11 Bacteria: Mycobacteria Flashcards
General characteristics
class
02 consumption
shape
cell wall
cell culture
Disease
class
acid fast bacteria
02 consumption
aerobic
shape
rod
cell wall
Cell membrane, peptidoglycan, then hydrophillic, waxy cell wall compromising mycolic acids and arabinogalactan (40% cell wall mass of ovr dry mass)
cell culture
rapidly growing (M. abscessus) and slowly growing (M. leprae, M. tuberculosis) species but also poortunistic like M. chimaera
Slowly growing evolved later and associated with pathogenicity and intracellular life cycle
Disease
Tuberculosis
Leprosis (leprae and lepromatosis)
NTM diesase (all others)
Drug resistance mechanism in general
cell wall impermeability
dormancy with low metabolic acitivity
beta lactamse and low affinity of Penicilin BP
other transpeptidases
methylase alters drug binding site from macrolides
3 main virulence mechanism
Adhesins (binding)
Toxins (effect on host cell)
Effector (mimic of euk. protein)
Secretion sytsem
name
function
Location
Genes
Name
Type 7 secretion system
Function
Survival in host and evasion of immune system
Location
does not span outer cell wall
Genes
5 of gene clusters with different functions of different secretion system, not every mycobateria have all system, M tuberculosis only with all 5
Mycobacterium abscessus
Disease
Smooth -> rough
Virulence factor
Virulence mechanism (smooth vs rough)
Disease
respiratory, skin, mucosal infections with most antibiotic resistance, only 45% treatment sucsess
Smooth -> rough
Mutation in efflux genes lead to transportation of GPL outside of cytosol, no efflux -> rough colony (associated with pathogenicity)
Virulence factor
cord factor Trehalose Dimycolate to protect against phagocytosis (phagosome)
Mechanism
taken up via biofilms, amebae, etc. -> innate immune response -> taken up by macrophages
Smooth: bacteria with GPL layer taken up in the phagosom, infected can be cleared most of the time
Rough: with TLR2 ligand taken up but cant be digested by phagosom, replicate extracellular, failed immune response
Mycobacterium chimaera
Pathogenicity
usually harmless, but hypervirulent sublinages occur linked to HCUs
Mycobacterium leprae /lepromatosis
Transmission
Disease
Therapy
General facts and why its hard to diagnose / work with?
Transmission
close contact with untreated patients
Disease
skin, nerves, mucosa, can take decades to develop, most cases India
Therapy
1-2 years: Dapsone, Rifampicin, Clofazimine
General facts and why its hard to diagnose
unculturable, gen time 12 days, only animal model armadillo, obligate intracellular
Cross immunity by M. tuberculosis could lead to decline in cases
Tuberculosis
High risk areas
species
Transmission
Lineages and mutations
High risk areas
South Africa, India
Species
Mycobacterium tuberculosis complex
Transmission
Airborne disease affecting humans, not in enviroment, 25% of world infected
Lineages and mutations
about 10 linegaes, 7 infecting humans, linage 2-4 depletion of TbD1
genomic segment Mtb-specific deletion1 region, MmpL involved in transport of large molecules: responsible for epidemics, increased resistance to ROS and hypoxid conditions
Tuberculosis vaccination
Name, what is it, protection and also used for ?
Lübeck disaster and what did it show?
in Future ?
BCG vaccine (Bacillus-Calmette-Guerin)
that is attenuated live vaccine lacking ESX-1 virulence genes
high protection in infant against meningitis, protection of pulmonary TB in adult just 0-80%, declines near equator due to cross immunization with NTMs
also used to treat bladder cancer
Lübeck
1930: contaminated BCG culture with virulent strain
there are some hyper-susceptible hosts, mortality follows dose response curve and there is a remarkable intrinsic resistance against tuberculosis (68%)
Future
many different antibiotica in all trial phases
Tuberculosis diagnostics
MGIT960
GeneXpert
line probe assay
Microscopy
Gene Sequencing
MGIT960
7 days: Myc. detection + drug susceptibility testing
GeneXpert
1 day: MTB complex detection + Rifampicin resistance testing
line probe assay
1-2 days: Myc. detection + DST
Microscopy
1 day: Myc. detection
Gene Sequencing
2 days: Species differentiation + Pyrazinamide resistance testing
First line TB therapy
MDR-TB therapy
First line
2HRZE4HR: Rifampicin, Isoniazid, Pyrazinamide, Ethambutol for 4 months, then Rifampicin and Isoniazide for another 2 months
MDR-TB
4-5 drugs up to 24 months, >14k pills, severe side effects, 50% cure rate, severe burden
The dogma of fitness costs
definition
e.g.
but ?
Resistant tuberculosis bacteria often dissapear from organs and susceptible remain because of the fitness costs the mutation resulting in resistancy brings with it
Rifampicin resistancy slows down RNA polyermase activity
Additional mutations can compensate reduced enzymatic activity to enhance fitness in vivo
