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ILOs > Pathogenesis of Mycobacterium tuberculosis (MED 1 ILOs) > Flashcards

Pathogenesis of Mycobacterium tuberculosis (MED 1 ILOs) Flashcards

1
Q

LOs

A
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2
Q

Probability that TB is transmitted depends on:

A
  • Infectiousness of person with TB disease (dose)
  • environment in which exposure occured
  • length of exposure
  • virulence (strength) of tubercle bacilli
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3
Q

Best way to stop transmission of TB is:

A

isolate infectious persons

provide effective treatment to infectious persons ASAP

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4
Q

Risk factors for TB

A
  • Socioeconomic status
  • Crowding
  • Immune suppression
  • Health care workers
  • POVERTY
  • Overall health/ immune system status
  • Alcoholism
  • Smoking
  • Diabetes
  • TB within the last 2 years
  • HIV co-infection
  • Strain virulence?
  • Genetic predisposition?
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5
Q

outcomes of exposure to TB

A

you get infected or you dont get infected

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6
Q

out of those that do get infected, what 2 things can happen next?

A

you get dormant TB (90%) or you get active TB (10)

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7
Q

dormant TB

A

asymtpomatic, subclinical

no tB disease

not infectious to others

can last a lifetime

presence if cellular immune response

5-10 % risk of reactivation

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8
Q

active TB

A

ill with symptoms and likely to die if left untreated

infectious

usually within 1-2 years of infection

result of local bacterial growth and dissemination

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9
Q

activation of infection results in

A

disease

post primary infectino/ secondary TB

due to loss of immune control of infection (in the granuloma)

active disease presentation

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10
Q

infection sites of TB

A
  • Pulmonary containment- 85% (usually apices due to aerobic loving bacteria)
  • infection starts in lungs then spreads to many parts of the body
  • extrapulmonaryTB is generally non-contagious and occurs more frequently in immunosuppressed individuals

possible::

  • lymph nodes
  • liver
  • millliary- disseminated (sapced out in small lesions)
  • bones and joints as potts disease
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11
Q

methods of diagnosing TB

A
  • often based on symptomatic presentation alone- Persistent cough, fever, night sweats, wight loss, chest pain, fatigue, loss of appetite
  • mycobacterial culture- SLOW, Colonies are dry, raised, irregular, white and may become yellow
  • AFB smear- sputum microscopy, low sensitivity
  • radiography- CXR look for lymphadenopathy and calcification
  • Molecular approaches- genexpert TB
  • TST (tuberculin skin test)
  • Interferon gamma release test (IGRA) blood test
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12
Q

TST (tuberculin skin tests/ mantoux)

A

TB antigens are planted under the skin- monitor for a cell mediated immune response

Creates indurations (bump less than 5mm no infection), oedema at site

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13
Q

Problems with TST

A
  • Cross reactivity with the BCG vaccination
  • Cannot distinguish active from latent very well
  • Low sensitivity (identify those with disease) and specificity (generate negative result for those who don’t have it)
  • Reader variability (some will say you have it vs some wont)
  • No good in HIV as. No immune response
  • Requires multiple visits, reading after 48-72 hours
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14
Q

interferon gamma release assay

A
  • blood test used to test for TB
  • measures IFN-gamma production in whole blood response to stimulation with MTb antrigens
  • these antigens are not present in BCG strains and do not cross react with the environmental antigens

positives- quick

negatives- does not distinguish between active and latent

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15
Q

prevention, treatment and resistance

A
  • priority in case origin identification and treatment
  • primarily of active TB in resource limiting settings
  • infection in kids can be common
  • HIV is hard to treat with TB
  • few new drugs
  • long chemotherapeutic treatments (months)- toxicity and resistance issues
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16
Q

what vaccine do we give for TB?

A
  1. BCG- M.bovis attenuated strain
  2. stops the DEVELOPMENT of infection. does not stop its progression
  3. protective against severe infection in children
  4. some efficacy in severity of disease among those vaccinated
  5. efficacy varies rgeatly depending on the levels of TB in the population
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17
Q

antitubercle drugs

A

combination therapy (this prevents resistance to one drug)

isoniazid with pyridoxine

rifampicin and ethambutol

long treatment period- come back and review for bacterial ab sensitivity

complex disease mau require monitoring

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18
Q
A
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19
Q
A
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20
Q

what are the 4 main drugs used to treat TB

A

isoniazid + pyridoxine

rifampicin + ethambutol

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21
Q

fluoroquinolone

A

inhibs DNA synthesis and supercoiling by targeting topoisomerases

22
Q
A
23
Q

rifamycin

A

: inhibs RNA synthesis by targeting RNA polymerase

24
Q

streptomycin

A

inhibs protein synthesis by trgeting 30S subunit

25
Q
A
26
Q

macrolides

A

target 23S ribosomal RNA, inhinbiting peptidyl transferase

27
Q

isoniazid and theionamide

A

inhibs mycolic acid synthesis

28
Q

ethambutol and pyrasinamide

A

inhibs cell wall synthesis

29
Q

relevance of mycolic acid in TB

A

found in the cell wall

helps the organism survive inside macrophages

30
Q

inherent defences of TB against drugs

A

drugs cannot penetrate cell wall

low pH- renders drug inactive

efflux pumps- drug removed from cell before it reaches the target

anaerobic conditions lead to dormant/ non-replicating state- drugs that block metabolic processes have no effect during state of dormancy

