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4.2 Medical Microbiology > Mycobacterium Tuberculosis > Flashcards

Mycobacterium Tuberculosis Flashcards

1
Q

What is tuberculosis, how long has it been around?

A

An ancient disease of mankind
Causative agent is mycobacterium tuberculosis
It has afflicted humans for about 70,000 years

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2
Q

Comment on the prevalence and mortality

A

Causes 8.6 million cases
Causes 1.4 million deaths

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3
Q

Why have we not been able to control tuberculosis

A

Even through significan changes in lifestyle and upgrades of modern medicine they havent been enough to compate the agility and toughness of tuberculosis

Paradigm for human-host pathogen adaptation:
- ‘Great white plague’
-‘the captain of all thos men deaths’

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4
Q

Comment on trends in incidence rates of TB

A

Countries with socio-economic problems tend to be more affected
High levels in Southern africa and india
Numbers decreased with covid as people werent coughing on each other and there was a decline in testing but numbers are now high
High numbers post covid as we are still detecting some of those cases we missed during lockdown

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5
Q

What are the three important steps in ending TB?

A

Integrated, patient-centred care and prevention
Bod policies and supportive systems
Intensified research and innovation

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6
Q

What was the plan to eradicate TB, how did we fair against targets?

A

To reduce TB incidence rate by 20% between 2015-2020 (we only got a 9% reduction)

To reduce TB deaths by 35% between 2015-2020 (we only got a 14% reduction)

To reduce % of people with TB facing catastrophic costs to 0% (49% still face catastrophic costs)

NB: high economic countries were going to support low economic countries etc

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7
Q

How much research is done on TB in Ireland

A

Ireland spends about 10million on research on TB bovis done mostly in UCD while only spending about 1 million on human TB

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8
Q

What is the strategy for addressing tuberculosis over the next few years?

A

The 2030 Global Strategy: they set out the three steps to addressing tuberculosis:
- integrated, patient centred care and prevention
- bold policies and supportive systems
- intensified research and innovation

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9
Q

What is the TB strategy for 2030s target, how do we meet this?

A

80% reduction in tuberculosis by 2030 met through:
- multidiscipinary TB workforce meetins
- MDTs
- presenting case studies etc

A lot has already been done in Ireland so its interesting to see if we will meet these targets

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10
Q

How does mycobacterium establish infection?

A

Spred is solely from person to person via inhalation of contaminated droplets

Mycobacterium evades upper respiratory airway defensins such as mucocillary action

Mycobacterium then reaches deep airways and alveoli from there it gets into macrophages

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11
Q

What is normally the role of alveolar macrophages?

A

They recognise foreign proteins on cell surfaces
They phagocytose foreign material
They fuse phagosomes and lysosomes -> this creates acidic conditions where bacteria cannot survive
Their hydrolytic enzymes break down foreign molecules

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12
Q

What happens to the macrophages in TB

A

Macrophages recognise foreign TB proteins on cell surfaces
Foreign material is phagocytosed
TB then inhibits fusion of the phagosome and lysosome -> lysosome action inhibited by TB
TB then proliferates inside macrophages
TB creates local infection in the lung and eventually crosses over the mucous barrier

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13
Q

Its important that TB invades what particular type of macrophage?

A

TB can only proliferate in naive macrophages, as these cannot work well

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14
Q

What is primary tuberculosis

A

Flu-like symptoms
asymptomatic of tb like symptoms
Patients often think they have a normal head cold

After 3 weeks a ghon focus is formed

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15
Q

What is a ghon focus

A

A ghon focus is formed approximately 3 weeks after infection
It is a product of the activation of cell mediated immunity
Its the production of a granuloma in the lung
also known as caseous necrosis
Tb is able to proliferate within this and cause local infection

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16
Q

How is a ghon focus formed and how does this affect pathogenicity?

A

Ghon focus begins when a barrier is formed around the infected macrophage
All cells inside the ghon begin to die -> this is what causes the caseous necrosis
TB love this invironment and will proliferate and cause infection
The focus will get bigger and bigger until it reaches a lymph node -> contain more naive cells for infection
TB infects these cells and thus forms a ghon complex

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17
Q

What is a ghon complex

A

This is where TB has spread to the hilar lymph node to infect immune cells
It is the extension of the ghon focus

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18
Q

What does the ghon complex progress to?

