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Flashcards in Mycobacterium Immunity Deck (99):
1

What influences transmission of M.tb?

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

2

What receptor recognises lipoarabinomannan?

C-type lectin receptors-mannose receptor

3

What recognises trehalose 6,6-dimycolate?

scavenger receptors

4

What induces IL-12 prodction?

TLR9 and TLR2

5

What is the function of IL-12 in TB?

deives DC maturation and activation of T cells

6

What is IL-1b secretion dependent on?

inflammasome and the RD1 region of mycobacteria

7

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

reduces the protective response to M.tb

8

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

reduces IL-12 nad TNF levels

9

What is the function of TNF in TB?

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

10

What is the function of type I IFNs?

associated with enhanced bacterial load and active disease

11

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

activation prevents TB causing phagosomal arrest

12

What is the effect of IFNy in mediating killing bacteria?

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

13

What effect does opsonisation have on bacterial killing?

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

14

What is the function of microRNAs?

regulate gene expression at post-tran iprtional level

15

What is the function of microRNAs during infection?

inhibit host autophagy; block apoptosis; suppress inflammatory cytokine production

16

How can microRNAs be used in TB identigication?

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

17

What is the effect of neutrophilia in TB?

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

18

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

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

19

What receptors do DCs use for phagocytosis?

CTLs e.g DC SIGN

20

What happens to M.tb infected DCs?

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

21

What activates mast cells in M.tb infection?

LAM activates their TLR2

22

What is the function of necrosis in M.tb?

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

23

What is apoptosis associated with in terms of the pathogen?

diminished pathogen viabiliy

24

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

3

25

What enzyme mediates the process of autophagy?

PI 3-kinase

26

How does autophagy help in fighting M.tb?

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

27

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

primarily cell mediated- Th1 not Th2

28

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

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

29

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

aggravated immunopathology and neutrophilia

30

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

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

31

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

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

32

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

enhanced susceptibility- increased neutrophils in granulomas

33

What is the ligand for yd T cells?

phospholigands

34

What is the ligand for CD1 T cells?

lipids

35

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

enters infected cells and kills M.tb

36

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

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

37

What are the effector functions of CD1 restricted T cells?

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

38

How does cross-priming occur to CD8 cells?

via apoptotic vesicles from infected macropahges

39

Where do yd T cells accumulate?

lungs and lymphoid tissue- seen in granulomas

40

What are the cytotoxic functiosn of yd T ells?

cytokine and granzyme B prodution

41

What happens to MHC II express ion in infected macropahges?

inhibited

42

When do DCs move to the peripheral lymphoid system?>

7-9 days post-infection

43

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

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

What are the risk factors for development of TB?

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

45

What is the only accepted biomarker of treatment response?

conversion to negative culture from sputum after 2 months of treatment

46

Waht is an issue with TST in latent infection?

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

47

What study demonstrates the heterogeneity of latent and active TB?

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

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

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

What is the caseous core a result of?

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

50

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

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

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

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

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

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

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

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

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

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

55

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

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

56

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

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

57

What effect do type I IFNs have on IFNy?

results in a loss of IFNy responsiveness

58

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

phagocytosis; autophagy and antimicrobial peptide production

59

What happens to mice deficient in Arg1 in Mtb?

better protection against MTb

60

What mycobacterial protein can induce M2 macrophage polarisation?

DnaK

61

What are the features of foamy macrophages?

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

62

Which Mtb products induce foamy macrophages?

mycolic acids; lipopeptides and early secretory antigen-6

63

What happens to DCs that are infected with Mtb?

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

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

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

65

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

nuetrophils

66

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

contain active antimicrobial peptides and lead to inhibition of bacterial replication

67

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

RD-1 virulence factors

68

What happens when TNF is knocked out?

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

What is hte major role of TNF in Mtb infection?

boosting intracellular killing of bacilli and maintaining the grnauloma

70

What happens to mice deficient in LXA4 with Mtb?

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

71

What happens to mice deficient in PGE2 with Mtb?

greater susceptbility with high bacterial loads in thel ung

72

What is the effect of MMP-9 in zebrafish?

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

What are the conflicting mechanisms for vitD in Mtb?

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

74

Which TLRs play a role host recognition of Mtb?

TLR2; TLR4 and TLR9

75

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

enhance phagolysosomal fusion

76

What happens to mice deficient in MyD88?

highly susceptible to MTb infection

77

What happens to mice deficient in TLR2?

defective granuloma formation and enhanced susceptibility to pulmonary TB

78

How do macropahges escape from phagosomes into macrophage cytosol?

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

79

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

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

80

What factor has been foudn to inhibit phagosome acidification?

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

81

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

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

82

How is Mtb ManLAM involved in immune evasion?

by binding to MR has been foudn to limit phagosome maturation

83

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

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

84

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

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

85

How many Mtb inhibit the fusion of lysosomes with phagosomes?

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

86

What is the function of apoptosis in Mtb infection?

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

87

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

blocks apoptosis and induces necrosis to evade or delay antigen presentation

88

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

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

89

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

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

90

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

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

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

IL-12

92

How do IFNy levels correlate with TB disease?

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

93

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

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

94

What suggests that type I IFNs exacerbate TB infection?

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

95

Why do type I IFNs exacerbate TB infection?

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

Which can induce high type I IFN responses in TB?

hypervirulent strains and concurrent viral infections

97

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

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

What happens to IL10 knock out mice?

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

99

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

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