Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Med Mycol ; 58(2): 181-186, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31131856

RESUMO

Talaromyces (Penicillium) marneffei is an emerging pathogen that causes significant morbidity and mortality in immunocompromised patients in endemic regions such as southeast Asia. The diagnosis of disseminated T. marneffei infection remains challenging in clinical practice. In the study, a well-validated real-time quantitative polymerase chain reaction (qPCR) target region of ITS1-5.8S-ITS2 and a Platelia galactomannan (GM) assay were compared for their diagnostic performance using serum samples from patients with or without human immunodeficiency virus (HIV). The results showed that this novel qPCR method is highly sensitive and specific for T. marneffei DNA detection in serum samples, and the limit of detection and species-specificity of qPCR were five copies of DNA and 100%, respectively. For detection in serum samples from 36 talaromycosis patients, the sensitivity of qPCR was 86.11% (31/36), including 20/20 (100%) patients with fungemia and 11/16 (68.75%) patients without fungemia. For the GM assay, the sensitivity was 80.56% (29/36) when the GM optical density cutoff index was ≥0.5, including 19/20 (95%) patients with fungemia and 10/16 (62.5%) patients without fungemia. These results indicate that the novel qPCR and GM assays can be used as a valuable tool in the diagnosis of T. marneffei infection. Serum samples are convenient hematological specimens for T. marneffei DNA quantification. Combining the GM assay and qPCR is more scientific and appropriate for diagnosing T. marneffei infection in endemic areas.


Assuntos
DNA Fúngico/sangue , Fungemia/diagnóstico , Mananas/sangue , Reação em Cadeia da Polimerase em Tempo Real , Talaromyces/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , China , DNA Intergênico/sangue , Feminino , Fungemia/microbiologia , Infecções por HIV/microbiologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Talaromyces/patogenicidade , Adulto Jovem
2.
Med Mycol ; 58(3): 351-361, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31290549

RESUMO

Talaromyces marneffei (T. marneffei), which used to be known as Penicillium marneffei, is the causative agent of the fatal systemic mycosis known as talaromycosis. For the purpose of understanding the role of methylcitrate cycle in the virulence of T. marneffei, we generated MCD deletion (ΔMCD) and complementation (ΔMCD+) mutants of T. marneffei. Growth in different carbon sources showed that ΔMCD cannot grow on propionate media and grew slowly on the valerate, valine, methionine, isoleucine, cholesterol, and YNB (carbon free) media. The macrophage killing assay showed that ΔMCD was attenuated in macrophages of mice in vitro, especially at the presence of propionate. Finally, virulence studies in a murine infection experiment revealed attenuated virulence of the ΔMCD, which indicates MCD is essential for T. marneffei virulence in the host. This experiment laid the foundation for the further study of the specific mechanisms underlying the methylcitrate cycle of T. marneffei and may provide suitable targets for new antifungals.


Assuntos
Genes Fúngicos , Talaromyces/genética , Talaromyces/patogenicidade , Fatores de Virulência/genética , Animais , Meios de Cultura/química , Feminino , Deleção de Genes , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células RAW 264.7 , Organismos Livres de Patógenos Específicos , Talaromyces/crescimento & desenvolvimento , Virulência
3.
Diagn Microbiol Infect Dis ; 96(3): 114959, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31836254

RESUMO

The pathogenic fungus Talaromyces (formerly Penicillium) marneffei is a thermally dimorphic fungus that can cause disseminated infection in patients with secondary immunodeficiency syndrome, in particular in the setting of advanced HIV infection. The areas of highest incidence are in Southeast Asia, Southern China, and Indian subcontinents. Talaromycosis (formerly penicilliosis) is identified as an AIDS-defining illness, and it has recently been recognized in non-HIV-associated patients with impaired cellular-mediated immunity. Microbiological culture is the gold standard method for the diagnosis of T. marneffei infection and usually requires up to 2-4 weeks for detectable growth to occur, which may result in a delay of appropriate treatment. Immunodiagnosis has become an alternative method for confirming talaromycosis. This article reviews various immunological tests for the diagnosis of talaromycosis, including a proposed novel rapid point-of-care assay using a new T. marneffei yeast phase-specific monoclonal antibody.


