skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: Responses to chemical cross-talk between the Mycobacterium ulcerans toxin, mycolactone, and Staphylococcus aureus
Abstract Buruli ulcer is a neglected tropical disease caused by the environmental pathogen, Mycobacterium ulcerans whose major virulence factor is mycolactone, a lipid cytotoxic molecule. Buruli ulcer has high morbidity, particularly in rural West Africa where the disease is endemic. Data have shown that infected lesions of Buruli ulcer patients can be colonized by quorum sensing bacteria such as Staphylococcus aureus, S. epidermidis, and Pseudomonas aeruginosa , but without typical pathology associated with those pathogens’ colonization. M. ulcerans pathogenesis may not only be an individual act but may also be dependent on synergistic or antagonistic mechanisms within a polymicrobial network. Furthermore, co-colonization by these pathogens may promote delayed wound healing, especially after the initiation of antibiotic therapy. Hence, it is important to understand the interaction of M. ulcerans with other bacteria encountered during skin infection. We added mycolactone to S. aureus and incubated for 3, 6 and 24 h. At each timepoint, S. aureus growth and hemolytic activity was measured, and RNA was isolated to measure virulence gene expression through qPCR and RNASeq analyses. Results showed that mycolactone reduced S. aureus hemolytic activity, suppressed hla promoter activity, and attenuated virulence genes, but did not affect S. aureus growth . RNASeq data showed mycolactone greatly impacted S. aureus metabolism. These data are relevant and significant as mycolactone and S. aureus sensing and response at the transcriptional, translational and regulation levels will provide insight into biological mechanisms of interspecific interactions that may play a role in regulation of responses such as effects between M. ulcerans , mycolactone, and S. aureus virulence that will be useful for treatment and prevention.  more » « less
Award ID(s):
1911457
PAR ID:
10253911
Author(s) / Creator(s):
; ; ; ; ; ;
Date Published:
Journal Name:
Scientific Reports
Volume:
11
Issue:
1
ISSN:
2045-2322
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; ; ; ; (, Microbiology Spectrum)
    Atack, John M. (Ed.)
    ABSTRACT Buruli ulcer disease is a neglected tropical disease caused by the environmental pathogen Mycobacterium ulcerans . The M. ulcerans major virulence factor is mycolactone, a lipid cytotoxic compound whose genes are carried on a plasmid. Although an exact reservoir and mode(s) of transmission are unknown, data provide evidence of both. First, Buruli ulcer incidence and M. ulcerans presence have been linked to slow-moving water with low oxygen. M. ulcerans has also been suggested to be sensitive to UV due to termination in crtI , encoding a phytoene dehydrogenase, required for carotenoid production. Further, M. ulcerans has been shown to cause disease following puncture but not when introduced to open abrasion sites, suggesting that puncture is necessary for transmission and pathology. Despite these findings, the function and modulation of mycolactone and other genes in response to dynamic abiotic conditions such as UV, temperature, and oxygen have not been shown. In this study, we investigated modulation of mycolactone and other genes on exposure to changing UV and oxygen microenvironmental conditions. Mycolactone expression was downregulated on exposure to the single stress high temperature and did not change significantly with exposure to UV; however, it was upregulated when exposed to microaerophilic conditions. Mycolactone expression was downregulated under combined stresses of high temperature and low oxygen, but there was upregulation of several stress response genes. Taken together, results suggest that temperature shapes M. ulcerans metabolic response more so than UV exposure or oxygen requirements. These data help to define the environmental niche of M. ulcerans and metabolic responses during initial human infection. IMPORTANCE Buruli ulcer is a debilitating skin disease caused by the environmental pathogen Mycobacterium ulcerans . M. ulcerans produces a toxic compound, mycolactone, which leads to tissue necrosis and ulceration. Barriers to preventing Buruli ulcer include an incomplete understanding of M. ulcerans reservoirs, how the pathogen is transmitted, and under what circumstances mycolactone and other M. ulcerans genes are expressed and produced in its natural environment and in the host. We conducted a study to investigate M. ulcerans gene expression under several individual or combined abiotic conditions. Our data showed that mycolactone expression was downregulated under combined stresses of high temperature and low oxygen but there was upregulation of several stress response genes. These data are among only a few studies measuring modulation of mycolactone and other M. ulcerans genes that could be involved in pathogen fitness in its natural environment and virulence while within the host. 
    more » « less
  2. ; ; ; ; ; (, PLOS ONE)
    de_Oliveira, Mozaniel Santana (Ed.)
    Mycolactone is a cytotoxic lipid metabolite produced byMycobacterium ulcerans, the environmental pathogen responsible for Buruli ulcer, a neglected tropical disease.Mycobacterium ulceransis prevalent in West Africa, particularly found in lentic environments, where mosquitoes also occur. Researchers hypothesize mosquitoes could serve as a transmission mechanism resulting in infection byM.ulceranswhen mosquitoes pierce skin contaminated withM.ulcerans. The interplay between the pathogen, mycolactone, and mosquito is only just beginning to be explored. A triple-choice assay was conducted to determine the host-seeking preference ofAedes aegyptibetweenM.ulceranswildtype (MU, mycolactone active) and mutant (MUlac-, mycolactone inactive). Both qualitative and quantitative differences in volatile organic compounds’ (VOCs) profiles of MU and MUlac-were determined by GC-MS. Additionally, we evaluated the interplay betweenAe.aegyptiproximity andM.ulceransmRNA expression. The results showed that mosquito attraction was significantly greater (126.0%) to an artificial host treated with MU than MUlac-. We found that MU and MUlacproduced differential profiles of VOCs associated with a wide range of biological importance from quorum sensing (QS) to human odor components. RT-qPCR assays showed that mycolactone upregulation was 24-fold greater for MU exposed toAe.aegyptiin direct proximity. Transcriptome data indicated significant induction of ten chromosomal genes of MU involved in stress responses and membrane protein, compared to MUlac-when directly having access to or in near mosquito proximity. Our study provides evidence of possible interkingdom interactions between unicellular and multicellular species that MU present on human skin is capable of interreacting with unrelated species (i.e., mosquitoes), altering its gene expression when mosquitoes are in direct contact or proximity, potentially impacting the production of its VOCs, and consequently leading to the stronger attraction of mosquitoes toward human hosts. This study elucidates interkingdom interactions between viableM.ulceransbacteria andAe.aegyptimosquitoes, which rarely have been explored in the past. Our finding opens new doors for future research in terms of disease ecology, prevalence, and pathogen dispersal outside of theM.ulceranssystem. 
