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Module 2 > Mycobacterium Immunity > Flashcards

Mycobacterium Immunity Flashcards

1
Q

What influences transmission of M.tb?

A

exposure duration and physical distance within shared space; mycobacterial load; immune status of the contact and index case

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2
Q

What receptor recognises lipoarabinomannan?

A

C-type lectin receptors-mannose receptor

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3
Q

What recognises trehalose 6,6-dimycolate?

A

scavenger receptors

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4
Q

What induces IL-12 prodction?

A

TLR9 and TLR2

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5
Q

What is the function of IL-12 in TB?

A

deives DC maturation and activation of T cells

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6
Q

What is IL-1b secretion dependent on?

A

inflammasome and the RD1 region of mycobacteria

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7
Q

What is the result of higher IL-10 in TB ?

A

reduces the protective response to M.tb

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8
Q

What is the effect of IL-10 on other cytokines?

A

reduces IL-12 nad TNF levels

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9
Q

What is the function of TNF in TB?

A

key role in granuloma formation and maintenance; absence gives reduced chemokine expression and phagocyte activation

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10
Q

What is the function of type I IFNs?

A

associated with enhanced bacterial load and active disease

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11
Q

What is the effect of macropahge activation on intracellular infection of TB?

A

activation prevents TB causing phagosomal arrest

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12
Q

What is the effect of IFNy in mediating killing bacteria?

A

stimulates ROI and RNI as well as autophagy- induces immunity related GTPases

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13
Q

What effect does opsonisation have on bacterial killing?

A

interaction with Fc-receptor promotes phagosome-lysosome fusion and increases ROI

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14
Q

What is the function of microRNAs?

A

regulate gene expression at post-tran iprtional level

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15
Q

What is the function of microRNAs during infection?

A

inhibit host autophagy; block apoptosis; suppress inflammatory cytokine production

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16
Q

How can microRNAs be used in TB identigication?

A

infection specific- therefore can be used as a biomarker for TB

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17
Q

What is the effect of neutrophilia in TB?

A

high levels can be detrimental to the clearing of M.tb

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18
Q

What is the potential effect of NETs in M.tb?

A

trap mycobacteria but do not kill them- however might help macropahge phagocytosis

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19
Q

What receptors do DCs use for phagocytosis?

A

CTLs e.g DC SIGN

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20
Q

What happens to M.tb infected DCs?

A

do not function optimally- M.tb inferferes with their maturation

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21
Q

What activates mast cells in M.tb infection?

A

LAM activates their TLR2

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22
Q

What is the function of necrosis in M.tb?

A

used by the bacteria to exit the macrophage, evade the host defences and spread

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23
Q

What is apoptosis associated with in terms of the pathogen?

A

diminished pathogen viabiliy

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24
Q

What caspase do both the extrinsic and intrinsic pathways of apoptosis converge upon?

A

3

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25
Q

What enzyme mediates the process of autophagy?

A

PI 3-kinase

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26
Q

How does autophagy help in fighting M.tb?

A

can eliminate intracellular M.tb by overcoming block in phagosome maturation and delivering bacteria to degradtive phagolysosome

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27
Q

What type of adaptive resposne is seen to M.tb?

A

primarily cell mediated- Th1 not Th2

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28
Q

What is the function of the humoral response to M.tb?

A

probably non-protective but role in opsonisation and blockage at mucosal surfaces

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29
Q

What is seen in B-cell deficient mice with M.tb infection?

A

aggravated immunopathology and neutrophilia

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30
Q

What is the evidence for involvement of CD4 cells in M.tb infection?

A

enhanced susceptibility in mice when knock out CD4 or MHC-II and in man- HIV

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31
Q

What is seen in CD1- restricted T cells knock outs in mic with TB?

A

no effect- however it appears the important isotype in humans is not present in mice

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32
Q

What happens to yd T cell knock out mice with TB?

A

enhanced susceptibility- increased neutrophils in granulomas

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33
Q

What is the ligand for yd T cells?

A

phospholigands

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34
Q

What is the ligand for CD1 T cells?

A

lipids

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35
Q

What is the function of granulysin produced by CD8 T cells?

A

enters infected cells and kills M.tb

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36
Q

What are the lipid antigens of TB that CD1 T cells recognise?

A

cell wall mycolic acids; PIM (phosphatidyl inositol mannoside) and lipoarabinomannan

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37
Q

What are the effector functions of CD1 restricted T cells?

A

pro-inflammatory cytokine production; cytolytic activity; granulysin killing of bacteria

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38
Q

How does cross-priming occur to CD8 cells?

A

via apoptotic vesicles from infected macropahges

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39
Q

Where do yd T cells accumulate?

A

lungs and lymphoid tissue- seen in granulomas

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40
Q

What are the cytotoxic functiosn of yd T ells?

A

cytokine and granzyme B prodution

41
Q

What happens to MHC II express ion in infected macropahges?

A

inhibited

42
Q

When do DCs move to the peripheral lymphoid system?>

A

7-9 days post-infection

43
Q

Whys is the understanding of cytokines and CD4 T cells rele in TB incomplete?

