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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
Give an example of a TB outbreak in Ireland
Massive outbreak in Baggot street Between 20-30 people infected All traced back to the one guy coughing in a pub
26
How does active infection occur?
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
27
What happens upon secondary exposure to tb
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
28
What is milliary TB?
Occurs in secondary infection Whereby TB spreads from the lung to the blood
29
Give an example of where miliary TB was missed?
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
30
How does latent TB become symptomatic disease?
Bronchopneumonia Miliary disease
31
What five features make mycobacterium tuberculosis unique?
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
32
shat virulence factors does tb lack?
Virulent capsule to avoid phagocytosis Pilli or other adhesions to adhere to host tissue Flagella for motility Enzymes and toxins Biofilms to persist
33
TB lacks a lot of significant virulence factors, why is this important
Virulence factors tend to be taregts for vaccines -> without these we cant produce vaccines against it etc
34
What three things must mycobacterium do to evade the innate immune system?
Optimum host niche Avoid microbicidal macrophages Recruit growth permissive macrophages
35
What four things must Mtu do to be successful?
Evade the host innate immune response Multiplication within the host cell Exit the host cell Transmit to a new host
36
What does tb need to do to multiply within the host cell?
TB needs to develop strategies to avoid or modulate the immune response in their favour
37
How does tb exit the host cell?
Apoptosis Necrosis Then transmission to a new host
38
What is the mtb cell wall composed of?
Outermost layer/capsule Cell wall-tripartite complex Conventional plasma membrane
39
What four things do we know about the mycobacterial cell wall?
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
40
Why are antibiotics generally not affective on the TB cell wall?
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
41
what is the plasma membrane of tb made of/
Phospholipid bilayer Glycolipids that extend into the periplasmic space NB: nothing special, same in all other bacteria
42
What is the mycobacerial cell wall composed of?
Cell wall Tripartite complex: - cross linked polymer of peptdoglycan - highly branched arabinogalactan polysaccharides - long chain mycolic acids
43
What are long chain mycolic acids?
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
What is the Mytb capsule made of?
Proteins and polysaccharides Pathogenic mycobacterium - primarily glucan and proteins - small amount of lipids Non-pathogens primarily proteins
45
What are the two phases of tb growth
Acive phase and stasis phase
46
What is the active phase of tb growth?
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
What is the stasis phase of tb growth?
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
What are our treatment targets for tb
Glucans and secrete protein that have a role in host interactions and virulence - treatment targets
49
Talk about the mtb cell wall
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
What two things are needed to make an optimum host environment for tb
An environment in which the pathogen can rapidly replicate Small aerosol droplets
51
What is needed to make an optimum host environment for tb?
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
Talk about tb in small aerosol droplets
1-3 bacteria in each droplet These can reach the lungs if the circumvent upper respiratory tract commensal microbiota
53
Talk about the research of tb on zebra fish
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
Why does TB keep its aerosols small?
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
What do microbicidal macrophages do normally?
They default to respond to comensal pathogens TLRs activated by PAMPS determine this activity
56
How does tb interact with macrophages
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
Talk about TB PAMPS
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
What specific molecule is responsible for PAMP cloaking in TB?
PDIM
59
What does PDIM stand for?
Pthiocerol dimycoceroserate
60
What is the role of PDIM
It inhibits toll-like receptor 2 wih sulfoglycolipids It masks surface antigens
61
How does MTB recruit naive macrophages?
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
What does PGL stand for?
Phenolic glycopolipid PGL
63
What does PGL induce expression of?
CCL2
64
Why is PGL considered an indirect virulence factor?
It is not expressed by all clinical isolates i.e. it is not absolutely required for virulence
65
What is the tripartite response?
Avoiding microbicidal macrophages Recruiting permissive macrophages
66
Under what scenario might TB fail to get down into the lung?
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
What are the three steps in the tripartite nnate immune evasion strategy?
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
What is significant about the ability of tb to replicate?
Its ability to replicate defines the pathogenesis of the mycobacterium
69
what is the normal pathogenic activity response in the lung
pathogens are phagocytosed by macrophages and enter the endocytic pathway
70
How do intracellular pathogens resist immune responses
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
Talk about the life of tb inside the macrophage
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
How can TB resist lysosomal fusioin to reside in non-acidified endosome-like compartments
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
What is responsible for inhibiting lysosomal fusion in TB?
Serine-threonine protein kinase PknG
74
What is responsible for blocking phagosome-lysosome fusion and promoting granuloma formation in tb?
Trehalose dimycolate
75
How can TB break out of the phagosome to reside in the cytosol?
TB has an ESX-1 Bacterial Secretory System This initiates the rupture of phagosomes and directly protects against reactive nitrogen species
76
What is a TB granuloma
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
What has research on granulomas shown?
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
What three things can TB do in a granuloma?
Avoid or modulate the immune response in their favour Exploit granulomas Expansion and dissemination in innate granuloma
79
In what two ways can TB undergo expansion from a granuloma
Spread to new macrophages from dying macrophages Macrophage cell death and re-phagocytosis allows for expansion of bacterial niche
80
How can TB spread to new macrophages from dying macrophages
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
Explain how TB can spread using granulomas
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
What does the ESX-1 bacterial secretory system do?
Mediates macrophage cell death and rephagocytosis
83
How is macrophage cell death and rephagocytosis by ESX-1 secretory system
Done through secretory factor ESAT 6 - this induces apoptosis of infected cells - this recruits macrophages by inducing metalloproteinase 9 (MMP9)
84
What does induction of MMP9 by ESAT6 do?
Increased MMP9 associated with increased severity and mortality e.g. in meningitis Decreased MMP9 associated with attenuated infection
85
What does ESAT 6 do other than inucing MMP9 and inducing apoptosis?
It can delay migration of T cells to the granuloma through immunosuppressive regulation of T cell populations
86
What changes occur in macrophages as granuloma matures and how does TB combat this
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
What are the two systems TB has in place to recruit macrophages?
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
Why is escape of the granuloma so important in TB
The evolutionary success of tb is dependen on is ability to exit the granuloma (host) and enter a new host and spread
89
How does TB spread to a new host?
Necrotic areas rupture into the bronchial tree TB is then aerosilised in cough droplets
90
What does escaping the granuloma depend on?
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
What promotes necrotic caseation in mature granulomas?
trehalose dimycolate
92
What does trehalose dimycolate promote?
Necrotic caseation in mature granulomas
93
How does necrosis enable spread?
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
What can induce necrosis in tb
Over or under production of tumour necrosis factor
95
Talk about the steps in tb spread
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
What does serpentine cord-like growth in tb mean
This means tb is trying to spread This form cant be readily engulfed by new macrophages -> instead looking to spread
97
Talk about the role of tumour necrosis factor
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
How is the granuloma modulated?
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
What % of infections are cleared?
Estimated to be 90% Dependent on: - initial immobilisation of innate immune mechanisms - adaptive immunity
100
Talk about the paradigm of host-adaptive microorganisms
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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