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Module 2 > Mycobacterium Pathogenesis > Flashcards

Mycobacterium Pathogenesis Flashcards

1
Q

What is the mechanism underlying granuloma formation?

A

resistance to microbicidal effects of a type 1 response results in chronic low level infection that requires an ongoing Th1 response to prevent pathogen proliferation and spread.

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2
Q

What is the characteristic feature of granulomas?

A

fusion of several macrophages to form multinucleated giant cells

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3
Q

Where are multinucleated giant cells found in the granuloma?

A

border of the central focus of macrophages and lympphcytes which surround them

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4
Q

Waht are type 1 cells?

A

NK cells ICL1 and Th1 cells

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5
Q

What are teh 3 general strategies for intracellular suvirval?

A

blockade of phagosome-lysosome fusion; escape from the phagosome into the cytosol and resistance for killing mechanisms within thep hagolysosome

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6
Q

What is tuberculin?

A

complex extract of peptides and carbohydrates derived from M.tuberculosis

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7
Q

Who gets a positive mantoux test?

A

those who have had BCG or have been infected by M.tb

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8
Q

What response causes a reaction with the mantoux test?

A

Th1 effector response- delayed type hypersensitivty reaction

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9
Q

What species make up the M.tb complex?

A

M.tb; M.africanuum and M.cannetti; M.bovis and M.microti

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10
Q

What does M. microti target?

A

small vertebrates

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11
Q

Which continent has all strains of M.tb and how does this relate to theories abotu the history of TB?

A

Africa- lines up with theory that TB evolved and spread with huams n

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12
Q

What is a problem with M.tb strains and research?

A

mainly made of Euro-American strains which does not reflect the global strain prevalence

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13
Q

What are teh 2 tests for determining latent TB?

A

TST and IGRA (immunoglobulin gamma release assay)

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14
Q

How is TB transmitted?

A

airborne

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15
Q

What is thought to vast amount of people who are connected with TB?

A

eliminate using their innate immune repsonse- will be completely in all testing as no T cell priming

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16
Q

What is multidrug resistant TB defined as?

A

resistance to at least isoniazid and rifampicin

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17
Q

What is XDR-TB defined as?

A

resistance to isoniazid and rifampicin; fluoroquinolone and any of the 3 injectable second line aminoglycosides

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18
Q

When is latent TB defined as being subclinical?

A

once there is positive culture or sputum smear- can transmit

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19
Q

What region of the genome is different between TB and BCG?

A

RD1

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20
Q

What does RD1 encode?

A

ESX-1 secretion system

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21
Q

what is the function of ESX-1?

A

once the bacteria have eben internalised in a phagosome by the host macropahges, ESX-1 mediates the delivery of bacterial productsi n to hte macropahge cytoplasm

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22
Q

What are the 2 broad outcomes of exposure to M.tb?

A

elimination or persistence of the pathogen

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23
Q

Why does a positive TST or IGRA not automatically mean a patient will benefit from LTBI treatment?

A

some individuals who sliminate the infection via the adaptive immune repsonse may have a positive test depending on whether they primed their T cells responses

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24
Q

What are the dominant cell type that M.tb infects?

A

alveolar macrophages

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25
Q

How do alveolar macropahges internalise M.tb?

A

receptor-mediated phagocytosis

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26
Q

What is the effect of surfactant D in M.tb phagocytosis?

A

can prevent it

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27
Q

What happens if the alveolar macrophages are no able to eliminate the bacteria?

A

bacteria invades the lung interstital tissue by direct infection fo the epithelium or the alveolar macropahges infected with M.tb migrating the lung parenchyma

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28
Q

What is one reason that M.tb uses the ESX-1 secretion system to inject bacterial products into the cytosol?

A

activation of cytosolic surveillance pathway resulting in a type I IFN response can help promote grwoth of intracellular bacterial pathogens

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29
Q

How is there georgraphical segreation in a grnuloma?

A

centre contains pro-inflammatory components whilst the surrounding tissue has anti-inflammatory ones

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30
Q

What suggests that other T-cell independet immune responses are involved in susceptibility to TB in HIV?