Assuntos
Micoses/diagnóstico , Micoses/imunologia , Testes Imediatos , Talaromyces/imunologia , Animais , Anticorpos Monoclonais/imunologia , Ásia Sudeste/epidemiologia , China/epidemiologia , Cromatografia de Afinidade , Infecções por HIV/complicações , Humanos , Camundongos , Micoses/epidemiologia , Talaromyces/patogenicidade
4.
Mycopathologia ; 184(6): 709-720, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31811603

RESUMO

Talaromycosis (penicilliosis) is a major fungal disease endemic across a narrow band of tropical countries of South and Southeast Asia. The etiologic agent is a thermally dimorphic fungus Talaromyces (Penicillium) marneffei, which was first isolated from a bamboo rat in Vietnam in 1956, but no formal description was published. In 1959, Professor Gabriel Segretain formally described it as a novel species Talaromyces (Penicillium) marneffei, and the human pathogenic potential of the fungus in Mycopathologia. The first natural human case of talaromycosis (penicillosis) was reported in 1973 and involved an American minister with Hodgkin's disease who lived in Southeast Asia. Sixty years after the discovery of the pathogen, talaromycosis caused by T. marneffei is recognized as an important human disease with the potential to cause high mortality in the absence of proper diagnosis and prompt treatment. Talaromycosis remains a significant infectious complication in HIV/AIDS patients and in patients with other immune defects. The disease is being recognized with an increasing frequency well beyond the traditional endemic areas. The natural reservoirs of T. marneffei in wild rodents are well-defined, which links the ecology with the epidemiology of talaromycosis in endemic areas. There is an urgent unmet need for rapid and affordable point-of-care diagnostic tests. We also need more clinical studies to define the best therapeutic options for the management of talaromycosis patients.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Micoses , Talaromyces , Animais , Antifúngicos/uso terapêutico , Reservatórios de Doenças/microbiologia , Humanos , Mortalidade , Micoses/diagnóstico , Micoses/imunologia , Micoses/microbiologia , Micoses/terapia , Micoses/transmissão , Prevalência , Fatores de Risco , Talaromyces/classificação , Talaromyces/isolamento & purificação , Talaromyces/patogenicidade
5.
BMC Infect Dis ; 19(1): 1034, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805893

RESUMO

BACKGROUND: The incidence of Taralomyces marneffei infection in HIV-infected individuals has been decreasing, whereas its rate is rising among non-HIV immunodeficient persons, particularly patients with anti-interferon-gamma autoantibodies. T. marneffei usually causes invasive and disseminated infections, including fungemia. T. marneffei oro-pharyngo-laryngitis is an unusual manifestation of talaromycosis. CASE PRESENTATION: A 52-year-old Thai woman had been diagnosed anti-IFNÉ£ autoantibodies for 4 years. She had a sore throat, odynophagia, and hoarseness for 3 weeks. She also had febrile symptoms and lost 5 kg in weight. Physical examination revealed marked swelling and hyperemia of both sides of the tonsils, the uvula and palatal arches including a swelling of the epiglottis, and arytenoid. The right tonsillar biopsy exhibited a few intracellular oval and elongated yeast-like organisms with some central transverse septum seen, which subsequently grew a few colonies of T. marneffei on fungal cultures. The patient received amphotericin B deoxycholate 45 mg/dayfor 1 weeks, followed by oral itraconazole 400 mg/day for several months. Her symptoms completely resolved without complication. CONCLUSION: In patients with anti-IFN-É£ autoantibodies, T. marneffei can rarely cause a local infection involving oropharynx and larynx. Fungal culture and pathological examination are warranted for diagnosis T. marneffei oro-pharyngo-laryngitis. This condition requires a long term antifungal therapy.


Assuntos
Antifúngicos/uso terapêutico , Laringite/tratamento farmacológico , Micoses/tratamento farmacológico , Faringite/tratamento farmacológico , Talaromyces/patogenicidade , Anfotericina B/uso terapêutico , Autoanticorpos/sangue , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Interferon gama/imunologia , Itraconazol/uso terapêutico , Laringite/microbiologia , Laringite/patologia , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium abscessus/patogenicidade , Micoses/etiologia , Micoses/microbiologia , Faringite/microbiologia , Faringite/patologia , Tailândia
6.
Mycopathologia ; 184(6): 721-729, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31599369

RESUMO

The fungus Talaromyces marneffei was described by Professor Gabriel Segretain in 1959, originally as a member of the genus Penicillium. As early as 60 years ago, its peculiarity in exhibiting temperature-dependent morphological dimorphism, its characteristic ability to secrete diffusing red pigment during the mycelial phase and its pathogenicity have already been recognised. Six decades have passed, and our understanding on this intriguing fungus has improved. Apart from the clinical aspect, we have gained a glimpse on its taxonomy, animal or environmental source(s), mechanism of thermal dimorphism, molecular genetics, virulence as well as pathogenesis. However, we are still on our way to get out of the talaromycosis mist. A lot more collective endeavour on T. marneffei research is needed to solve the jigsaw puzzle.


