Pathogenesis of Mycobacterium tuberculosis (MED 1 ILOs) Flashcards
LOs
Probability that TB is transmitted depends on:
- Infectiousness of person with TB disease (dose)
- environment in which exposure occured
- length of exposure
- virulence (strength) of tubercle bacilli
Best way to stop transmission of TB is:
isolate infectious persons
provide effective treatment to infectious persons ASAP
Risk factors for TB
- 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?
outcomes of exposure to TB
you get infected or you dont get infected
out of those that do get infected, what 2 things can happen next?
you get dormant TB (90%) or you get active TB (10)
dormant TB
asymtpomatic, subclinical
no tB disease
not infectious to others
can last a lifetime
presence if cellular immune response
5-10 % risk of reactivation
active TB
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
activation of infection results in
disease
post primary infectino/ secondary TB
due to loss of immune control of infection (in the granuloma)
active disease presentation
infection sites of TB
- 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
methods of diagnosing TB
- 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
TST (tuberculin skin tests/ mantoux)
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
Problems with TST
- 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
interferon gamma release assay
- 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
prevention, treatment and resistance
- 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
what vaccine do we give for TB?
- BCG- M.bovis attenuated strain
- stops the DEVELOPMENT of infection. does not stop its progression
- protective against severe infection in children
- some efficacy in severity of disease among those vaccinated
- efficacy varies rgeatly depending on the levels of TB in the population
antitubercle drugs
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
what are the 4 main drugs used to treat TB
isoniazid + pyridoxine
rifampicin + ethambutol
fluoroquinolone
inhibs DNA synthesis and supercoiling by targeting topoisomerases
rifamycin
: inhibs RNA synthesis by targeting RNA polymerase
streptomycin
inhibs protein synthesis by trgeting 30S subunit
macrolides
target 23S ribosomal RNA, inhinbiting peptidyl transferase
isoniazid and theionamide
inhibs mycolic acid synthesis
ethambutol and pyrasinamide
inhibs cell wall synthesis
relevance of mycolic acid in TB
found in the cell wall
helps the organism survive inside macrophages
inherent defences of TB against drugs
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
TB emergence of resistance
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
Mycobacterium resistance types
MDR-TB
X-DR
multidrug resistant TB
develeoping during treatment process to 2 (isoniazid and rifampcin) this is natural. treat with second line drugs
XDR- TB
extended. includes resistance to secind and third line drugs. there is no standardized treatment available
mycobacterium tuberculosis complex
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
general characteristics of mycobacterium
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
cell wall of mtb
- 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
mycolic acid
characteristic of mycobacterium
acid fastness
immunostimulatory
mtb pathogenesis
- 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)
early progression of TB
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
stages of infection
disease course has 3 main stages:
- Invasion- pre-cellular immune response
- Persistance- post cellular response
- Reactivation- secondary acute infection-
stage 1 invasion
- 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
why can this organism use so many receptors to invade cells
- 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
problem with using receptors in innate immunity
tb can use them to invade cells
induction of cellular immunity
- 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
macrophage reactivation by the cellular immune system
- 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
stage 2 inhibition of phagosomal maturation
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
graniuloma in MTB infection
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
steps in tubercle/ granuloma formation
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
kinds of granuloma (5)
ficrocalcific
non-necrotic
caseous
suppurative
cavitary
factors associated with bacterial latency
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
Stage 3 MTB reactivation
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