A

Ranke complex or disease eradication or latentinfection

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19
Q

What is the ranke complex?

A

This is where fibrosis and calcification of the tissue encapsulating the granuloma form
Scar tissue is layed down
-> this can have two results -> the cells inside will either die but in most cases will survive and result in a latent infection

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20
Q

How can the Ranke complex result in disease eradication?

A

If the cells trapped inside the fibrotic tissue die then the tb will be eradicated

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21
Q

How does the ranke complex progress to latent infection

A

If viable cells are trapped in the complex and cannot be killed they will remain inside waiting for an opportunity to reactivate

These patients wont be infections, and will be auramine O negative but between 2-5 years down the line they will have a reactivation

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22
Q

When will latent tb reactivate?

A

2-5 years down the line

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23
Q

What % of latent TB becomes active?

A

Between 5-20% become active within 5 years

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24
Q

What are some risk factors for disease progression into active TB

A

Immunosuppression
Malnutrition - particularly vitamin D deficiency
Diabetes
Alcohol abuse

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25
Q

Give an example of a TB outbreak in Ireland

A

Massive outbreak in Baggot street
Between 20-30 people infected
All traced back to the one guy coughing in a pub

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26
Q

How does active infection occur?

A

Active infection occurs when the immune system is compromised and:

Activation of Ghon Focus
Exogenous re-infection -> secondary infection if unlucky patient
Spread to one/both upper lobes
Oxygenated area

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27
Q

What happens upon secondary exposure to tb

A

Memory T cells release cytokines
Formation of areas of caseous necrosis
Formation of cavities
Allow dissemination of bacteria

Memory T cells are already formed so theyll recognise TB much quicker -> these release cytokines -> lots of caseous necrosis form quickly which causes cavities in the lung often seen on autopsy -> these cavities allow bacteria to then spread to the blood and cause millerary TB

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28
Q

What is milliary TB?

A

Occurs in secondary infection
Whereby TB spreads from the lung to the blood

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29
Q

Give an example of where miliary TB was missed?

A

A baby was born with TB -> CSF positive for TB on biofire
However mother and rest of family were negative
Staff and everyone involved were screened and all were negative
The mother had milary TB (latent TB) i.e. it had spread to reproductive organs and baby was then born with TB

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30
Q

How does latent TB become symptomatic disease?

A

Bronchopneumonia
Miliary disease

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31
Q

What five features make mycobacterium tuberculosis unique?

A

Dependent on human host for survival and evolution
Lacks classical virulence factors
Used by mucosal pathogens for colonisation - selective colonisation advantage
Uses macrophages to trasverse mucosal barrier and to persist in these
Employs cell wall lipids as a novel mechanism

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32
Q

shat virulence factors does tb lack?

A

Virulent capsule to avoid phagocytosis
Pilli or other adhesions to adhere to host tissue
Flagella for motility
Enzymes and toxins
Biofilms to persist

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33
Q

TB lacks a lot of significant virulence factors, why is this important

A

Virulence factors tend to be taregts for vaccines
-> without these we cant produce vaccines against it etc

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34
Q

What three things must mycobacterium do to evade the innate immune system?

A

Optimum host niche
Avoid microbicidal macrophages
Recruit growth permissive macrophages

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35
Q

What four things must Mtu do to be successful?

A

Evade the host innate immune response
Multiplication within the host cell
Exit the host cell
Transmit to a new host

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36
Q

What does tb need to do to multiply within the host cell?

A

TB needs to develop strategies to avoid or modulate the immune response in their favour

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37
Q

How does tb exit the host cell?

A

Apoptosis
Necrosis

Then transmission to a new host

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38
Q

What is the mtb cell wall composed of?

A

Outermost layer/capsule
Cell wall-tripartite complex
Conventional plasma membrane

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39
Q

What four things do we know about the mycobacterial cell wall?