Assuntos
Talaromyces , Animais , Humanos , Estágios do Ciclo de Vida , Talaromyces/classificação , Talaromyces/citologia , Talaromyces/metabolismo , Talaromyces/patogenicidade
7.
Mycopathologia ; 184(6): 735-745, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473910

RESUMO

Knowledge about the clinical and laboratory characteristics and prognosis of Talaromyces marneffei infection in children is limited. A retrospective study was conducted on pediatric patients with disseminated T. marneffei infection in a clinical setting. Extracted data included demographic information (age and sex), clinical features, laboratory findings, treatment, and prognosis. Eleven HIV-negative children were enrolled. The male/female ratio was 8:3. The median age of onset was 17.5 months (3.5-84 months). The mortality rate in these children was 36.36% (4/11). Seven children had underlying diseases. All of the children had multiple immunoglobulin abnormalities and immune cell decline. Ten children received voriconazole treatment, and most of the children (7/10) had a complete response to therapy at primary and long-term follow-up assessment; only three children died of talaromycosis. One patient recovered from talaromycosis but died of leukemia. The child who received itraconazole treatment also showed clinical improvement. No adverse events associated with antifungal therapies were recorded during and after the treatment. Talaromycosis is an indicator disease for undiagnosed severe immunodeficiencies in children. Awareness of mycoses in children by pediatricians may prompt diagnosis and timely treatment. Voriconazole is an effective, well-tolerated therapeutic option for disseminated T. marneffei infection in non-HIV-infected children.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS , Micoses , Talaromyces , Voriconazol/uso terapêutico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Criança , Pré-Escolar , China , Feminino , HIV-1 , Humanos , Lactente , Itraconazol/efeitos adversos , Itraconazol/uso terapêutico , Masculino , Micoses/tratamento farmacológico , Micoses/imunologia , Micoses/microbiologia , Micoses/mortalidade , Estudos Retrospectivos , Talaromyces/efeitos dos fármacos , Talaromyces/patogenicidade , Voriconazol/efeitos adversos
8.
BMC Infect Dis ; 19(1): 707, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399065

RESUMO

BACKGROUND: Talaromyces marneffei is a thermally dimorphic fungus endemic in south-east Asia. It predominantly occurs in both immunocompromised and immunosuppressed patients and can be fatal if diagnosis and treatment are delayed. The clinical manifestations of T. marneffei infection are nonspecific and rapid diagnosis of T. marneffei infection remains challenging. CASE PRESENTATION: A 24-year-old man came to our outpatient department with the sign of common skin lesions. The lesions were cuticolor follicular papules with or without central umbilication, nodules and acne-like lesions, which are common in syringoma, steatocystoma multiplex and trichoepithelioma. A dermatoscopy examination was performed to differentiate these skin lesions. The dermatoscopic images revealed circular or quasi-circular whitish amorphous structure with a central brownish keratin plug, providing the diagnostic clues of T. marneffei infection. Therefore, a skin scrapings culture, skin biopsy and serological detection for human immunodeficiency virus (HIV) were performed. The final diagnosis of this patient was T. marneffei and HIV co-infection. CONCLUSION: Rapid diagnosis of T. marneffei infection is clinically challenging since presenting clinical manifestations are nonspecific with significant overlap with other common conditions. This case highlights that dermatoscopy is a promising tool for the rapid diagnosis of T. marneffei infection in patients with nonspecific skin lesions, assisting clinicians to avoid delayed diagnosis or misdiagnosis.


Assuntos
Dermoscopia/métodos , Micoses/diagnóstico , Talaromyces/patogenicidade , Anfotericina B/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , China , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Itraconazol/administração & dosagem , Itraconazol/uso terapêutico , Masculino , Micologia/métodos , Micoses/tratamento farmacológico , Adulto Jovem
9.
BMC Infect Dis ; 19(1): 745, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455239

RESUMO

BACKGROUND: Due to the similar clinical, lung imaging, and pathological characteristics, talaromycosis is most commonly misdiagnosed as tuberculosis. This study aimed to identify the characteristics of talaromycosis pleural effusion (TMPE) and to distinguish TMPE from tuberculosis pleural effusion (TPE). METHODS: We enrolled 19 cases each of TMPE and TPE from Guangxi, China. Patients' clinical records, pleural effusion tests, biomarker test results, and receiver operating characteristic curves were analyzed. RESULTS: In total, 39.8% (65/163) of patients exhibited serous effusion, of whom 61 were non-human immunodeficiency virus (HIV)-infected patients; 68.85% of the non-HIV-infected patients (42/61) had TMPE. Thoracentesis was performed only in 19 patients, all of whom were misdiagnosed with tuberculosis and received long-term anti-tuberculosis treatment. In four of these patients, interleukin (IL)-23, IL-27, and interferon-gamma (IFN-γ) measurements were not performed since pleural effusion samples could not be collected because the effusion had been drained prior to the study. In the remaining 15 patients, pleural effusion samples were collected. Talaromyces marneffei was isolated from the pleural effusion and pleural nodules. Most TMPEs were characterized by yellowish fluid, with marked elevation of protein content and nucleated cell counts. However, neutrophils were predominantly found in TMPEs, and lymphocytes were predominantly found in TPEs (both p < 0.05). Adenosine deaminase (ADA) and IFN-γ levels in TMPEs were significantly lower than those in TPEs (all p < 0.05) and provided similar accuracies for distinguishing TMPEs from TPEs. IL-23 concentration in TMPEs was significantly higher than that in TPEs (p < 0.05), and it provided similar accuracy for diagnosing TMPEs. IL-27 concentrations in TMPEs were significantly lower than those in TPEs (all p < 0.05) but was not useful for distinguishing TMPE from TPE. CONCLUSIONS: Talaromycosis can infringe on the pleural cavity via the translocation of T. marneffei into the pleural space. Nonetheless, this phenomenon is still commonly neglected by clinicians. TMPE is a yellowish fluid with exudative PEs and predominant neutrophils. Higher neutrophil counts and IL-23 may suggest talaromycosis. Higher lymphocyte counts, ADA activity, and IFN-γ concentration may suggest tuberculosis.


