emma (L11) Flashcards
phylogenetic analysis and evolution of mycobacterium ulcerans, marinum and tuberculosis
Uclerans group is pathogens of humans
Other group is pathogens of amphibian and fish
Specialism in evolution - both pathogens produce a weird toxin mycolactone (large lactone that has analgesic properties, when you get the infection, and you get the symptoms on the skin, you still feel no pain or irritation) - so most people ignore it and don’t report it to clinics, so it disseminates and becomes more difficult to treat
BURULI ULCER cause by Mycobacterium ulcerans
indolent necrotizing disease of the skin, subcutaneous tissue, and bone. Buruli ulcer is presently the third most common mycobacterial disease of humans, after
Tuberculosis and leprosy, and the least understood of the three.
AUSTRALIA AND AFRICA
Epidermis formed a fold around the area
Full of macolactone - will subvert the immune system and stop the macrophage and the whole immune response (T cell activation and cellular response)
Kills the pain, can be ignored
Dermis is infected, begins to separate, the ferling in is separating from the upper layer
Underneath, there is a lot of destruction of the dermal layer and will develop into the bone - IRREVERSIBLE DEFORMITY - causes decay of the osteomyelitis and of the bone trabecula
Destroying the bone marrow and so the marrow too
conditions that are similar between M ulcerans and M . tuberculosis
Lipoglycans lipomannan (LM), mannose or arabinose-capped lipoarabinomannan (ManLAM and AraLAM) major virulence factors They scavenge reactive oxygen species in phagosome and allow macrophage colonisation
mycolactone targets scaffolding proteins which control actin dynamics in adherent cells and lead to cell death
also prevents production of many proteins. IMMUNE EVASION
immune evasion allows persistent or latent infection in macrophages and results in TLR2 dependent inhibition.
a reduction in antigen presentation causes a general mechanism of negative-feedback regulation that prevents excessive T cell-mediated inflammation
M ulcerans displays no tropism for schwann cells, causing degeneration. mycolactone diffuses into schwann cell to cause the painlessness that characterises the disease
Three features of M ulcerans as determinant for the pathogenesis of BU:
The low optimal temperature of growth that makes the skin its preferential target
- M ulcerans behaves as an intracellular microorganism triggering inflammatory cell responses and cell mediated immunity (and latency capability)
- The mycolactone-associated high cytotoxicity that contrasts with the intracellular traits of its mycobacterial nature (and analgesic effect)
- Bacillus Calmette-Guérin (BCG) vaccination was found to protect humans against BU osteomyelitis
Immunosuppressive effects of mycolactone
Immune system is compromised and instead of producing chemokines (proteins that activate t cells), we have dendritic cells and macrophages that are compromised to produce the chemokines
Chemokines would have stimulated the MHC reactivity which then in the lymph system, activate the t cells
REDUCTION OF T CELLS
mycolactone biosynthesis
Mycolatone is produced by repeating units of polyketides - SECONDARY METABOLISM and uses the components of primary metabolic fat synthesis (not that different from the antibiotic erythromycin
It’s like fat synthesis but without the reduction (making fat and allow the keto groups to be unsatisfied, so they round up and cyclise - produces polyketides)
The polyketide chain can cause cell death
Proposed transmission pathways of M. ulcerans
between the environment, mosquitoes, possums and humans:
- possums ingest ulcerans from env or infected by insects
- possums shed and amplify ulcerans
- insect vectors infected from possums or env
- ulcerans transmitted to humans by insect vector or direct contact with env
what is the insect vector?
aquatic bugs called HEMIPTERA act as the vector in africa
humans cleared out the forest and the vegetation and got more engaged in fishing and farming closer to the river
so the insects only had humans as targets now.
key difference between the endemic and non endemic areas
HUMAN ACTIVITY
non endemic area was largely unaffected by human activity
endemic area was deforested for agriculture and fishing
disrupting the environment like this has been identified as factors potentially favouring the establishment of M. ulcerans in remodelled environments.
evolution of M. ulcerans as a pathogen
- it is closely related phylogenetically to M tuberculosis, but causes Buruli ulcer disease
- Replication and persistence in BU lesions is influenced by production of mycolactone
- it induces apoptosis of infected host cells, inhibits production of the proinflammatory cytokine TNF-a by macrophages, and suppresses dendritic cell priming of T cells
- Mycolactone can diffuse from infected skin tissue to lymphoid organs (location of immune suppressive functions)
- Mycolactone also damages nerve cells, which contributes to the painlessness of BU
- genes required for mycolactone synthesis are carried on a virulence plasmid (horizontal gene transfer)
- other mycobacterial virulence factors were apparently lost by reductive evolution
treatment of buruli ulcer
- antimycobacterial drugs is effective in vitro
(no convincing evidence for effects in patients with BU)
(this is due to the lack of appropriate clinical trials and irreversible tissue damage once diagnosed too late)
2.As in leprosy and tuberculosis, treatment schedules included two or more active compounds, because monotherapy is bound to result in selection of drug-resistant strains
(a study gave 30 patients either rifampin+clofazimine, or placebo)
Johne’s disease and Mycobacterium avium subspecies paratuberculosis
Mycobacterium avium subspecies paratuberculosis (MAP), which causes Johne’s disease: severe wasting disease with chronic diarrhoea in cattle
DO WE NEED TO KNOW?
IF YES, MORE INFO ON L11 S21
Crohn’s disease
Some evidence for an association between MAP and Crohn’s disease
This supports MAP as a causal agent in Crohn’s disease
Strict regulations about MAP in cattle - gets passed in milks so have to check carefully so that humans don’t get infected through ingesting milk (the disease survives pasteurisation