A

frequency and cytokine proilfe of mycobacteria-specific T cells did not correlate with protection from or susceptibility to the subsequent development of TB- things understood as critical components do not translate into immune correlates of protection against disease

44
Q

What are the risk factors for development of TB?

A

HIV coinfection; immunodeficiency; DM; overcrowding; malnutrition; general poverty

45
Q

What is the only accepted biomarker of treatment response?

A

conversion to negative culture from sputum after 2 months of treatment

46
Q

Waht is an issue with TST in latent infection?

A

more frequently negative in those individuals most at risk of progression to active disease- young; alederly and immunosuppressed

47
Q

What study demonstrates the heterogeneity of latent and active TB?

A

cynomolgus macaque model of TB- where the same mode of infection resulted in varying pathological presentations: rapid active disease; slower progression to active disease; and thsoe who had no evidence of disease

48
Q

What is the blood transcriptional signature of active TB dependent upon?

A

IFN-inducible blood transcriptional signature which is diminshed upon treatment- extent of signature correlated with the extent of radiographic disease- present only in 10-20% of latent individuals

49
Q

What is the caseous core a result of?

A

cell lysis and the result of a central hypoxic, hostile environemtn

50
Q

What suggests the inhibition of apoptosis by TB is a virulence mechanism?

A

inactivation of the secA2 gene which encodes a component of a virulence protein secretion system, enchanced epoptosis by diminishing secretion of mycobacterial superoxide simutase and increased priming of CD8 cells and CD4 responses

51
Q

Why happens to M.tb infected macropahges that undergo apoptosis?

A

rapidly englufed by uninfected mcarophages through a process- efferocytosis which further compartmentalises the bacilli, delivering the bacilli within the apoptotic cell to the lysosome

52
Q

How do virulent strains of M.tb cause macrophage necrosis rather than apototosis?

A

induce LXA4 and inhibit PGE2 production- mice which cannot synthesise LXA4 undergo apotosis even with virulent M.tb and mcroaphges which cannot produce PGE2 undergo necrosis even with avriulent strains

53
Q

Although high neutrophils are generally detrimental in TB, what protective role can they play?

A

facilitate activation of naive antigen specific CD4 cells by delivering bacilli to DCs in a form that makes DCs more effective initiators of CD4 T cell activation

54
Q

What effect does proapoptotic strains of M.tb have on neutrophils?

A

fewer bacteria per neurtophils, accelerated bacterial acquisitionby DCs and earler trafficking of DCs to lymph nodes and faster CD4 priming

55
Q

What determines whether neitrophils have a protective or detrimental effect during M.tb infection?

A

may be determined by the genetics of the pathogen and host as well as the stage of TB disease

56
Q

Why may neutrophilia during TB indicate failed Th1 immunity or loss of IFNy responsiveness?

A

IFNy inhibits CD4 production of IL17 impairing both neutrophil survival and accumulation of pathogenic neutrophils in the infected lung

57
Q

What effect do type I IFNs have on IFNy?

A

results in a loss of IFNy responsiveness

58
Q

Give examples of macrophage functions that can be enhanced by vitamin D tx?

A

phagocytosis; autophagy and antimicrobial peptide production

59
Q

What happens to mice deficient in Arg1 in Mtb?

A

better protection against MTb

60
Q

What mycobacterial protein can induce M2 macrophage polarisation?

A

DnaK

61
Q

What are the features of foamy macrophages?

A

reduced phagocytosis; reduced antigen processing capacity and increased secretion of TGF-b

62
Q

Which Mtb products induce foamy macrophages?

A

mycolic acids; lipopeptides and early secretory antigen-6

63
Q

What happens to DCs that are infected with Mtb?

A

reduced surface expression of b2 integrin and have reduced ability to reach the LNs and initiate adaptive immune responses; increased expression of CD13 which inhibited T-cell activation

64
Q

What happens with mannose-capped lipoarabinomannan binds to DC-SIGN?

A

induces the production of IL-10 which impairs DC maturation and expression of co-stimulatory molecules; inhibts IL-12 production

65
Q

Which are the most abundant cell type appearing bronchoalveolar lavage and sputu of active po TB pts?

A

nuetrophils

66
Q

What happens when apoptotic neutrpohils and purified neutrophils granules are taken up by macrophages?

A

contain active antimicrobial peptides and lead to inhibition of bacterial replication

67
Q

What area of the Mtb genome is involved in inducing neutrophil necrosis and prevention of their apoptosis?

A

RD-1 virulence factors

68
Q

What happens when TNF is knocked out?

A

M.tb is fatal, with increased bacillayr load and necrosis within granulomas; increased susceptibility and in persistent TB results in fatal reactivation of infection (anti-TNF with RA)

69
Q

What is hte major role of TNF in Mtb infection?

A

boosting intracellular killing of bacilli and maintaining the grnauloma

70
Q

What happens to mice deficient in LXA4 with Mtb?

A

(LXA4 promotes necrosis)- resistnant to Mtb infection with lower bacterial loads in the lung

71
Q

What happens to mice deficient in PGE2 with Mtb?