Assuntos
Micoses/etiologia , Derrame Pleural/microbiologia , Tuberculose Pleural/diagnóstico , Adenosina Desaminase/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Interferon gama/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Interleucinas/metabolismo , Linfócitos/microbiologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Micoses/microbiologia , Neutrófilos/microbiologia , Neutrófilos/patologia , Derrame Pleural/diagnóstico , Derrame Pleural/tratamento farmacológico , Curva ROC , Talaromyces/patogenicidade , Tuberculose Pleural/tratamento farmacológico , Tuberculose Pleural/etiologia
10.
Chin Med J (Engl) ; 132(16): 1909-1918, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31348027

RESUMO

BACKGROUND: Little study has investigated the differences between Talatomyces marneffei (T. marneffei) respiratory infection and tuberculosis and the prognostic factors of such infection. This study investigated the characteristics and prognostic factors of T. marneffei infections with respiratory lesions and the causes of misdiagnosis. METHODS: Clinical characteristics and prognoses of patients with T. marneffei infections with respiratory system lesion were investigated. T. marneffei diagnosis followed isolation from clinical specimens using standard culture, cytology, and histopathology. Survival curves were estimated by using Kaplan-Meier analysis, with log-rank test to compare differences in survival rates between groups. Univariate and multivariate Cox regression analyses were also performed to assess significant differences in clinical characteristics of overall survival. RESULTS: Of 126 patients diagnosed with T. marneffei infections, 63 (50.0%) had T. marneffei respiratory system infections; 38.1% (24/63) were misdiagnosed as having tuberculosis. Human immunodeficiency virus (HIV) infection, CD4/CD8 < 0.5, percentage of CD4 T cells <42.8%, and length of time from onset to confirmation of diagnosis >105 days were potential risk factors for poor prognoses. Length of time from onset to confirmation of diagnosis persisted as an independent predictor of all-cause mortality in multivariate analysis (odds ratio: 0.083, 95.0% confidence interval: 0.021-0.326, P < 0.001). However, the size of the lung lesions, dyspnea, thoracalgia, mediastinal lymphadenopathy, and pleural effusion did not significantly predict overall survival. There was no significant difference in prognosis according to the type of treatment. CONCLUSIONS: T. marneffei infections involving the respiratory system are common. The critical determinants of prognosis are HIV infection, CD4/CD8, percentage of CD4 T cells, type of treatment, and the time range from onset to confirmation of diagnosis. Rapid and accurate diagnosis is crucial for improving prognosis.


Assuntos
Sistema Respiratório/microbiologia , Talaromyces/patogenicidade , Adolescente , Adulto , Idoso , Antifúngicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Micoses/microbiologia , Micoses/patologia , Prognóstico , Estudos Retrospectivos , Talaromyces/efeitos dos fármacos , Adulto Jovem
11.
Virulence ; 10(1): 277-291, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30880596

RESUMO

Aspartyl proteases are a widely represented class of proteolytic enzymes found in eukaryotes and retroviruses. They have been associated with pathogenicity in a range of disease-causing microorganisms. The dimorphic human-pathogenic fungus Talaromyces marneffei has a large expansion of these proteases identified through genomic analyses. Here we characterize the expansion of these genes (pop - paralogue of pep) and their role in T. marneffei using computational and molecular approaches. Many of the genes in this monophyletic family show copy number variation and positive selection despite the preservation of functional regions and possible redundancy. We show that the expression profile of these genes differs and some are expressed during intracellular growth in the host. Several of these proteins have distinctive localization as well as both additive and epistatic effects on the formation of yeast cells during macrophage infections. The data suggest that this is a recently evolved aspartyl protease gene family which affects intracellular growth and contributes to the pathogenicity of T. marneffei.


