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Buruli ulcer is an emerging chronic infectious skin disease caused by Mycobacterium ulcerans. Mycolactone, an exotoxin produced by the bacterium, is the only identified virulence factor so far, but the functions of this toxin and the mechanisms of disease progression remain unclear. By interfering Sec61 translocon, mycolactone inhibits the Sec61-dependent co-translational translocation of newly synthesized proteins, such as induced cytokines and immune cell receptors, into the endoplasmic reticulum. However, in regard to IL-1ß, which is secreted by a Sec61-independent mechanism, mycolactone has been shown to induce IL-1ß secretion via activation of inflammasomes. In this study, we clarified that cytokine induction, including that of IL-1ß, in infected macrophages was suppressed by mycolactone produced by M. ulcerans subsp. shinshuense, despite the activation of caspase-1 through the inflammasome activation triggered in a manner independent of mycolactone. Intriguingly, mycolactone suppressed the expression of proIL-1ß as well as TNF-α at the transcriptional level, suggesting that mycolactone of M. ulcerans subsp. shinshuense may exert additional inhibitory effect on proIL-1ß expression. Remarkably, constitutively produced IL-18 was cleaved and mature IL-18 was actually released from macrophages infected with the causative mycobacterium. IL-18-deficient mice infected subcutaneously with M. ulcerans exhibited exacerbated skin inflammation during the course of disease progression. On the other hand, IL-1ß controls bacterial multiplication in skin tissues. These results provide information regarding the mechanisms and functions of the induced cytokines in the pathology of Buruli ulcer.
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Úlcera de Buruli , Mycobacterium ulcerans , Animales , Ratones , Úlcera de Buruli/microbiología , Inflamasomas/metabolismo , Interleucina-18/metabolismo , Mycobacterium ulcerans/metabolismo , Macrólidos/metabolismo , Citocinas/metabolismo , Progresión de la Enfermedad , InflamaciónRESUMEN
Infective endocarditis (IE), characterized by inflammation of the endocardial surface of the heart and its valves, results from infections caused by Staphylococcus, Streptococcus and Acinetobacter species and less commonly fungi. Acinetobacter-induced IE is a relatively rare condition with significant morbidity and mortality worldwide. Notably, its mortality rate is greater than that of endocarditis induced by the Haemophilus species, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae. Although it is rare, Acinetobacter-induced IE caused by A. baumannii might bring unique therapeutic challenges such as increased antibiotic resistance. Therefore, it is vital to understand perfectly the possible pathophysiologic and antibiotic resistance mechanisms adopted by A. baumannii during IE. This review discusses the probable underlying pathomechanisms involved in A. baumannii-induced IE and highlights the potential antibiotic resistance mechanisms, suggesting therapeutic targets for A. baumannii-induced IE.
Infective endocarditis (IE), known as inflammation of the thin membrane that lines the inside of the heart, results from infections from microbes (e.g., Staphylococcus, Streptococcus and Acinetobacter species and, less commonly, fungi). IE caused by a special microbe called the Acinetobacter species is an uncommon condition with substantial death rates globally. Although it is not common, IE caused by Acinetobacter species, especially A. baumannii, might be difficult to treat due to increased antibiotic resistance. Therefore, it is important to understand the possible disease and antibiotic resistance mechanisms of A. baumannii during IE. This review explains the possible underlying disease mechanisms involved in IE caused by A. baumannii and highlights the potential antibiotic resistance mechanisms, suggesting possible treatment options for IE caused by A. baumannii.
