Lecture 11. Environmental Mycobacteria; Mycobacteria ulcerans - Buruli Ulcer Flashcards
What are environmental or non-tuberculous mycobacteria (NTM)?
Ubiquitous in environment – saprophytic organisms
Cause disease infrequently – opportunistic pathogens
In immunocompetent and immunocompromised people
No person-person transmission
Pulmonary disease is most common especially with those who have pre-existing lung disease
Also localised infections in lymph nodes, skin, soft tissue and rarely bones
Often misdiagnosed as TB
What can the risk factors of NTM disease be categorised as?
Host
Environmental
Organism
Where has NTM increased in prevalence?
North America, Europe, Asia over last few decades
What was the increase in NTM prevalence in the US from the early 1980s to 2013?
2.4 cases/100,000 to 15.2cases/100.000
What was the increase in NTM prevalence in the UK from 1995 to 2006?
0.9 cases/100,000 to 2.9 cases/100,000
What does disseminated mean?
Spreads throughout the body
What does pulmonary mean?
Targets the lungs
What classes of clinical diseases can environmental mycobacteria cause?
Pulmonary disease
Disseminated disease
Lymphadenitis (enlargement of lymph nodes, often infection)
Cutaneous disease
Nosocomial disease
What are examples of diseases caused by environmental mycobacteria?
Cervical lymphadenitis (head and neck)
Swimming pool granuloma
Buruli ulcer (M. ulcerans)
What is the treatment for NTMs?
Prolonged multi-drug therapy for pulmonary NTM (12-24 months)
What are the complications that are caused by NTMs?
High rates of re-infection (rather than recurrence)
Frequent adverse drug reactions
20-40% of MAC-lung disease patients initially fail to respond
Drug resistance
Co-morbidity
What is the causative agent of Buruli ulcer infection?
Mycobacterium ulcerans
What is a Buruli ulcer?
An indolent necrotising disease of the skin, subcutaneous tissue and bone
Indolent = causing little or no pain
Necrotising = death of tissues
Compared with TB and leprosy, how common and understood is Buruli ulcer?
Buruli is the third most common mycobacterial disease of humans, after tuberculosis and leprosy, and the least understood of the three
What is Buruli ulcer (BU) characterised by?
Painless, necrotic skin lesions
Which specie of mycobacterium is M. ulcerans closely related to?
M. tuberculosis
What profoundly influences the replication and persistence of M. ulcerans in BU lesions?
Production of mycolactone (a cytotoxin that has immunosuppressive properties)
Where is BU most prevalent?
West and Central Africa (Ivory Coast and Ghana most affected)
Previously reported cases in South America and China
How are humans infected with BU?
Little evidence of human to human transmission
Humans are infected from the environment or vectors
What is the environmental transmission route of BU into humans?
In endemic regions, the disease is highly focal and usually associated with wetlands or coastal regions
PCR testing of environmental samples, such as water, aquatic plants, soil, and detritus from swamps, has found evidence of M. ulcerans
What is the vector transmission route of BU into humans?
Insects such as mosquitoes and water-residing biting arthropods have been associated with M. ulcerans epidemiologically and via PCR testing and therefore proposed as vectors for transmission
In Victoria, Australia, evidence suggests that native possums might be involved in transmission
What were the key finding of detecting M. ulcerans DNA within the insect tissues from an endemic area?
Some types of insect more positive than others
Seasonal effect
Non-endemic area had no PCR positive insect pools
What is one of the key differences between endemic and non-endemic areas of M. ulcerans?
Human activity was far greater in areas where M. ulcerans was endemic (deforestation, agricultural and fishing activities)
Interventions disrupting the environment have been identified, in several studies, as factors potentially favouring the establishment of M. ulcerans in remodelled environments
What did a recent study testing mosquitos show?
66,000 mosquitos captured and tested, 5/1000 were positive for M. ulcerans (PCR)
Genome sequencing showed that M. ulcerans from people, possums and mosquitoes in same area were identical
Mouse model showed that mosquitoes can transmit M. ulcerans
What are the proposed transmission pathways of M. ulcerans between the environment, mosquitos, possums and humans?
Possums ingest M. ulcerans from the environment and/or infected by an insect vector
Possums amplify and shed M. ulcerans into the environment
Insect vectors become contaminated with M. ulcerans from the environment and/or from contact with infected possums
M. ulcerans transmitted to humans via insect vector and/or direct contact with contaminated environment
Rare cases of direct transmission from possum to human after bite
How does BU disease progress?
