Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.
Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial dise...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://doi.org/10.1371/journal.pntd.0002101 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850161947760132096 |
|---|---|
| author | Fred Stephen Sarfo Paul J Converse Deepak V Almeida Jihui Zhang Clive Robinson Mark Wansbrough-Jones Jacques H Grosset |
| author_facet | Fred Stephen Sarfo Paul J Converse Deepak V Almeida Jihui Zhang Clive Robinson Mark Wansbrough-Jones Jacques H Grosset |
| author_sort | Fred Stephen Sarfo |
| collection | DOAJ |
| description | Mycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli. |
| format | Article |
| id | doaj-art-bacc632cdff94fe9ae86bd20401e1b02 |
| institution | OA Journals |
| issn | 1935-2727 1935-2735 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj-art-bacc632cdff94fe9ae86bd20401e1b022025-08-20T02:22:40ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352013-01-0173e210110.1371/journal.pntd.0002101Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease.Fred Stephen SarfoPaul J ConverseDeepak V AlmeidaJihui ZhangClive RobinsonMark Wansbrough-JonesJacques H GrossetMycobacterium ulcerans infection causes a neglected tropical disease known as Buruli ulcer that is now found in poor rural areas of West Africa in numbers that sometimes exceed those reported for another significant mycobacterial disease, leprosy, caused by M. leprae. Unique among mycobacterial diseases, M. ulcerans produces a plasmid-encoded toxin called mycolactone (ML), which is the principal virulence factor and destroys fat cells in subcutaneous tissue. Disease is typically first manifested by the appearance of a nodule that eventually ulcerates and the lesions may continue to spread over limbs or occasionally the trunk. The current standard treatment is 8 weeks of daily rifampin and injections of streptomycin (RS). The treatment kills bacilli and wounds gradually heal. Whether RS treatment actually stops mycolactone production before killing bacilli has been suggested by histopathological analyses of patient lesions. Using a mouse footpad model of M. ulcerans infection where the time of infection and development of lesions can be followed in a controlled manner before and after antibiotic treatment, we have evaluated the progress of infection by assessing bacterial numbers, mycolactone production, the immune response, and lesion histopathology at regular intervals after infection and after antibiotic therapy. We found that RS treatment rapidly reduced gross lesions, bacterial numbers, and ML production as assessed by cytotoxicity assays and mass spectrometric analysis. Histopathological analysis revealed that RS treatment maintained the association of the bacilli with (or within) host cells where they were destroyed whereas lack of treatment resulted in extracellular infection, destruction of host cells, and ultimately lesion ulceration. We propose that RS treatment promotes healing in the host by blocking mycolactone production, which favors the survival of host cells, and by killing M. ulcerans bacilli.https://doi.org/10.1371/journal.pntd.0002101 |
| spellingShingle | Fred Stephen Sarfo Paul J Converse Deepak V Almeida Jihui Zhang Clive Robinson Mark Wansbrough-Jones Jacques H Grosset Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease. PLoS Neglected Tropical Diseases |
| title | Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease. |
| title_full | Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease. |
| title_fullStr | Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease. |
| title_full_unstemmed | Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease. |
| title_short | Microbiological, histological, immunological, and toxin response to antibiotic treatment in the mouse model of Mycobacterium ulcerans disease. |
| title_sort | microbiological histological immunological and toxin response to antibiotic treatment in the mouse model of mycobacterium ulcerans disease |
| url | https://doi.org/10.1371/journal.pntd.0002101 |
| work_keys_str_mv | AT fredstephensarfo microbiologicalhistologicalimmunologicalandtoxinresponsetoantibiotictreatmentinthemousemodelofmycobacteriumulceransdisease AT pauljconverse microbiologicalhistologicalimmunologicalandtoxinresponsetoantibiotictreatmentinthemousemodelofmycobacteriumulceransdisease AT deepakvalmeida microbiologicalhistologicalimmunologicalandtoxinresponsetoantibiotictreatmentinthemousemodelofmycobacteriumulceransdisease AT jihuizhang microbiologicalhistologicalimmunologicalandtoxinresponsetoantibiotictreatmentinthemousemodelofmycobacteriumulceransdisease AT cliverobinson microbiologicalhistologicalimmunologicalandtoxinresponsetoantibiotictreatmentinthemousemodelofmycobacteriumulceransdisease AT markwansbroughjones microbiologicalhistologicalimmunologicalandtoxinresponsetoantibiotictreatmentinthemousemodelofmycobacteriumulceransdisease AT jacqueshgrosset microbiologicalhistologicalimmunologicalandtoxinresponsetoantibiotictreatmentinthemousemodelofmycobacteriumulceransdisease |