A

Acid fast bacilli
Low permeability - contributes to resistance of the organism
High lipid content -> has a whole lipid layer of mycolic acids
Slow growers -> takes 8-12 weeks to grow in conventional culture

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40
Q

Why are antibiotics generally not affective on the TB cell wall?

A

Low permeability
But also cause its really slow growing and takes ags to form -> so antibiotics that affect cell wall synthesis their affects arent as evident as this occurs over a longer period etc

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41
Q

what is the plasma membrane of tb made of/

A

Phospholipid bilayer
Glycolipids that extend into the periplasmic space

NB: nothing special, same in all other bacteria

42
Q

What is the mycobacerial cell wall composed of?

A

Cell wall
Tripartite complex:
- cross linked polymer of peptdoglycan
- highly branched arabinogalactan polysaccharides
- long chain mycolic acids

43
Q

What are long chain mycolic acids?

A

Free lipids and glycolipids such as PGM and PDIM which make the cell wall waxy

NB: they are the most important structure of TB

44
Q

What is the Mytb capsule made of?

A

Proteins and polysaccharides
Pathogenic mycobacterium - primarily glucan and proteins - small amount of lipids
Non-pathogens primarily proteins

45
Q

What are the two phases of tb growth

A

Acive phase and stasis phase

46
Q

What is the active phase of tb growth?

A

Abundant during active growth in early infection
The initial phase of infection where everything is in abundance
Lots of proteins are secrete here etc hence its a good point where we can target treatment but patients usually only think they have a cold at this point

47
Q

What is the stasis phase of tb growth?

A

Metabolism of the core wall layers is reduced -> seen in chronic infection

Metabolism slows down
We dont have many targets of treatment here but this is when we usually diagnose patients

48
Q

What are our treatment targets for tb

A

Glucans and secrete protein that have a role in host interactions and virulence - treatment targets

49
Q

Talk about the mtb cell wall

A

There are chemically distinct cell envelopes that exist in different cells at different infection stages
Particular cell envelope of a mycobacterial cell at any given moment partly determines how that cell will respond to the immune system and antibiotics
How do they do this, we still dont know but its probably going to be a possible treatment option in the future

50
Q

What two things are needed to make an optimum host environment for tb

A

An environment in which the pathogen can rapidly replicate

Small aerosol droplets

51
Q

What is needed to make an optimum host environment for tb?

A

Alveolar space deep within the lung
Circument host commensal aliance
- host defenses and the immune system as well as
- commensal microbiata which confer colonisation resistance

52
Q

Talk about tb in small aerosol droplets

A

1-3 bacteria in each droplet
These can reach the lungs if the circumvent upper respiratory tract commensal microbiota

53
Q

Talk about the research of tb on zebra fish

A

Much of our knowledge comes from zebra fish -> these are transparent fish in which we can fluorescently tag white cells and track through the fish

Can be done on alveolar cells deep in the lungs

54
Q

Why does TB keep its aerosols small?

A

The smaller the aerosol the further down in the lung it can get before being blocked etc

Its much harder to compete in the upper resp tract as there is a lot of non specific immune responnses up here and TB can often get killed in the cross fire

TB avoid this by keeping aerosols small so they can get down to the alveoli

We found this out by experimenting on zebra fishes and following them down into the lung etc

55
Q

What do microbicidal macrophages do normally?

A

They default to respond to comensal pathogens

TLRs activated by PAMPS determine this activity

56
Q

How does tb interact with macrophages

A

There are abberant respons by Mt to avoid microbicidal macrophages

TB inhibits its on detection as well as the activation of cytokine responses

Instead tb recruits naive marophages to sites of infection

57
Q

Talk about TB PAMPS

A

TB still has normal PAMPs which stimulate normal immune responses but it also has PDIM

PDIM is a surface lipid which sits ontop of PAMPs present on TB to cloak them

This prevents TLRs from recognising PAMPs

Macrophages cant recognise the TB then

This is one of the main virulence factors of TB

Only clinical isolates have this - knowckout strains will not e virulent etc

58
Q

What specific molecule is responsible for PAMP cloaking in TB?

A

PDIM

59
Q

What does PDIM stand for?