Assuntos
Ácido Aspártico Proteases/genética , Interações Hospedeiro-Patógeno , Macrófagos/microbiologia , Talaromyces/crescimento & desenvolvimento , Talaromyces/genética , Animais , Evolução Molecular , Proteínas Fúngicas/genética , Humanos , Camundongos , Células THP-1 , Talaromyces/patogenicidade
12.
Artigo em Inglês | MEDLINE | ID: mdl-30420478

RESUMO

Amphotericin B deoxycholate (DAmB) is a first-line agent for the initial treatment of talaromycosis. However, little is known about the population pharmacokinetics and pharmacodynamics of DAmB for talaromycosis. Pharmacokinetic data were obtained from 78 patients; among them, 55 patients had serial fungal CFU counts in blood also available for analysis. A population pharmacokinetic-pharmacodynamic model was fitted to the data. The relationships between the area under the concentration-time curve (AUC)/MIC and the time to blood culture sterilization and the time to death were investigated. There was only modest pharmacokinetic variability in the average AUC, with a mean ± standard deviation of 11.51 ± 3.39 mg·h/liter. The maximal rate of drug-induced kill was 0.133 log10 CFU/ml/h, and the plasma concentration of the DAmB that induced the half-maximal rate of kill was 0.02 mg/liter. Fifty percent of patients sterilized their bloodstreams by 83.16 h (range, 13 to 264 h). A higher initial fungal burden was associated with a longer time to sterilization (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.36 to 0.70; P < 0.001). There was a weak relationship between AUC/MIC and the time to sterilization, although this did not reach statistical significance (HR, 1.03; 95% CI, 1.00 to 1.06, P = 0.091). Furthermore, there was no relationship between the AUC/MIC and time to death (HR, 0.97; 95% CI, 0.88 to 1.08; P = 0.607) or early fungicidal activity {slope = log[(0.500 - 0.003·(AUC/MIC)]; P = 0.319} adjusted for the initial fungal burden. The population pharmacokinetics of DAmB are surprisingly consistent. The time to sterilization of the bloodstream may be a useful pharmacodynamic endpoint for future studies. (This study has been registered at the ISRCTN registry under no. ISRCTN59144167.).


Assuntos
Antifúngicos/uso terapêutico , Talaromyces/patogenicidade , Adulto , Anfotericina B/farmacocinética , Anfotericina B/uso terapêutico , Antifúngicos/farmacocinética , Área Sob a Curva , Ácido Desoxicólico/farmacocinética , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Penicillium/efeitos dos fármacos , Penicillium/patogenicidade , Talaromyces/efeitos dos fármacos
13.
BMC Infect Dis ; 18(1): 379, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30086724

RESUMO

BACKGROUND: Talaromyces marneffei, is an opportunistic pathogenic fungus that is most commonly reported in Southeast Asia and disseminated T.marneffei infection predominantly occurs in patients with immunodeficiency. With a potential to invade multiple organs, it can be fatal for patients if diagnosis and treatment are delayed. In current clinical practice, the diagnosis of T.marneffei infection relies heavily on tissue culture and histologic analysis, which may suffer from limited positive rate and is sometimes time consuming. The rapid and accurate diagnosis of disseminated T.marneffei infection remains challenging. CASE PRESENTATION: A 22-year-old man gradually developed fever, cough, lower extremities weakness, jaundice and rash, for which a 3-month extensive investigation failed to reach a diagnosis. After admitted into our hospital, laboratory and radiological tests revealed multiple lesions in the patient's brain, spinal cord, and lungs. We performed next generation sequencing on the patient's skin tissue, bone marrow, blood and cerebrospinal fluid, which all identified numerous Talaromyces marneffei nucleotide sequences and leaded to the rapid diagnosis and treatment of disseminated T.marneffei infection. CONCLUSIONS: This case underline the clinical significance of T.marneffei as a possible pathogen in immune-competent patients. This successful application of the next generation sequencing assisting the rapid diagnosis of disseminated T.marneffei infection provides a new perspective in the clinical approach to the systematic fungi infections and highlights the potential of this technique in rapid etiological diagnosis.


Assuntos
Ensaios de Triagem em Larga Escala , Infecções Fúngicas Invasivas/diagnóstico , Talaromyces/genética , Talaromyces/isolamento & purificação , Diagnóstico Precoce , Soronegatividade para HIV , Ensaios de Triagem em Larga Escala/métodos , Humanos , Infecções Fúngicas Invasivas/microbiologia , Masculino , Penicillium/genética , Penicillium/isolamento & purificação , Penicillium/patogenicidade , Sensibilidade e Especificidade , Talaromyces/patogenicidade , Fatores de Tempo , Adulto Jovem
14.
mBio ; 9(3)2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895639