Resistance to M. ulcerans has been associated with the development of Th1 type responses
Granuloma observed during progression to healing
Progression of disease due primarily to mycolactone – an exotoxin
Where do skin ulcers caused by BU form?
Lower legs
Oedematous lesions still form well into antibiotic treatment and require debridement +/2 skin grafting
What are the features that promote pathogenesis of M. ulcerans?
The low optimal temperature of growth (29–33°C) that makes the skin its preferential target
M. ulcerans behaves as an intracellular pathogen triggering inflammatory cell responses and cell mediated immunity
Unusual toxin production, mycolactone-associated high cytotoxicity that contrasts with the intracellular traits of its mycobacterial nature
In advanced BU lesions, extracellular clusters of M. ulcerans reside in necrotic subcutaneous tissue and are protected from infiltrating leukocytes by the cytotoxic activity of secreted mycolactone
Mycolactone also has immunosuppressive properties
What is mycolactone?
A polyketide cytotoxin that has immunosuppressive properties
What are the precise cellular targets of mycolactone?
Remain mysterious
It induces apoptosis of infected host cells
Inhibits production of the proinflammatory cytokine TNF-α by macrophages
Suppresses dendritic cell priming of T cells
What can mycolactone synthesised by M. ulcerans diffuse from and what does this do?
Mycolactone synthesised by M. ulcerans can diffuse from infected skin tissue to lymphoid organs within mononuclear cells, where it may exert some of these immune suppressive functions
What contributes to the painlessness brought on by BU
Mycolactone causing nerve cell damage
What genes are required for mycolactone synthesis and how were these genes acquired?
The genes required for mycolactone synthesis are carried on a virulence plasmid, pMUM001, that was apparently acquired by horizontal gene transfer from an unknown source
Why were other mycobacterial virulence factors lost by reductive evolution within M. ulcerans?
Because mycolactone came to dominate the interaction of M. ulcerans with its human host, following acquisition of pMUM001 other mycobacterial virulence factors were apparently lost
Summary of disease progression of BU
Infection
Pre-ulcerative infection
Ulcerative infection
Spontaneous healing, treatment
How is BU diagnosed?
Clinical diagnosis
Microscopy - smear
Culture
IS2404 PCR-based tests DNA based
How is BU treated?
Multi-drug therapy to reduce selection of drug-resistant strains
Combination of rifampicin (10 mg/kg once daily) and clarithromycin (7.5 mg/kg twice daily) is now the WHO recommended treatment
Surgery and hospital treatment of wounds for skin grafts
In well-developed lesions with ongoing necrosis due to the effects of high mycolactone toxin load then the removal of this tissue is necessary
Physiotherapy and rehabilitation
How are wounds caused by BU managed?
Healing time can be months or years to heal even after antibiotic treatment
Improved wound dressings emerging from other ulcer diseases eg diabetes
How can BU infection be prevented and controlled?
Identification of high risk zones
Vaccines
Avoiding risky behaviours in endemic areas
How are high risk zones of M. ulcerans identified?
Active surveillance, case management, treatment
What is an example of how identification of a high risk zone prevented BU disease spread?
Republic of Congo
Identification of this zone as a high-risk area for BU disease helped the MoH improve early detection, biological confirmation and treatment programs
What vaccines are there for M. ulcerans?
Some protection seen with BCG but inconsistent
Vaccines specific to M. ulcerans, targeting a mycolyl transferase (antigen 85A) of the bacteria being tested
How can risky behaviours in endemic areas be avoided?
Swimming, fishing , agricultural works
Mosquito nets may help if insect borne (eg Australia), good pre-existing wound care, protective clothing to prevent wounds
What are the research priorities for NTMs recommended in the US and UK?
Rapid diagnostic tools fast identification of infecting species
Methods in development for rapid point of care: ELISA (immune assay), LAMP (nucleic acid amplification), mycolactone specific tests
Simple and cheap screening tool to identify patients
Faster initiation of appropriate treatment and ultimately, superior care
What is Telacebec?
A new anti-tuberculous drug developed by a Korean company Qurient
Extreme potent activity against Mycobacterium ulcerans in animal studies, reducing treatment duration from 8 to 2 weeks
What can shorten the duration of standard treatment time (8 weeks)?
Combining the standard treatment (rifampicin and clarithromycin) with amoxicillin/clavulanate shortens treatment time to 4 weeks