A

Pthiocerol dimycoceroserate

60
Q

What is the role of PDIM

A

It inhibits toll-like receptor 2 wih sulfoglycolipids
It masks surface antigens

61
Q

How does MTB recruit naive macrophages?

A

It produces PGL which induces macrophage chemoine CCL2 which recruits macrophages for infection

PGL is not required for virulence unlike PDIM but its expression increases infectivity by enhancing the recruitment of permissive macrophage thus is called an indirec virulence factor

62
Q

What does PGL stand for?

A

Phenolic glycopolipid PGL

63
Q

What does PGL induce expression of?

A

CCL2

64
Q

Why is PGL considered an indirect virulence factor?

A

It is not expressed by all clinical isolates i.e. it is not absolutely required for virulence

65
Q

What is the tripartite response?

A

Avoiding microbicidal macrophages
Recruiting permissive macrophages

66
Q

Under what scenario might TB fail to get down into the lung?

A

In a commensal rich niche
-> this means there is an endless suplly of PAMPS stiulating macrophages
-> this means MTU gets killed as collateral damage

So even if host is optimal/niche etc it might not always result in infection

67
Q

What are the three steps in the tripartite nnate immune evasion strategy?

A
  1. avoiding microbicidal macrophages
  2. recruiting permissive macrophages
  3. optimum host niche

Now once recruited tb has the opportunity to survive within macrophages and transvers host epithelial barriers

68
Q

What is significant about the ability of tb to replicate?

A

Its ability to replicate defines the pathogenesis of the mycobacterium

69
Q

what is the normal pathogenic activity response in the lung

A

pathogens are phagocytosed by macrophages and enter the endocytic pathway

70
Q

How do intracellular pathogens resist immune responses

A

They thwart/modulate/exploit or avoid the endocytic pathway of phagocytosis
They resist lysosomal fusion to reside in non-acidified endosome-like compartments
They survive acidification to be able o reside in acidified lysosome-like compartments (tolerant organisms)
Break out of the phagosome altogether to reside in the cytosol

NB: intracellular organisms have to be able to do at least one of these three things but TB can do all three

71
Q

Talk about the life of tb inside the macrophage

A

TB can resist lysosomal fusion to reside in non-acidified endosome-like compartments

TB can survive acidification to be able to reside in acidified lysosome-like compartments

Break out of the phagosome altogether to reside in the cytosol

TB can break out of the phagosome altogether to reside in the cytosol

72
Q

How can TB resist lysosomal fusioin to reside in non-acidified endosome-like compartments

A

Serine-threonine protein kinase PknG- inhibits lysosomal fusion

Trehalose dimycolate is also thought to have a role in blocking phagosome-lysosome fusion and promoting granuloma formation

73
Q

What is responsible for inhibiting lysosomal fusion in TB?

A

Serine-threonine protein kinase PknG

74
Q

What is responsible for blocking phagosome-lysosome fusion and promoting granuloma formation in tb?

A

Trehalose dimycolate

75
Q

How can TB break out of the phagosome to reside in the cytosol?

A

TB has an ESX-1 Bacterial Secretory System

This initiates the rupture of phagosomes and directly protects against reactive nitrogen species

76
Q

What is a TB granuloma

A

It is a hallmark of TB infection
It has an essential host protective strucutre
Its essentially a fortress containing a complex mixture of diverse host cells that wall off bacteria
The more complicated the granuloma the more TB in the granuloma

77
Q

What has research on granulomas shown?

A

Research has shown that even though host immune responses form the granuloma it is actually TB controlling the granuloma
TB mediated granuloma not our immune response as we previously thought
TB exploits granulomas that host immune system produces
TB can multiply within and then spread from them

78
Q

What three things can TB do in a granuloma?