RESUMO

Talaromyces marneffei is the most important thermal dimorphic fungus causing systemic mycosis in Southeast Asia. We report the discovery of a novel partitivirus, Talaromyces marneffeipartitivirus-1 (TmPV1). TmPV1 was detected in 7 (12.7%) of 55 clinical T. marneffei isolates. Complete genome sequencing of the seven TmPV1 isolates revealed two double-stranded RNA (dsRNA) segments encoding RNA-dependent RNA polymerase (RdRp) and capsid protein, respectively. Phylogenetic analysis showed that TmPV1 occupied a distinct clade among the members of the genus Gammapartitivirus Transmission electron microscopy confirmed the presence of isometric, nonenveloped viral particles of 30 to 45 nm in diameter, compatible with partitiviruses, in TmPV1-infected T. marneffei Quantitative reverse transcription-PCR (qRT-PCR) demonstrated higher viral load of TmPV1 in the yeast phase than in the mycelial phase of T. marneffei Two virus-free isolates, PM1 and PM41, were successfully infected by purified TmPV1 using protoplast transfection. Mice challenged with TmPV1-infected T. marneffei isolates showed significantly shortened survival time (P < 0.0001) and higher fungal burden in organs than mice challenged with isogenic TmPV1-free isolates. Transcriptomic analysis showed that TmPV1 causes aberrant expression of various genes in T. marneffei, with upregulation of potential virulence factors and suppression of RNA interference (RNAi)-related genes. This is the first report of a mycovirus in a thermally dimorphic fungus. Further studies are required to ascertain the mechanism whereby TmPV1 enhances the virulence of T. marneffei in mice and the potential role of RNAi-related genes in antiviral defense in T. marneffeiIMPORTANCETalaromyces marneffei (formerly Penicillium marneffei) is the most important thermal dimorphic fungus in Southeast Asia, causing highly fatal systemic penicilliosis in HIV-infected and immunocompromised patients. We discovered a novel mycovirus, TmPV1, in seven clinical isolates of T. marneffei TmPV1 belongs to the genus Gammapartitivirus of the family Partitiviridae We showed that TmPV1 enhanced the virulence of T. marneffei in mice, with shortened survival time and higher fungal burden in the organs of mice challenged with TmPV1-infected T. marneffei isolates than in those of mice challenged with virus-free isogenic isolates. Transcriptomics analysis showed that TmPV1 altered the expression of genes involved in various cellular processes in T. marneffei, with upregulation of potential virulence factors and suppression of RNAi machinery which may be involved in antiviral defense. This is the first report of a mycovirus in a thermal dimorphic fungus. The present results offer insights into mycovirus-fungus interactions and pathogenesis of thermal dimorphic fungi.


Assuntos
Micovírus/isolamento & purificação , Micoses/microbiologia , Vírus de RNA/isolamento & purificação , Vírus de RNA/fisiologia , Talaromyces/patogenicidade , Talaromyces/virologia , Animais , Feminino , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Micovírus/classificação , Micovírus/genética , Micovírus/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Filogenia , Vírus de RNA/classificação , Vírus de RNA/genética , Talaromyces/genética , Talaromyces/fisiologia , Proteínas Virais/genética , Proteínas Virais/metabolismo , Virulência , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
15.
PLoS Pathog ; 14(6): e1007063, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29883484

RESUMO

Neutrophils and macrophages provide the first line of cellular defence against pathogens once physical barriers are breached, but can play very different roles for each specific pathogen. This is particularly so for fungal pathogens, which can occupy several niches in the host. We developed an infection model of talaromycosis in zebrafish embryos with the thermally-dimorphic intracellular fungal pathogen Talaromyces marneffei and used it to define different roles of neutrophils and macrophages in infection establishment. This system models opportunistic human infection prevalent in HIV-infected patients, as zebrafish embryos have intact innate immunity but, like HIV-infected talaromycosis patients, lack a functional adaptive immune system. Importantly, this new talaromycosis model permits thermal shifts not possible in mammalian models, which we show does not significantly impact on leukocyte migration, phagocytosis and function in an established Aspergillus fumigatus model. Furthermore, the optical transparency of zebrafish embryos facilitates imaging of leukocyte/pathogen interactions in vivo. Following parenteral inoculation, T. marneffei conidia were phagocytosed by both neutrophils and macrophages. Within these different leukocytes, intracellular fungal form varied, indicating that triggers in the intracellular milieu can override thermal morphological determinants. As in human talaromycosis, conidia were predominantly phagocytosed by macrophages rather than neutrophils. Macrophages provided an intracellular niche that supported yeast morphology. Despite their minor role in T. marneffei conidial phagocytosis, neutrophil numbers increased during infection from a protective CSF3-dependent granulopoietic response. By perturbing the relative abundance of neutrophils and macrophages during conidial inoculation, we demonstrate that the macrophage intracellular niche favours infection establishment by protecting conidia from a myeloperoxidase-dependent neutrophil fungicidal activity. These studies provide a new in vivo model of talaromycosis with several advantages over previous models. Our findings demonstrate that limiting T. marneffei's opportunity for macrophage parasitism and thereby enhancing this pathogen's exposure to effective neutrophil fungicidal mechanisms may represent a novel host-directed therapeutic opportunity.


