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      Mycobacterium ulcerans in Mosquitoes Captured during Outbreak of Buruli Ulcer, Southeastern Australia

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          Abstract

          Mosquitoes positive for M. ulcerans were linked to outbreaks of Buruli ulcer in humans.

          Abstract

          Buruli ulcer (BU) occurs in >30 countries. The causative organism, Mycobacterium ulcerans, is acquired from the environment, but the exact mode of transmission is unknown. We investigated an outbreak of BU in a small coastal town in southeastern Australia and screened by PCR mosquitoes caught there. All cases of BU were confirmed by culture or PCR. Mosquitoes were trapped in multiple locations during a 26-month period. BU developed in 48 residents of Point Lonsdale/Queenscliff and 31 visitors from January 2001 through April 2007. We tested 11,504 mosquitoes trapped at Point Lonsdale (predominantly Aedes camptorhynchus). Forty-eight pools (5 species) were positive for insertion sequence IS 2404 (maximum likelihood estimate 4.3/1,000), and we confirmed the presence of M. ulcerans in a subset of pools by detection of 3 additional PCR targets.

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          Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence.

          Mycobacterium ulcerans is the causative agent of Buruli ulcer, a severe human skin disease that occurs primarily in Africa and Australia. Infection with M. ulcerans results in persistent severe necrosis without an acute inflammatory response. The presence of histopathological changes distant from the site of infection suggested that pathogenesis might be toxin mediated. A polyketide-derived macrolide designated mycolactone was isolated that causes cytopathicity and cell cycle arrest in cultured L929 murine fibroblasts. Intradermal inoculation of purified toxin into guinea pigs produced a lesion similar to that of Buruli ulcer in humans. This toxin may represent one of a family of virulence factors associated with pathology in mycobacterial diseases such as leprosy and tuberculosis.
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            Reductive evolution and niche adaptation inferred from the genome of Mycobacterium ulcerans, the causative agent of Buruli ulcer.

            Mycobacterium ulcerans is found in aquatic ecosystems and causes Buruli ulcer in humans, a neglected but devastating necrotic disease of subcutaneous tissue that is rampant throughout West and Central Africa. Here, we report the complete 5.8-Mb genome sequence of M. ulcerans and show that it comprises two circular replicons, a chromosome of 5632 kb and a virulence plasmid of 174 kb. The plasmid is required for production of the polyketide toxin mycolactone, which provokes necrosis. Comparisons with the recently completed 6.6-Mb genome of Mycobacterium marinum revealed >98% nucleotide sequence identity and genome-wide synteny. However, as well as the plasmid, M. ulcerans has accumulated 213 copies of the insertion sequence IS2404, 91 copies of IS2606, 771 pseudogenes, two bacteriophages, and multiple DNA deletions and rearrangements. These data indicate that M. ulcerans has recently evolved via lateral gene transfer and reductive evolution from the generalist, more rapid-growing environmental species M. marinum to become a niche-adapted specialist. Predictions based on genome inspection for the production of modified mycobacterial virulence factors, such as the highly abundant phthiodiolone lipids, were confirmed by structural analyses. Similarly, 11 protein-coding sequences identified as M. ulcerans-specific by comparative genomics were verified as such by PCR screening a diverse collection of 33 strains of M. ulcerans and M. marinum. This work offers significant insight into the biology and evolution of mycobacterial pathogens and is an important component of international efforts to counter Buruli ulcer.
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              Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans.

              Mycobacterium ulcerans (MU), an emerging human pathogen harbored by aquatic insects, is the causative agent of Buruli ulcer, a devastating skin disease rife throughout Central and West Africa. Mycolactone, an unusual macrolide with cytotoxic and immunosuppressive properties, is responsible for the massive s.c. tissue destruction seen in Buruli ulcer. Here, we show that MU contains a 174-kb plasmid, pMUM001, bearing a cluster of genes encoding giant polyketide synthases (PKSs), and polyketide-modifying enzymes, and demonstrate that these are necessary and sufficient for mycolactone synthesis. This is a previously uncharacterized example of plasmid-mediated virulence in a Mycobacterium, and the emergence of MU as a pathogen most likely reflects the acquisition of pMUM001 by horizontal transfer. The 12-membered core of mycolactone is produced by two giant, modular PKSs, MLSA1 (1.8 MDa) and MLSA2 (0.26 MDa), whereas its side chain is synthesized by MLSB (1.2 MDa), a third modular PKS highly related to MLSA1. There is an extreme level of sequence identity within the different domains of the MLS cluster (>97% amino acid identity), so much so that the 16 ketosynthase domains seem functionally identical. This is a finding of significant consequence for our understanding of polyketide biochemistry. Such detailed knowledge of mycolactone will further the investigation of its mode of action and the development of urgently needed therapeutic strategies to combat Buruli ulcer.
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                Author and article information

                Journal
                Emerg Infect Dis
                Emerging Infect. Dis
                EID
                Emerging Infectious Diseases
                Centers for Disease Control and Prevention
                1080-6040
                1080-6059
                November 2007
                : 13
                : 11
                : 1653-1660
                Affiliations
                [* ]Austin Health, Melbourne, Victoria, Australia
                []University of Melbourne, Melbourne, Victoria, Australia
                []Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
                [§ ]Monash University, Melbourne, Victoria, Australia
                []Department of Primary Industries, Melbourne, Victoria, Australia
                [# ]Department of Human Services, Melbourne, Victoria, Australia
                Author notes
                Address for correspondence: Paul D.R. Johnson, Infectious Diseases Department, Austin Health, PO Box 5555, Heidelberg 3084, Melbourne, Victoria, Australia; email: paul.johnson@ 123456austin.org.au
                Article
                06-1369
                10.3201/eid1311.061369
                3375796
                18217547
                c0f527cf-e5ba-46a9-a069-bee8c1da5e91
                History
                Categories
                Research

                Infectious disease & Microbiology
                mycobacterium ulcerans,buruli ulcer,bairnsdale ulcer,mosquito,vector,transmission,australia,research

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