Mycobacterium Immunity Flashcards
What influences transmission of M.tb?
exposure duration and physical distance within shared space; mycobacterial load; immune status of the contact and index case
What receptor recognises lipoarabinomannan?
C-type lectin receptors-mannose receptor
What recognises trehalose 6,6-dimycolate?
scavenger receptors
What induces IL-12 prodction?
TLR9 and TLR2
What is the function of IL-12 in TB?
deives DC maturation and activation of T cells
What is IL-1b secretion dependent on?
inflammasome and the RD1 region of mycobacteria
What is the result of higher IL-10 in TB ?
reduces the protective response to M.tb
What is the effect of IL-10 on other cytokines?
reduces IL-12 nad TNF levels
What is the function of TNF in TB?
key role in granuloma formation and maintenance; absence gives reduced chemokine expression and phagocyte activation
What is the function of type I IFNs?
associated with enhanced bacterial load and active disease
What is the effect of macropahge activation on intracellular infection of TB?
activation prevents TB causing phagosomal arrest
What is the effect of IFNy in mediating killing bacteria?
stimulates ROI and RNI as well as autophagy- induces immunity related GTPases
What effect does opsonisation have on bacterial killing?
interaction with Fc-receptor promotes phagosome-lysosome fusion and increases ROI
What is the function of microRNAs?
regulate gene expression at post-tran iprtional level
What is the function of microRNAs during infection?
inhibit host autophagy; block apoptosis; suppress inflammatory cytokine production
How can microRNAs be used in TB identigication?
infection specific- therefore can be used as a biomarker for TB
What is the effect of neutrophilia in TB?
high levels can be detrimental to the clearing of M.tb
What is the potential effect of NETs in M.tb?
trap mycobacteria but do not kill them- however might help macropahge phagocytosis
What receptors do DCs use for phagocytosis?
CTLs e.g DC SIGN
What happens to M.tb infected DCs?
do not function optimally- M.tb inferferes with their maturation
What activates mast cells in M.tb infection?
LAM activates their TLR2
What is the function of necrosis in M.tb?
used by the bacteria to exit the macrophage, evade the host defences and spread
What is apoptosis associated with in terms of the pathogen?
diminished pathogen viabiliy
What caspase do both the extrinsic and intrinsic pathways of apoptosis converge upon?
3
What enzyme mediates the process of autophagy?
PI 3-kinase
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
What type of adaptive resposne is seen to M.tb?
primarily cell mediated- Th1 not Th2
What is the function of the humoral response to M.tb?
probably non-protective but role in opsonisation and blockage at mucosal surfaces
What is seen in B-cell deficient mice with M.tb infection?
aggravated immunopathology and neutrophilia
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
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
What happens to yd T cell knock out mice with TB?
enhanced susceptibility- increased neutrophils in granulomas
What is the ligand for yd T cells?
phospholigands
What is the ligand for CD1 T cells?
lipids
What is the function of granulysin produced by CD8 T cells?
enters infected cells and kills M.tb
What are the lipid antigens of TB that CD1 T cells recognise?
cell wall mycolic acids; PIM (phosphatidyl inositol mannoside) and lipoarabinomannan
What are the effector functions of CD1 restricted T cells?
pro-inflammatory cytokine production; cytolytic activity; granulysin killing of bacteria
How does cross-priming occur to CD8 cells?
via apoptotic vesicles from infected macropahges
Where do yd T cells accumulate?
lungs and lymphoid tissue- seen in granulomas
What are the cytotoxic functiosn of yd T ells?
cytokine and granzyme B prodution
What happens to MHC II express ion in infected macropahges?
inhibited
When do DCs move to the peripheral lymphoid system?>
7-9 days post-infection
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
What are the risk factors for development of TB?
HIV coinfection; immunodeficiency; DM; overcrowding; malnutrition; general poverty
What is the only accepted biomarker of treatment response?
conversion to negative culture from sputum after 2 months of treatment
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
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
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
What is the caseous core a result of?
cell lysis and the result of a central hypoxic, hostile environemtn
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
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
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
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
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
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
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
What effect do type I IFNs have on IFNy?
results in a loss of IFNy responsiveness
Give examples of macrophage functions that can be enhanced by vitamin D tx?
phagocytosis; autophagy and antimicrobial peptide production
What happens to mice deficient in Arg1 in Mtb?
better protection against MTb
What mycobacterial protein can induce M2 macrophage polarisation?
DnaK
What are the features of foamy macrophages?
reduced phagocytosis; reduced antigen processing capacity and increased secretion of TGF-b
Which Mtb products induce foamy macrophages?
mycolic acids; lipopeptides and early secretory antigen-6
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
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
Which are the most abundant cell type appearing bronchoalveolar lavage and sputu of active po TB pts?
nuetrophils
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
What area of the Mtb genome is involved in inducing neutrophil necrosis and prevention of their apoptosis?
RD-1 virulence factors
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)
What is hte major role of TNF in Mtb infection?
boosting intracellular killing of bacilli and maintaining the grnauloma
What happens to mice deficient in LXA4 with Mtb?
(LXA4 promotes necrosis)- resistnant to Mtb infection with lower bacterial loads in the lung
What happens to mice deficient in PGE2 with Mtb?
greater susceptbility with high bacterial loads in thel ung
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
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
Which TLRs play a role host recognition of Mtb?
TLR2; TLR4 and TLR9
How do IFNy and IL-22 produced by NK clels inhibit intracellular growth?
enhance phagolysosomal fusion
What happens to mice deficient in MyD88?
highly susceptible to MTb infection
What happens to mice deficient in TLR2?
defective granuloma formation and enhanced susceptibility to pulmonary TB
How do macropahges escape from phagosomes into macrophage cytosol?
via ESAT-6 secretion system-1 (ESX-1)
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
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
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
How is Mtb ManLAM involved in immune evasion?
by binding to MR has been foudn to limit phagosome maturation
What is thought to allow Mtb survival in low pH conditions?
aprABC locus (acid and phagosome regulated) - modulates cell wall lipid synthesis
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
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
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
How does Mtb use apoptosis and necrosis generally in immune evasion?
blocks apoptosis and induces necrosis to evade or delay antigen presentation
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
What is seen in T cell responses in M.tb?
delay in onset of T cell activation and functional effector T cell responses
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;
What is the induction of protective IFNy T cell responses against M.tb dependent on?
IL-12
How do IFNy levels correlate with TB disease?
IFNy levels are highest in patients with more severe disease nad dominsh with anti-TB chemotherapy
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
What suggests that type I IFNs exacerbate TB infection?
mice deficient in type I IFN receptors have reduced bacterial load and increased survival
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
Which can induce high type I IFN responses in TB?
hypervirulent strains and concurrent viral infections
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
What happens to IL10 knock out mice?
decreased bacterial loads in lungs and spleens of M.tb infected mice
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