A

some studies indicate the risk of active TB disease is enhanced during hte early stage of HIV infection- when the number of CD4 cells is normal

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31
Q

Why is it unclear whether enhanced T cell repsonses give better protection?

A

in mice, increasing the total CD4 T cell responses lead to reduced protectio nand enahnced mortality

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32
Q

What suggests that M.tb might benefit from antigen-specfici CD4 T cell activation?

A

genomic studies of genes involved in the production of immunodominant CD4 T cell antigens do not vary across strains and lineages

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33
Q

How does M.tb develop drug ressitance?

A

through genetic mutations- not natural transformation

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34
Q

What are the 2 main mechanisms of M.tb drug resistance?

A

target modification; defective enzyme that converts a pro-drug into an active drug

35
Q

What are the 2 tests available for identification of LTBI?

A

TST and the IGRA

36
Q

What is the benefit of IGRA over TST?

A

IGRA can distinguish between BCG-induced and M.tb infection induced postiive TST

37
Q

How is TST perfomed?

A

intradermal infection of 5 tuberculin units of purified protein derivative

38
Q

What are the disadvantages of TST?

A

specificity is compromised by BCG vaccination and exposure to non-tuberculous mycobacteria; limited predictive value- most individuals with positive TST do not progress to active TB

39
Q

How is IGRA carried out?

A

in vitro blood test of cell-mediated immune response- measure T cell release of IFNy following stimulation by RD1-encoded antigens

40
Q

Why are RD1 antigens more specigic for M.tb than PPD antigens?

A

they are not encoded in the genome of any BCG vaccine strains or most species of non-tuberculous mycobacteria

41
Q

What are the 4 main technologies for detection of active TB disease?

A

imaging-CXR and PET-CT; microscopy of sputum; culture based methodsl moelcualr tests

42
Q

What is LAM rapid test?

A

detection of lipoarabinomannan antigen in urine

43
Q

When should LAM rapid test be used?

A

HIB positive adults with signs of active TB with <100 CD4 or very ill HIV patients (specificity and sensitivity is highest in these patients)

44
Q

What does the Xpert TB/Rif assay detect?

A

detect mycobacterium tb complex and ressitance to rifampicin

45
Q

How does Xpert MTB/RIF assay work?

A

nucelic acid amplification system test using sputum

46
Q

Why is sputum smear microscopy difficult in children?

A

young children are unable to produce sputum; disease may be extrapulmonary and low numbers of bacilli in children with TB

47
Q

What are the methods of detection of drug resistance?

A

phenotypic; culture-based (ability of bacteria to grow in presence of anti-TB drugs); moeclular based (detection of genetic mutations)

48
Q

What is the efficacy of BCG vaccine against pulmonary TB in adults?

A

0-80%

49
Q

What is the effect of BCG vaccine in children?

A

infants and 5 years protects from severe, extrapulmonary forms of active TB disease– 50-80%

50
Q

What is the most common drug to be resistant to in TB?

A

isoniazid

51
Q

What is the lifetime risk of latent TB converting to active TB?

A

10%

52
Q

What happens when bacteria are phagocytosed by alveolar macrophages?

A

pro-inflammatory response; recruit mononuclear cells; buidling blocks for granuloma

53
Q

What is the caseum?

A

area rich in lipis and debris from necrotic macropahges

54
Q

What is foudn between the macropahges and lymphocytes in the granuloma?

A

fibrotic region with ECM and fibroblasts

55
Q

What happens when there is breakdown of the granuloma?

A

stimatulion of mycobacterial growth and then release of large numbers of bacteria

56
Q

What is recruited to the phagosome to reduce the pH?

A

V-H ATPase

57
Q

What are the features of live BCG phagosomes?

A

limited acidication-reduced V-ATPase; contain early endosome markers- Rab5 and 14 (blocking lysosome fusion)

58
Q

What are the 3 strategies for mycobacterial arrest of phagosome maturation?