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Acinetobacter baumannii , Endocarditis Bacteriana , Endocarditis , Acinetobacter baumannii/genética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Farmacorresistencia Microbiana , Eikenella corrodens , Endocarditis/tratamiento farmacológico , Endocarditis/microbiología , Endocarditis Bacteriana/tratamiento farmacológico , Endocarditis Bacteriana/microbiología , HumanosRESUMEN
BACKGROUND: Buruli ulcer is a tissue necrosis infection caused by an environmental mycobacterium called Mycobacterium ulcerans (MU). The disease is most prevalent in rural areas with the highest rates in West and Central African countries. The bacterium produces a toxin called mycolactone which can lead to the destruction of the skin, resulting in incapacitating deformities with an enormous economic and social burden on patients and their caregivers. Even though there is an effective antibiotic treatment for BU, the control and management rely on early case detection and rapid diagnosis to avert morbidities. The diagnosis of Mycobacterium ulcerans relies on smear microscopy, culture histopathology, and PCR. Unfortunately, all the current laboratory diagnostics have various limitations and are not available in endemic communities. Consequently, there is a need for a rapid diagnostic tool for use at the community health centre level to enable diagnosis and confirmation of suspected cases for early treatment. The present study corroborated the diagnostic performance and utility of fluorescent-thin layer chromatography (f-TLC) for the diagnosis of Buruli ulcer. METHODOLOGY/PRINCIPAL FINDINGS: The f-TLC method was evaluated for the diagnosis of Buruli ulcer in larger clinical samples than previously reported in an earlier preliminary study Wadagni et al. (2015). A total of 449 patients suspected of BU were included in the final data analysis out of which 122 (27.2%) were positive by f-TLC and 128 (28.5%) by PCR. Using a composite reference method generated from the two diagnostic methods, 85 (18.9%) patients were found to be truly infected with M. ulcerans, 284 (63.3%) were uninfected, while 80 (17.8%) were misidentified as infected or noninfected by the two methods. The data obtained was used to determine the discriminatory accuracy of the f-TLC against the gold standard IS2404 PCR through the analysis of its sensitivity, specificity, positive (+LR), and negative (-LR) likelihood ratio. The positive (PPV) and negative (NPV) predictive values, area under the receiver operating characteristic curve Azevedo et al. (2014), and diagnostic odds ratio were used to assess the predictive accuracy of the f-TLC method. The sensitivity of f-TLC was 66.4% (85/128), specificity was 88.5% (284/321), while the diagnostic accuracy was 82.2% (369/449). The AUC stood at 0.774 while the PPV, NPV, +LR, and-LR were 69.7% (85/122), 86.9% (284/327), 5.76, and 0.38, respectively. The use of the rule-of-thumb interpretation of diagnostic tests suggests that the method is good for use as a diagnostic tool. CONCLUSIONS/SIGNIFICANCE: Larger clinical samples than previously reported had been used to evaluate the f-TLC method for the diagnosis of Buruli ulcer. A sensitivity of 66.4%, a specificity of 88.5%, and diagnostic accuracy of 82.2% were obtained. The method is good for diagnosis and will help in making early clinical decisions about the patients as well as patient management and facilitating treatment decisions. However, it requires a slight modification to address the challenge of background interference and lack of automatic readout to become an excellent diagnostic tool.
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Úlcera de Buruli , Mycobacterium ulcerans , Úlcera de Buruli/diagnóstico , Úlcera de Buruli/epidemiología , Cromatografía en Capa Delgada/métodos , Ghana/epidemiología , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
Data on molecular characterization of coagulase-negative staphylococci causing neonatal sepsis in low-income countries are highly limited. This report highlights the isolation of three Staphylococcus epidermidis non-genome assembly strains (NGASs) from blood samples from neonates with unknown transmission sources. Pathogenic factors and sources of transmission of these strains warrant further investigation.
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Efforts to control the spread of Buruli ulcer--an emerging ulcerative skin infection caused by Mycobacterium ulcerans--have been hampered by our poor understanding of reservoirs and transmission. To help address this issue, we compared whole genomes from 18 clinical M. ulcerans isolates from a 30 km2 region within the Asante Akim North District, Ashanti region, Ghana, with 15 other M. ulcerans isolates from elsewhere in Ghana and the surrounding countries of Ivory Coast, Togo, Benin and Nigeria. Contrary to our expectations of finding minor DNA sequence variations among isolates representing a single M. ulcerans circulating genotype, we found instead two distinct genotypes. One genotype was closely related to isolates from neighbouring regions of Amansie West and Densu, consistent with the predicted local endemic clone, but the second genotype (separated by 138 single nucleotide polymorphisms [SNPs] from other Ghanaian strains) most closely matched M. ulcerans from Nigeria, suggesting another introduction of M. ulcerans to Ghana, perhaps from that country. Both the exotic genotype and the local Ghanaian genotype displayed highly restricted intra-strain genetic variation, with less than 50 SNP differences across a 5.2 Mbp core genome within each genotype. Interestingly, there was no discernible spatial clustering of genotypes at the local village scale. Interviews revealed no obvious epidemiological links among BU patients who had been infected with identical M. ulcerans genotypes but lived in geographically separate villages. We conclude that M. ulcerans is spread widely across the region, with multiple genotypes present in any one area. These data give us new perspectives on the behaviour of possible reservoirs and subsequent transmission mechanisms of M. ulcerans. These observations also show for the first time that M. ulcerans can be mobilized, introduced to a new area and then spread within a population. Potential reservoirs of M. ulcerans thus might include humans, or perhaps M. ulcerans-infected animals such as livestock that move regularly between countries.