Assuntos
Aspergillus fumigatus/patogenicidade , Imunidade Inata/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Esporos Fúngicos/imunologia , Talaromyces/patogenicidade , Peixe-Zebra/imunologia , Animais , Leucócitos/imunologia , Leucócitos/microbiologia , Macrófagos/microbiologia , Camundongos , Neutrófilos/microbiologia , Peroxidase/metabolismo , Fagocitose , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/microbiologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-28861398

RESUMO

Fungal infections are an increasing public health problem, particularly in immunocompromised individuals. While these pathogenic fungi show polyphyletic origins with closely related non-pathogenic species, many undergo morphological transitions to produce pathogenic cell types that are associated with increased virulence. However, the characteristics of these pathogenic cells that contribute to virulence are poorly defined. Talaromyces marneffei grows as a non-pathogenic hyphal form at 25°C but undergoes a dimorphic transition to a pathogenic yeast form at 37°C in vitro and following inhalation of asexual conidia by a host. Here we show that this transition is associated with major changes in central carbon metabolism, and that these changes are correlated with increased virulence of the yeast form. Comprehensive metabolite profiling and 13C-labeling studies showed that hyphal cells exhibited very active glycolytic metabolism and contain low levels of internal carbohydrate reserves. In contrast, yeast cells fully catabolized glucose in the mitochondrial TCA cycle, and store excess glucose in large intracellular pools of trehalose and mannitol. Inhibition of the yeast TCA cycle inhibited replication in culture and in host cells. Yeast, but not hyphae, were also able to use myo-inositol and amino acids as secondary carbon sources, which may support their survival in host macrophages. These analyses suggest that T. marneffei yeast cells exhibit a more efficient oxidative metabolism and are capable of utilizing a diverse range of carbon sources, which contributes to their virulence in animal tissues, highlighting the importance of dimorphic switching in pathogenic yeast.


Assuntos
Metabolômica , Talaromyces/crescimento & desenvolvimento , Talaromyces/metabolismo , Talaromyces/patogenicidade , Aminoácidos/metabolismo , Animais , Metabolismo dos Carboidratos , Carbono/metabolismo , Ciclo do Ácido Cítrico , Regulação Fúngica da Expressão Gênica , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Hifas/crescimento & desenvolvimento , Hifas/metabolismo , Inositol/metabolismo , Macrófagos/microbiologia , Mitocôndrias/metabolismo , Micoses , Esporos Fúngicos/crescimento & desenvolvimento , Esporos Fúngicos/metabolismo , Coloração e Rotulagem , Células THP-1 , Talaromyces/citologia , Temperatura , Virulência , Leveduras/citologia , Leveduras/crescimento & desenvolvimento , Leveduras/metabolismo
17.
PLoS Negl Trop Dis ; 10(8): e0004907, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27560160

RESUMO

BACKGROUND: Talaromyces marneffei is an opportunistic dimorphic fungus prevalent in Southeast Asia. We previously demonstrated that Mp1p is an immunogenic surface and secretory mannoprotein of T. marneffei. Since Mp1p is a surface protein that can generate protective immunity, we hypothesized that Mp1p and/or its homologs are virulence factors. METHODOLOGY/PRINCIPAL FINDINGS: We examined the pathogenic roles of Mp1p and its homologs in a mouse model. All mice died 21 and 30 days after challenge with wild-type T. marneffei PM1 and MP1 complemented mutant respectively. None of the mice died 60 days after challenge with MP1 knockout mutant (P<0.0001). Seventy percent of mice died 60 days after challenge with MP1 knockdown mutant (P<0.0001). All mice died after challenge with MPLP1 to MPLP13 knockdown mutants, suggesting that only Mp1p plays a significant role in virulence. The mean fungal loads of PM1 and MP1 complemented mutant in the liver, lung, kidney and spleen were significantly higher than those of the MP1 knockout mutant. Similarly, the mean load of PM1 in the liver, lung and spleen were significantly higher than that of the MP1 knockdown mutant. Histopathological studies showed an abundance of yeast in the kidney, spleen, liver and lung with more marked hepatic and splenic necrosis in mice challenged with PM1 compared to MP1 knockout and MP1 knockdown mutants. Likewise, a higher abundance of yeast was observed in the liver and spleen of mice challenged with MP1 complemented mutant compared to MP1 knockout mutant. PM1 and MP1 complemented mutant survived significantly better than MP1 knockout mutant in macrophages at 48 hours (P<0.01) post-infection. The mean fungal counts of Pichia pastoris GS115-MP1 in the liver (P<0.001) and spleen (P<0.05) of mice were significantly higher than those of GS115 at 24 hours post-challenge. CONCLUSIONS/SIGNIFICANCE: Mp1p is a key virulence factor of T. marneffei. Mp1p mediates virulence by improving the survival of T. marneffei in macrophages.