    more » « less
  3. ; ; ; ; ; ; ; ; ; ; et al (, Infectious Diseases of Poverty)
    Abstract BackgroundSeasonal patterns of mycobacterial infections affecting humans and animals remain a complex and understudied aspect of infectious disease dynamics. These intra-annual patterns are increasingly relevant in the context of global climate change, which may influence the timing and geographic spread of these diseases. A better understanding of such patterns could improve surveillance, prevention, and control strategies. MethodsWe conducted a mixed-methods bibliometric review combining bibliographic searches and scoping analysis to synthesize decades of research on the seasonality of mycobacterial infections in humans and animals. We systematically searched three major scientific databases—Scopus, PubMed-MEDLINE, and Web of Science—for articles published between 1971 and April 2023. From an initial dataset of 1830 unique articles, we identified and analysed 122 studies that met predefined inclusion criteria. We extracted information on pathogen type, statistical methods, geographic location, and host species. In addition, we conducted a co-citation network analysis to identify key methodological influences and research clusters. ResultsThe retained studies encompassed tuberculosis, Buruli ulcer, bovine tuberculosis, and other mycobacterial diseases such as leprosy and Johne’s disease. Most articles focused on tuberculosis in humans, followed by Buruli ulcer caused byMycobacterium ulcerans. There was a marked increase in studies on seasonal trends in tuberculosis and Buruli ulcer over time, with notable variation in geographic and methodological coverage. Research was heavily concentrated in the northern hemisphere, especially in China, while southern regions remained underrepresented. Advanced statistical tools, including generalized linear models and time-series analyses, were instrumental in detecting seasonality, particularly for tuberculosis and Buruli ulcer. ConclusionSeasonality appears to be a common yet understudied feature of many mycobacterial infections. Greater interdisciplinary collaboration and the use of appropriate analytical tools are essential to better understand these patterns, especially in underrepresented regions. Addressing methodological and geographic gaps will be crucial to improve responses to these diseases in a changing global environment. 
    more » « less
  4. ; ; ; ; ; ; ; ; ; ; et al (, PLOS Computational Biology)
    Lofgren, Eric (Ed.)
    Pathogens such as bacteria, fungi and viruses are important components of soil and aquatic communities, where they can benefit from decaying and living organic matter, and may opportunistically infect human and animal hosts. One-third of human infectious diseases is constituted by sapronotic disease agents that are natural inhabitants of soil or aquatic ecosystems. They are capable of existing and reproducing in the environment outside of the host for extended periods of time. However, as ecological research on sapronosis is infrequent and epidemiological models are even rarer, very little information is currently available. Their importance is overlooked in medical and veterinary research, as well as the relationships between free environmental forms and those that are pathogenic. Here, using dynamical models in realistic aquatic metacommunity systems, we analyze sapronosis transmission, using the human pathogenMycobacterium ulceransthat is responsible for Buruli ulcer. We show that the persistence of bacilli in aquatic ecosystems is driven by a seasonal upstream supply, and that the attachment and development of cells to aquatic living forms is essential for such pathogen persistence and population dynamics. Our work constitutes the first set of metacommunity models of sapronotic disease transmission, and is highly flexible for adaptation to other types of sapronosis. The importance of sapronotic agents on animal and human disease burden needs better understanding and new models of sapronosis disease ecology to guide the management and prevention of this important group of pathogens. 
    more » « less
  5. ; ; ; ; ; ; ; ; ; ; et al (, FEMS Microbiology Reviews)
    ABSTRACT Understanding the interactions of ecosystems, humans and pathogens is important for disease risk estimation. This is particularly true for neglected and newly emerging diseases where modes and efficiencies of transmission leading to epidemics are not well understood. Using a model for other emerging diseases, the neglected tropical skin disease Buruli ulcer (BU), we systematically review the literature on transmission of the etiologic agent, Mycobacterium ulcerans (MU), within a One Health/EcoHealth framework and against Hill's nine criteria and Koch's postulates for making strong inference in disease systems. Using this strong inference approach, we advocate a null hypothesis for MU transmission and other understudied disease systems. The null should be tested against alternative vector or host roles in pathogen transmission to better inform disease management. We propose a re-evaluation of what is necessary to identify and confirm hosts, reservoirs and vectors associated with environmental pathogen replication, dispersal and transmission; critically review alternative environmental sources of MU that may be important for transmission, including invertebrate and vertebrate species, plants and biofilms on aquatic substrates; and conclude with placing BU within the context of other neglected and emerging infectious diseases with intricate ecological relationships that lead to disease in humans, wildlife and domestic animals. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email