A

greater susceptbility with high bacterial loads in thel ung

72
Q

What is the effect of MMP-9 in zebrafish?

A

regulates monocyte recruitment to the granuloma and also is involved in lung matrix destruction and worse outcomes in TB-modulates the immune repsonse and drives pathology

73
Q

What are the conflicting mechanisms for vitD in Mtb?

A

antagnoises Mtb-induced Th1 immunity but is required for IFNy mediated restriction of intracellular growth of Mtb; and induction of cathelicidn and autophagy

74
Q

Which TLRs play a role host recognition of Mtb?

A

TLR2; TLR4 and TLR9

75
Q

How do IFNy and IL-22 produced by NK clels inhibit intracellular growth?

A

enhance phagolysosomal fusion

76
Q

What happens to mice deficient in MyD88?

A

highly susceptible to MTb infection

77
Q

What happens to mice deficient in TLR2?

A

defective granuloma formation and enhanced susceptibility to pulmonary TB

78
Q

How do macropahges escape from phagosomes into macrophage cytosol?

A

via ESAT-6 secretion system-1 (ESX-1)

79
Q

What is seen with activation of NOD2 by muamyl dipeptide in human alveolar macrophages infected with Mtb?

A

increase intracellular control of bacterial growth and recruitment of autophagy-associated proteins to the bacteria-containing autophagosome

80
Q

What factor has been foudn to inhibit phagosome acidification?

A

Mtb PIMs ; and a protein tyrosine phosphatase PtpA which binds to the H-subunit of macrophage vaculoar H-ATPase

81
Q

What is the potential mechanism by which Mtb PIMs inhibit phagosome acidification?

A

promote fusion between phagosome and early endosomes which may involve Rab14 which is specifically recruited to mycobacteria to favour this process

82
Q

How is Mtb ManLAM involved in immune evasion?

A

by binding to MR has been foudn to limit phagosome maturation

83
Q

What is thought to allow Mtb survival in low pH conditions?

A

aprABC locus (acid and phagosome regulated) - modulates cell wall lipid synthesis

84
Q

What indicates a TLR4 mediated pathway for the induction of autophagy?

A

Mtb localisation to autophagosomes in infected macrophages markedly increased when cells were treated with LPS

85
Q

How many Mtb inhibit the fusion of lysosomes with phagosomes?

A

selectively exludes the GTPase Rab7 (a late endosomal marker) and LAMP1 while retaining Rab5 on the phagosome

86
Q

What is the function of apoptosis in Mtb infection?

A

restricts Mtb growth during the early phase of infection and induces the acquired cellular immune repsonse

87
Q

How does Mtb use apoptosis and necrosis generally in immune evasion?

A

blocks apoptosis and induces necrosis to evade or delay antigen presentation

88
Q

What suggests that CD4 T cells are important in controlling Mtb?

A

CD4 deficient mice are unable to control bacterial growth and succumb to disease; HIV patients are highly susceptbile to TB

89
Q

What is seen in T cell responses in M.tb?

A

delay in onset of T cell activation and functional effector T cell responses

90
Q

What may cause the delay in T cell responses with TB?

A

Mtb inhibtion of apoptosis of macrophages and neutropjils which delays or inhibits the antigen presenting capacity of DCs; regulatory CD4 T cells which inhibit and delay the arrival of effector T cells during early TB and IL-10 which delays production of IFNy and IL-17;

91
Q

What is the induction of protective IFNy T cell responses against M.tb dependent on?

A

IL-12

92
Q

How do IFNy levels correlate with TB disease?

A

IFNy levels are highest in patients with more severe disease nad dominsh with anti-TB chemotherapy

93
Q

Why is there thought to be additional qualitative defects in CD4 T cells other than deficiency in HIV?

A

risk of TB is increased from the time of HIV-1 acquisition before CD4 T cell deficiency is profound

94
Q

What suggests that type I IFNs exacerbate TB infection?

A

mice deficient in type I IFN receptors have reduced bacterial load and increased survival

95
Q

Why do type I IFNs exacerbate TB infection?

A

suppreses production of host-protective cytokines eg IL-1: TNF and IL-12 perhaps by induction of IL-10; impairs responsiveness to host-protective cytokines- preventing macropahge activation by Th1

96
Q

Which can induce high type I IFN responses in TB?

A

hypervirulent strains and concurrent viral infections

97
Q

What are the major mechanisms by which IL-10 dampens the immune response?

A

inhibits the antigen-presenting function of macrophages and DCs and the production of cytokines eg IL-12 reducing Th1 responses; inhibits nitric oxide and production of TNF reducing intracellular killling

98
Q

What happens to IL10 knock out mice?

A

decreased bacterial loads in lungs and spleens of M.tb infected mice

99
Q

What demonstrates the importance of afinely regulated immune response to control TB?

A

CD4 T cells are required for M.tb infection, however when there is deletion of PD1 (a regulator of prolioferation and cytokine production) there is als oincreased susceptibility to ifnection

Module 2 (38 decks)

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