binds MBL-associated serine protease (MASP)

40
Q

avoidance of complement via polysaccharide capsules?

A

Bacterial polysaccharide capsules:

-poor activators
-long side chains (O antigens) fix C3b - prevent access to membrane
-capsules rich in sialic acid promote interaction
with H and I factors and thus promotes MAC dissociation - eg Group B Streps, Neisseria meningitidis, E.coli K1

  • outer layer of G-ve bacteria can rapidly shed C5b-C9 MAC
  • C3a and C5a proteases
  • coat self with non-complement fixing IgA

e.g. The M-protein of S. pyogenes binds factor H of the complement pathway
and this leads to the degradation of the opsonin C3b by factor I and the formation of C3 convertase

41
Q

Streptococcus pneumoniae

A

inhalation into the lung

colonises by the nasopharynx due to adhesion molecules, produces secretory IgA proteases during colonisation so they can invade further after post-viral damage - viral infection will damage structure of epithelial cells.

switches on genes for pneumolysin, a toxin that damages pneumocyte membranes - destroys defensive barriers allowing bacteria to replicate there

escapes phagocytosis via capsules

Inflammatory process driven by teichoic acids

pneumonia - bacteraemia - meningitis and septicaemia

42
Q

immune response to imp bacteria?

A

look at table

43
Q

Antigenic Variation - Definitions

A

successive expression of alternative forms of an antigen - in a specific clone or its progeny

Phase variation - ON/OFF of an antigen at low frequency
- occurs: during course of infection in an individual host or during spread of microbe through a community

44
Q

what is antigenic variation a strategy for

A

immune evasion and pathogenesis

45
Q

Antigenic Diversity/ polymorphisms (slow, rare)

A
  • genetically stable and alternative forms of antigens
    in a population of microbes
    e.g. serotypes of Strep.pneumoniae
46
Q

Neisseria gonorrhoeae - Paradigm of immune evasion as a pathogenic mechanism

A
  • surface components interact with host cell
  • components vary at high frequency in a population of bacteria
  • variation to avoid immune response
47
Q

Phase and antigenic variation in Neisseria affects what?

A

affects cell surface components: capsule, pilus, opa, outer and inner membrane

All of these structures can undergo either:

  1. Phase variation i.e. an ON-OFF switch (capsule, Opa’s)
  2. Antigenic variation e.g. pilins (or both phase and antigenic)
48
Q

Mechanisms of phase variation in bacteria?

A

Intra-genomic recombination e.g. N.gonorrhoeae Pillins

49
Q

Host derived Environmental triggers of toxin Synthesis and Release

A

Bacterial toxin production - tightly controlled
Regulatory elements - sensitive to environmental signals found in host

1. Diphtheria toxin - totally repressed by adequate Iron.    
Limiting iron (i.e. in blood) - toxin de-repressed  = expressed
  1. Cholera toxin and related virulence factors (adhesins) - controlled by environmental osmolarity and temperature
  2. B. pertussis, induction of different virulence components – staggered attachment factors are produced initially to establish the infection, toxins are synthesized and released later to counter the host defences and promote bacterial survival.
50
Q

How bacteria avoid the immune response – innate and adaptive summary

A

INNATE:

  • C3a and C5A proteases
  • opsonisation (binding) inhibition
  • complement activation inhibition
  • survival inside macrophages

ADAPTIVE

  • antigen presentation inhibition
  • blockage of cell cycle progression
  • apoptosis inhibition
  • superantigens and appropriate immune activation
  • Ig binding proteins (protein A)
  • sIgA proteases

host mimicry - M protein
Phase and antigenic variation

51
Q

Virulence Factors that promote Bacterial colonisation and survival?

A

pili - adherence to mucosal surfaces

non-fimbrial adhesins - tight binding to cells

sIgA proteases - prevent trapping in mucin

siderophores - iron acquisition

capsules - prevent phagocytosis and block complement

altered LPS - serum resistance, no MAC

Ca5 peptidases - downregulation of complement signalling

surface protein variation - evade immunity

toxic proteins/enzymes - kill PMN’s, damage tissues

52
Q

communications in Infections - Host-pathogen interactions

A

Signalling – TLRs, PRRs and PAMPs

  1. Inter- and intra – cellular communications in eukaryotic cells
    • signalling
    -receptors and signal transduction
    e.g. G-proteins
    ion channels
    second messengers e.g. cAMP
    actin, microtubules
  2. Bacterial signalling - 2 component signal transduction systems
    Quorum sensing
    Cytokine mimics
  3. Bacterial reception of host signals
    adaptation through gene expression

I&I year 3 (25 decks)

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