A

Avoid or modulate the immune response in their favour
Exploit granulomas
Expansion and dissemination in innate granuloma

79
Q

In what two ways can TB undergo expansion from a granuloma

A

Spread to new macrophages from dying macrophages

Macrophage cell death and re-phagocytosis allows for expansion of bacterial niche

80
Q

How can TB spread to new macrophages from dying macrophages

A
  1. bacterial nnumbers increase in macrophages
  2. programmed cell death - apoptosis -> viable bacteria remain encased within the dying cell
  3. recruitment of new uninfected macrophages
  4. dying cell components are engulfed by new macrophages
81
Q

Explain how TB can spread using granulomas

A

From here TB can now be picked up by more macrophages and can spread disease
TB can trigger apoptosis of cells in order to spread etc
TB has a whole new sense of life etc and begins again and again etc etc

82
Q

What does the ESX-1 bacterial secretory system do?

A

Mediates macrophage cell death and rephagocytosis

83
Q

How is macrophage cell death and rephagocytosis by ESX-1 secretory system

A

Done through secretory factor ESAT 6
- this induces apoptosis of infected cells
- this recruits macrophages by inducing metalloproteinase 9 (MMP9)

84
Q

What does induction of MMP9 by ESAT6 do?

A

Increased MMP9 associated with increased severity and mortality e.g. in meningitis
Decreased MMP9 associated with attenuated infection

85
Q

What does ESAT 6 do other than inucing MMP9 and inducing apoptosis?

A

It can delay migration of T cells to the granuloma through immunosuppressive regulation of T cell populations

86
Q

What changes occur in macrophages as granuloma matures and how does TB combat this

A

Macrophages become more microbicidal as granuloma matures

However TB rapidly adapts to this hotile environment and transcribes new genes to aid intraccellular survival e.g. efflux pumps -> TB make the best of a bad situation

87
Q

What are the two systems TB has in place to recruit macrophages?

A

PGL-CCL2 initially -> to recruit naive cells at start of infection
But this transitions to ESAT-MMP9 later on -> for the recruitment of macrophages to allow TB to spread

88
Q

Why is escape of the granuloma so important in TB

A

The evolutionary success of tb is dependen on is ability to exit the granuloma (host) and enter a new host and spread

89
Q

How does TB spread to a new host?

A

Necrotic areas rupture into the bronchial tree
TB is then aerosilised in cough droplets

90
Q

What does escaping the granuloma depend on?

A

Depends on macrophage death either through aptosis or necrosis

Apoptosis: tb remains encased in dead cell
Necrosis: tb released into extracellular millieu-caseum - the ideal bacterial growth medium

91
Q

What promotes necrotic caseation in mature granulomas?

A

trehalose dimycolate

92
Q

What does trehalose dimycolate promote?

A

Necrotic caseation in mature granulomas

93
Q

How does necrosis enable spread?

A

Necrosis essentially blows everyhing up
But some bacteria survive
This bacteria can then spread into the bronchial tree and spread when a person coughs etc

94
Q

What can induce necrosis in tb

A

Over or under production of tumour necrosis factor

95
Q

Talk about the steps in tb spread

A

TB increases multiplication - serpentine cord like growth occurs -> this is not readily engulfed by macrophages

Granuloma shifts to favour necrosis - this is not fully understood

Disseminates infection through the egress of infected macrophages to new sites

Either over or under regulation of tumor necrosis factor

96
Q

What does serpentine cord-like growth in tb mean

A

This means tb is trying to spread
This form cant be readily engulfed by new macrophages -> instead looking to spread

97
Q

Talk about the role of tumour necrosis factor

A

It is either over or under regulated

Over production -> results in increased ROS which has a dual effect - this kills macrophages and mycobacterium - some mycobacterium escape extracellularly - replicate exponentially

TNF deficiency -> mycobacterium grow exponentially within the macrophage, macrophage dies and releases them to extracellular

98
Q

How is the granuloma modulated?

A

Modulate the host response to infection to build and modify the formation of the granuloma:
1. intracellula growth
2. extrtacellular growth that also favours transmission

99
Q

What % of infections are cleared?

A

Estimated to be 90%

Dependent on:
- initial immobilisation of innate immune mechanisms
- adaptive immunity

100
Q

Talk about the paradigm of host-adaptive microorganisms

A

Co-evolved with the human immune system
Deletion and insertion of genes to adapt to evolution of the host immune response

Trump cards such as host immune evasion, mmodulation and exploitation

4.2 Medical Microbiology (20 decks)

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