A

interactiosn with surface receptors; modification of phagosomal lumen; modification of phagosomal membrane

59
Q

What is the effect of CR3 uptake of Mtb?

A

prevents respiratory burst; blocks phagosome maturation

60
Q

What does uptake of Mtb by TLR2 stimualte?

A

IL-12 and iNOS

61
Q

How does Mtb modify the phagosomal lumen?

A

secreted acid phosphatase; lipoarabinomannan; protein kinase G

62
Q

What is the effect of secreted acid phosphatase?

A

cleaves PI 3-kinase and blocks phagosome-late endosome fusion (PIP3 is essential for phagolysosome biosynthesis)

63
Q

What is the effect of lipoarabinomannan?

A

inactivates macrophages; scavenges oxidative radicals

64
Q

What is the effect of protein kinase G

?

A

protein kinase G- blocks delivery of mycobacteria to lysosome

65
Q

What happens when AX20017 is used to block protein kinase G?

A

M.tb are found in the lysosome

66
Q

How does M.tb modify the phagosomal membrane?

A

mycobacterial lipids/proteins traffic out of immature phagosome

67
Q

What proteins are invovled in trafficing mycobacterial lipids/proteins out of immature phagosome?

A

PDIM and PIM (pthiocerol dimycocerasat and phosphatidylinositol mannosides)

68
Q

What do lipids released in to vacuole accumulate in?

A

multilamellar bodies which are released by exocytosis

69
Q

What happens to the exosomes with lipids from M.tb?

A

internalised by neighbouring cells

70
Q

Why is treatment difficult and prolonged?

A

cell wall; slow replication time; intra-cellular niche

71
Q

Which TB drug is classed as bactericidal and target rapidly dividing bacilli?

A

isoniazid

72
Q

Which TB drugs are considered sterilising drugs killing persistent, nonreplicating organisms?

A

rifampicin and pyrazinamide

73
Q

What is antibiotic tolerance?

A

reduced susceptibility to killing by cell wall-active antibiotics- feature of persistent bacilli and LTBI- rate of bacterial killing is proportional to the rate of bacterial replication and metabolic activity

74
Q

What is dormancy?

A

bacteria are viable but exhibit reduced metabolic activity

75
Q

Waht is LTBI traditionally thought of?

A

population of nonreplicating, metabolically quiescent organisms that have entered a dormant state as an adaptive response to immune-based containment mechanisms

76
Q

What suggests that the classical definition of LTBI of dormancy is incorrect?

A

isoniazid can prevent reactivation disease indicates that some portion of bacilli are sporadically multiplying

77
Q

How is the population of LTBI considered?

A

heterogenous bacillary population with some more rapidly replicating and some which are metabolically quiescent

78
Q

How do LTBI arise?

A

6-8 weeks after infection, granulomas undergo necrosis killing the majority of tubercle bacilli and destruction of host tissue with the small proportion of bacilli surviving in an altered state- LTBI

79
Q

What suggests the importance of CD4 T cells in anti-TB immunity?

A

knock out mice have a much greater increase in bacillary numbers and death rate ; also prevent reactivation as depletion 6 months after infection results in rapid reactivation

80
Q

What suggests that the role of CD4 cells in their protection is independent of IFNy and macropahge activation?

A

CD4 depletion did not result in diminshed expression of IFny or iNOS activity

81
Q

What suggests that protein kinase G is important in Mycobacterial pathogenicitiyu?

A

it is the only soluble kinase maintained in all pathogenic mycobacteria including mycobacterium leprae- which is considered to have the minimal genes required for pathogenicity- without tey show attenuated phenotype, cannot resist lysosomal transfer and are rapidly degraded

82
Q

How is protein kinase G thought to work?

A

phosphorylates a host molecule therby preventing the actiivty of the host factor in carrying out phagosome-lysosome fusion

83
Q

Why is protein kinase G an attractive target for inhibition?

A

this wouldn’t be interfering with mycoabcterial physiology but allowing macrophage to carry out its innate antimicrobail activity; its secreted so drug does not need to get through teh impermeable mycobacterial cell wall

Module 2 (38 decks)

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