31
Q

TB emergence of resistance

A

slow replicative rate- more time for mutations to accrew

mutations to TSG and proto-oncogenes lead to multiple drug resistance

alterations in enzymes means that pro-drugs arent converted to their active forms

alteration of drug target composition means that the drug cant be recognised

32
Q

Mycobacterium resistance types

A

MDR-TB

X-DR

33
Q

multidrug resistant TB

A

develeoping during treatment process to 2 (isoniazid and rifampcin) this is natural. treat with second line drugs

34
Q

XDR- TB

A

extended. includes resistance to secind and third line drugs. there is no standardized treatment available

35
Q

mycobacterium tuberculosis complex

A

group of organisms that will casue infections in humans

Mycobacterium tuberculosis

Bovis (BCG)

Africanum and many more

These can all casue TB iun humans and animals (zoonotic)

all members have different host preferences

all are obligate pathogens

show 990.5% sequence similarity within the group

36
Q

general characteristics of mycobacterium

A

slightly curved rod shaped bacilli

aerobic

non motile

can show filamentous branching (myco)

thick lipid rich cell wall

can remain dormant, non-spore forming

multiplies slowly

acid-fast resists stain decolouristaion with acid/ alcohol

37
Q

cell wall of mtb

A
  • peptidoglycan wall aboce lipid bilayer
  • behaves like gram positive
  • lipid rich structure- mycolic acids
  • unique and responsible for much of its virukence
  • plasma membrane associated proteins
  • Cord factor-inhibits migration of leukocytes, causes chronic granulomas
38
Q

mycolic acid

A

characteristic of mycobacterium

acid fastness

immunostimulatory

39
Q

mtb pathogenesis

A
  • Majority of pathology has been related to the host immune response to infection
  • Pathogen also plays a role in its own virulence
  • Some strains are more pathogenic than others
  • Known virulence factors are used to subvert the host immunity (efflux pumps)
40
Q

early progression of TB

A

First 4-6 weeks Exposure →innate response (chance for elimination) →adaptive response (Chance for elim)

Organism hides from immune system in granulomas →years to decades →granuloma degrades and releases bacteria 

41
Q

stages of infection

A

disease course has 3 main stages:

  1. Invasion- pre-cellular immune response
  2. Persistance- post cellular response
  3. Reactivation- secondary acute infection-
42
Q

stage 1 invasion

A
  • Mtb is a facultative intracellular pathogen requires replication in macrophages
  • mtb initiates macrophage phagocytosis by making contact with macrophage mannose, complement and TOLL- like 2 receptors
  • Reside in phagosome
  • Receptors utilised are those associated with an innate response like C-type lectin receptors (CLRs), nod-like receptors (NLRs), scavenger rectpors, complement receptors and toll-like receptors (TLR)
  • Some prevent lysis in phagolysosome by preventing fusion
  • The ability to infect macrophages is a key pathogenic determinant for bacterial spread
43
Q

why can this organism use so many receptors to invade cells

A
  • cell wall complexity allows it to interact with multiple receptors
  • mtb surviving may ne dependant on the receptors incolved during phagocytosis (some receptors normally lead to phagocytosis)
  • a) e.g., via the CR3 receptor which inhibits macrophage activation
44
Q

problem with using receptors in innate immunity

A

tb can use them to invade cells

45
Q

induction of cellular immunity

A
  • TH1 mediated immunity is crucial
  • you want more th1 involvement than th2
  • production of IFN- gamma by T cells leads to macrophage activation and death of Mtb infected cells

cellular immunity is crucial for controllimng TB. HIV targets and kills these cells making reactivation more likely to occur

46
Q

macrophage reactivation by the cellular immune system

A
  • interferon gamma overcomes the endosome like arrest that mtb imposes, delivering the vacteria to autolysosomes where growth is stopped.
    • mtb fights thhis by resisting oxidatice stress and suverting cell death pathways (necrosis and apoptosis)
  • if necrotic, pieces will disseminate into other areas
47
Q

stage 2 inhibition of phagosomal maturation

A

Mtb causes:

  • Impaired fusion of phagosome with lysosome
  • Inhibition of phagosome acidification
    • Inefficient recruitment of proton ATP-ase pump
    • Results in lack of acidification of the phagosome
  • Modified maturation of phagosome
    • Overexpression of Rab5 on the phagosomes harbouring bacilli causes maturation arrest at early endosomal stage
48
Q

graniuloma in MTB infection

A

Organised aggregate of immune cells that surround a foci of infected tissues.

classic lesion seen in MTB infection

infected macrophages produce a strong pro inflam response TNF-a is key. these signal recuit more cells to the site

49
Q

steps in tubercle/ granuloma formation

A

macrophages alone arent enough for intiation of the granuloma forming multinucleated giant cells (MGCs)

infected macrophages release tnf-a to attract more cells

mtb products participate in granuloma production- something mtb wants as part of pathogenesis

foamy macrophages

T cells and B cells and neutrophils

50
Q

kinds of granuloma (5)

A

ficrocalcific

non-necrotic

caseous

suppurative

cavitary

51
Q

factors associated with bacterial latency

A

ability to alter phagolysosome maturation

mtb can persist within endosomes for years

centre of the granuloma is hypoxic, little nutrient availabilty, low pH → causes a shift in response (latency associated genes) → dormancy allows organism to survive

52
Q

Stage 3 MTB reactivation

A

likely due to the host immune response

caused by immune suppresion of some sort

HIV is a potent factor for reactivation for latency

Rescusitation promoting factors are critical components for revival

tissue destruction allows for bacterial dissemination and transmission

ILOs (5 decks)

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