Assuntos
Macrófagos/microbiologia , Glicoproteínas de Membrana/imunologia , Talaromyces/patogenicidade , Fatores de Virulência/imunologia , Fatores de Virulência/isolamento & purificação , Animais , Antígenos de Fungos/genética , Antígenos de Fungos/imunologia , Técnicas de Silenciamento de Genes , Humanos , Rim/microbiologia , Fígado/microbiologia , Fígado/patologia , Pulmão/microbiologia , Glicoproteínas de Membrana/genética , Camundongos , Mutação , Micoses/imunologia , Pichia/crescimento & desenvolvimento , Pichia/fisiologia , Baço/microbiologia , Baço/patologia , Talaromyces/genética , Talaromyces/crescimento & desenvolvimento , Fatores de Virulência/genética
18.
Am J Trop Med Hyg ; 95(2): 426-30, 2016 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-27273648

RESUMO

Talaromyces marneffei (formerly known as Penicillium marneffei) is a dimorphic fungus endemic in south and southeast Asia. It is not only commonly found in human immunodeficiency virus (HIV)-infected patients, but also among HIV-negative immunocompromised patients. The infection caused by this pathogen can disseminate hematogenously to other locations. Herein, we report for the first time two cases complicated with a rare disease or involving a rare site: in the first case, T. marneffei infection was complicated by Langerhans cell histiocytosis, whereas the second case showed clear etiological evidence of pleural nodules and pleural effusion caused by T. marneffei and diagnosed by thoracoscopic pleural biopsy.


Assuntos
Histiocitose de Células de Langerhans/microbiologia , Hospedeiro Imunocomprometido , Micoses/microbiologia , Infecções Oportunistas/microbiologia , Derrame Pleural/microbiologia , Talaromyces/isolamento & purificação , Feminino , HIV , Histiocitose de Células de Langerhans/diagnóstico por imagem , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/diagnóstico por imagem , Micoses/imunologia , Micoses/patologia , Infecções Oportunistas/diagnóstico por imagem , Infecções Oportunistas/imunologia , Infecções Oportunistas/patologia , Derrame Pleural/diagnóstico por imagem , Derrame Pleural/imunologia , Derrame Pleural/patologia , Tomografia por Emissão de Pósitrons , Talaromyces/crescimento & desenvolvimento , Talaromyces/patogenicidade , Toracoscopia
19.
Virulence ; 7(6): 702-17, 2016 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-27224737

RESUMO

Talaromyces (Penicillium) marneffei is an emerging opportunistic pathogen associated with HIV infection, particularly in Southeast Asia and southern China. The rapid uptake and killing of T. marneffei conidia by phagocytic cells along with the effective induction of an inflammatory response by the host is essential for disease control. T. marneffei produces a number of different laccases linked to fungal virulence. To understand the role of the various laccases in T. marneffei, laccase-encoding genes were investigated. Targeted single, double and triple gene deletions of laccases encoding lacA, lacB, and lacC showed no significant phenotypic effects suggesting redundancy of function. When a fourth laccase-encoding gene, pbrB, was deleted in the ΔlacA ΔlacB ΔlacC background, the quadruple mutant displayed delayed conidiation and the conidia were more sensitive to H2O2, sodium dodecyl sulfate (SDS), and antifungal agents than wild-type and other transformants. Conidia of the quadruple mutant showed marked differences in their interaction with the human monocyte cell line, THP-1 such that phagocytosis was significantly higher when compared with the wild-type at one and 2 hours of incubation while the phagocytic index was significantly different from 15 to 120 minutes. In addition, killing of the quadruple mutant by THP-1 cells was more efficient at 2 and 4 hours of incubation. The levels of the proinflammatory cytokines TNF-α, IL-1ß and IL-6 from THP-1 cells infected with the quadruple mutant were also significantly increased in comparison with wild-type. The results demonstrate that production of laccases by T. marneffei actually promotes the pathogen's resistance to innate host defenses.


Assuntos
Lacase/genética , Lacase/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Talaromyces/enzimologia , Talaromyces/patogenicidade , Antifúngicos/farmacologia , Linhagem Celular , Deleção de Genes , Genes Fúngicos , Humanos , Peróxido de Hidrogênio/farmacologia , Imunidade Inata , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Monócitos/microbiologia , Fenótipo , Dodecilsulfato de Sódio/farmacologia , Esporos Fúngicos/efeitos dos fármacos , Talaromyces/efeitos dos fármacos , Talaromyces/genética , Fator de Necrose Tumoral alfa/imunologia
20.
Future Microbiol ; 11(4): 511-26, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27073980

RESUMO

Organism-wide approaches examining the genetic mechanisms controlling growth and proliferation have proven to be a powerful tool in the study of pathogenic fungi. For many fungal pathogens techniques to study transcription and protein expression are particularly useful, and offer insights into infection processes by these species. Here we discuss the use of approaches such as differential display, suppression subtractive hybridization, microarray, RNA-seq, proteomics, genetic manipulation and infection models for the AIDS-defining pathogen Talaromyces marneffei. Together these methods have broadened our understanding of the biological processes, and genes that underlie them, which are involved in switching between the saprophytic and pathogenic states of T. marneffei, the maintenance of these two specialized cell types and its ability to cause disease.


Assuntos
Micoses/microbiologia , Micoses/patologia , Talaromyces/citologia , Talaromyces/patogenicidade , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Talaromyces/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA