Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.374
Filtrar
1.
Eur Rev Med Pharmacol Sci ; 24(8): 4519-4522, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32373989

RESUMO

The number of global COVID-19 infected cases is increased rapidly to exceed 370 thousand. COVID-19 is transmitted between humans through direct contact and touching dirty surfaces. This paper aims to find the similarity between DNA sequences of COVID-19 in different countries, and to compare these sequences with three different diseases [HIV, Hand-Foot-Mouth disease (HFMD), and Cryptococcus]. The study used pairwise distance, maximum likelihood tree, and similarity between amino acid to find the results. The results showed that different three main types of viruses namely, COVID-19 are found. The virus in both Italy and Iran is not similar to COVID-19 in China and USA. While, two viruses were spread in Wuhan (before and after December 26, 2019). Besides Cryptococcus and HFMD are found as dominant diseases with Group 1 and Group 3, respectively. Authors claim that the current virus in Italy and Iran that killed thousands of people is not COVID-19 based on the available data.


Assuntos
Betacoronavirus/classificação , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Sequência de Aminoácidos , Infecções por Coronavirus/virologia , Cryptococcus neoformans , Enterovirus , HIV , Doença de Mão, Pé e Boca , Humanos , Irã (Geográfico)/epidemiologia , Itália/epidemiologia , Pandemias , Pneumonia Viral/virologia , Alinhamento de Sequência , Análise de Sequência de DNA
2.
PLoS Negl Trop Dis ; 14(3): e0008137, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32231354

RESUMO

BACKGROUND: Fluconazole is used in combination with amphotericin B for induction treatment of cryptococcal meningitis and as monotherapy for consolidation and maintenance treatment. More than 90% of isolates from first episodes of cryptococcal disease had a fluconazole minimum inhibitory concentration (MIC) ≤4 µg/ml in a Gauteng population-based surveillance study of Cryptococcus neoformans in 2007-2008. We assessed whether fluconazole resistance had emerged in clinical cryptococcal isolates over a decade. METHODOLOGY AND PRINCIPAL FINDINGS: We prospectively collected C. neoformans isolates from 1 January through 31 March 2017 from persons with a first episode of culture-confirmed cryptococcal disease at 37 South African hospitals. Isolates were phenotypically confirmed to C. neoformans species-complex level. We determined fluconazole MICs (range: 0.125 µg/ml to 64 µg/ml) of 229 C. neoformans isolates using custom-made broth microdilution panels prepared, inoculated and read according to Clinical and Laboratory Standards Institute M27-A3 and M60 recommendations. These MIC values were compared to MICs of 249 isolates from earlier surveillance (2007-2008). Clinical data were collected from patients during both surveillance periods. There were more males (61% vs 39%) and more participants on combination induction antifungal treatment (92% vs 32%) in 2017 compared to 2007-2008. The fluconazole MIC50, MIC90 and geometric mean MIC was 4 µg/ml, 8 µg/ml and 4.11 µg/ml in 2017 (n = 229) compared to 1 µg/ml, 2 µg/ml and 2.08 µg/ml in 2007-2008 (n = 249) respectively. Voriconazole, itraconazole and posaconazole Etests were performed on 16 of 229 (7%) C. neoformans isolates with a fluconazole MIC value of ≥16 µg/ml; only one had MIC values of >32 µg/ml for these three antifungal agents. CONCLUSIONS AND SIGNIFICANCE: Fluconazole MIC50 and MIC90 values were two-fold higher in 2017 compared to 2007-2008. Although there are no breakpoints, higher fluconazole doses may be required to maintain efficacy of standard treatment regimens for cryptococcal meningitis.


Assuntos
Antifúngicos/farmacologia , Criptococose/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Farmacorresistência Fúngica , Fluconazol/farmacologia , Adulto , Cryptococcus neoformans/isolamento & purificação , Feminino , Hospitais , Humanos , Masculino , Testes de Sensibilidade Microbiana , Estudos Prospectivos , África do Sul
3.
Adv Exp Med Biol ; 1204: 1-30, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32152941

RESUMO

Most fungal species are harmless to humans and some exist as commensals on mucocutaneous surfaces. Yet many fungi are opportunistic pathogens, causing life-threatening invasive infections when the immune system becomes compromised. The fungal cell wall contains conserved pathogen-associated molecular patterns (PAMPs), which allow the immune system to distinguish between self (endogenous molecular patterns) and foreign material. Sensing of invasive microbial pathogens is achieved through recognition of PAMPs by pattern recognition receptors (PRRs). One of the predominant fungal-sensing PRRs is the C-type lectin receptor (CLR) family. These receptors bind to structures present on the fungal cell wall, eliciting various innate immune responses as well as shaping adaptive immunity. In this chapter, we specifically focus on the four major human fungal pathogens, Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Pneumocystis jirovecii, reviewing our current understanding of the CLRs that are involved in their recognition and protection of the host.


Assuntos
Fungos/imunologia , Imunidade Inata/imunologia , Lectinas Tipo C/imunologia , Aspergillus fumigatus/imunologia , Candida albicans/imunologia , Cryptococcus neoformans/imunologia , Humanos , Padrões Moleculares Associados a Patógenos/imunologia , Pneumocystis carinii/imunologia
4.
PLoS Pathog ; 16(2): e1008240, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32106253

RESUMO

Cryptococcus neoformans is an opportunistic human pathogen, which causes serious disease in immunocompromised hosts. Infection with this pathogen is particularly relevant in HIV+ patients, where it leads to around 200,000 deaths per annum. A key feature of cryptococcal pathogenesis is the ability of the fungus to survive and replicate within the phagosome of macrophages, as well as its ability to be expelled from host cells via a novel non-lytic mechanism known as vomocytosis. Here we show that cryptococcal vomocytosis from macrophages is strongly enhanced by viral coinfection, without altering phagocytosis or intracellular proliferation of the fungus. This effect occurs with distinct, unrelated human viral pathogens and is recapitulated when macrophages are stimulated with the anti-viral cytokines interferon alpha or beta (IFNα or IFNß). Importantly, the effect is abrogated when type-I interferon signalling is blocked, thus underscoring the importance of type-I interferons in this phenomenon. Lastly, our data help resolve previous, contradictory animal studies on the impact of type I interferons on cryptococcal pathogenesis and suggest that secondary viral stimuli may alter patterns of cryptococcal dissemination in the host.


Assuntos
Coinfecção , Criptococose , Cryptococcus neoformans , Infecções por HIV , HIV-1 , Macrófagos , Coinfecção/imunologia , Coinfecção/microbiologia , Coinfecção/patologia , Coinfecção/virologia , Criptococose/imunologia , Criptococose/microbiologia , Criptococose/patologia , Criptococose/virologia , Cryptococcus neoformans/imunologia , Cryptococcus neoformans/patogenicidade , Células HEK293 , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Interferon-alfa/imunologia , Interferon beta/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Macrófagos/virologia , Transdução de Sinais/imunologia
5.
BMC Infect Dis ; 20(1): 91, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000709

RESUMO

BACKGROUND: We compared the cryptococcal antigen detection and imaging findings between immunocompetent and immunocompromised patients in whom pulmonary cryptococcosis had been diagnosed. The aim of our study was to determine whether the patient's immune status and radiography affect the detection of cryptococcal antigen. METHODS: According to whether they took immunosuppressive drugs or not, seventy and eight adult patients with pulmonary cryptococcosis were divided into two groups: the immunocompetent group and the immunocompromised group. According to the detection of CrAg, each group was divided into the CrAg+ group and the CrAg- group. Then, clinical records, laboratory examinations and computed tomography findings were collected and analyzed. RESULTS: No difference was found in baseline characteristics, clinical symptoms, and laboratory investigations. By comparing CrAg detection in these two groups, it was found that the number of CrAg+ cases in the immunocompetent group was more than that in the immunocompromised group. And in the immunocompetent group, diffuse lesions were more common in CrAg+ group and limited lesions were more frequently observed in CrAg- group. CONCLUSIONS: The patient's immune status and radiography would affect the detection of cryptococcal antigen. And serum CrAg could be a useful tool for the diagnosis of pulmonary cryptococcosis in immunocompetent patients with extensive lung involvement.


Assuntos
Antígenos de Fungos/sangue , Criptococose/diagnóstico por imagem , Criptococose/imunologia , Cryptococcus neoformans/imunologia , Hospedeiro Imunocomprometido , Pneumopatias Fúngicas/diagnóstico por imagem , Pneumopatias Fúngicas/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criptococose/tratamento farmacológico , Testes Diagnósticos de Rotina/métodos , Feminino , Seguimentos , Humanos , Testes Imunológicos , Imunossupressores/uso terapêutico , Pneumopatias Fúngicas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Adulto Jovem
7.
PLoS Negl Trop Dis ; 14(1): e0007984, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31929533

RESUMO

Cryptococcal meningoencephalitis (CM) remains the most prevalent invasive fungal infection worldwide. The main objective of this study was to describe the prevalence of CM and cryptococcal infection in HIV-infected patients in Madagascar. The secondary objectives were to assess the adjusted prevalence of CM according to clinical presentation and patient characteristics, to determine crude 90-day survival according to cryptococcal antigen (CrAg) status and CM, and to identify the genotypes of Cryptococcus clinical isolates. This cross-sectional study was carried out at two urban hospitals in Antananarivo (central highlands) and Toamasina (east coast) between November 2014 and December 2016. Consecutive HIV-infected adults presenting with CD4 cell counts ≤200/µl were enrolled. Lateral flow immunoassays of CrAg were performed on serum for all patients, and on cerebrospinal fluid for patients with CM symptoms. MALDI-ToF MS, ITS sequencing, and determinations of the molecular and mating types of the isolates were performed. Fluconazole is the only drug for CM treatment available in Madagascar. Patients were treated orally, with high doses (1200 mg/day) for 10-12 weeks and then with 200 mg/day. Minimum inhibitory concentrations were determined for amphotericin B, flucytosine, voriconazole and fluconazole in E-tests. Overall prevalence was 13.2% (95% CI 7.9-20.3) for cryptococcal infection and 10.9% (95% CI 6.1-17.5) for CM, among the 129 HIV-infected patients studied. The 90-day mortality rate was 58.8% (10/17) in CrAg-positive patients and 17.9% (20/112) in CrAg-negative patients (p<0.001). The 13 Cryptococcus strains obtained at baseline were all Cryptococcus neoformans var. grubii, genotypes VNI-αA (3 isolates), VNII-αA (4 isolates) or hybrid VNI/VNII-αAAα (6 isolates), suggesting high diversity. Two strains acquired fluconazole resistance after four and five months of exposure, respectively. The prevalence of cryptococcosis is high in Madagascar and this serious condition is life-threatening in HIV-infected patients. These findings will be used to raise the awareness of national authorities to strengthen the national HIV/AIDS control program.


Assuntos
Cryptococcus neoformans/isolamento & purificação , Infecções por HIV/complicações , Meningite Criptocócica/complicações , Meningite Criptocócica/microbiologia , Adulto , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , Humanos , Madagáscar/epidemiologia , Masculino , Meningite Criptocócica/epidemiologia , Pessoa de Meia-Idade
8.
PLoS Pathog ; 16(1): e1008201, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31945142

RESUMO

Fungal pathogens represent a major human threat affecting more than a billion people worldwide. Invasive infections are on the rise, which is of considerable concern because they are accompanied by an escalation of antifungal resistance. Deciphering the mechanisms underlying virulence traits and drug resistance strongly relies on genetic manipulation techniques such as generating mutant strains carrying specific mutations, or gene deletions. However, these processes have often been time-consuming and cumbersome in fungi due to a number of complications, depending on the species (e.g., diploid genomes, lack of a sexual cycle, low efficiency of transformation and/or homologous recombination, lack of cloning vectors, nonconventional codon usage, and paucity of dominant selectable markers). These issues are increasingly being addressed by applying clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 mediated genetic manipulation to medically relevant fungi. Here, we summarize the state of the art of CRISPR-Cas9 applications in four major human fungal pathogen lineages: Candida spp., Cryptococcus neoformans, Aspergillus fumigatus, and Mucorales. We highlight the different ways in which CRISPR has been customized to address the critical issues in different species, including different strategies to deliver the CRISPR-Cas9 elements, their transient or permanent expression, use of codon-optimized CAS9, and methods of marker recycling and scarless editing. Some approaches facilitate a more efficient use of homology-directed repair in fungi in which nonhomologous end joining is more commonly used to repair double-strand breaks (DSBs). Moreover, we highlight the most promising future perspectives, including gene drives, programmable base editors, and nonediting applications, some of which are currently available only in model fungi but may be adapted for future applications in pathogenic species. Finally, this review discusses how the further evolution of CRISPR technology will allow mycologists to tackle the multifaceted issue of fungal pathogenesis.


Assuntos
Sistemas CRISPR-Cas , Micologia/métodos , Aspergillus fumigatus/genética , Cryptococcus neoformans/genética , Previsões , Edição de Genes , Humanos , Mucorales/genética
9.
Nat Chem Biol ; 16(3): 337-344, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932719

RESUMO

Infection by the fungal pathogen Cryptococcus neoformans causes lethal meningitis, primarily in immune-compromised individuals. Colonization of the brain by C. neoformans is dependent on copper (Cu) acquisition from the host, which drives critical virulence mechanisms. While C. neoformans Cu+ import and virulence are dependent on the Ctr1 and Ctr4 proteins, little is known concerning extracellular Cu ligands that participate in this process. We identified a C. neoformans gene, BIM1, that is strongly induced during Cu limitation and which encodes a protein related to lytic polysaccharide monooxygenases (LPMOs). Surprisingly, bim1 mutants are Cu deficient, and Bim1 function in Cu accumulation depends on Cu2+ coordination and cell-surface association via a glycophosphatidyl inositol anchor. Bim1 participates in Cu uptake in concert with Ctr1 and expression of this pathway drives brain colonization in mouse infection models. These studies demonstrate a role for LPMO-like proteins as a critical factor for Cu acquisition in fungal meningitis.


Assuntos
Cobre/metabolismo , Cryptococcus neoformans/metabolismo , Oxigenases de Função Mista/metabolismo , Animais , Criptococose/metabolismo , Cryptococcus neoformans/patogenicidade , Modelos Animais de Doenças , Feminino , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Meningite/metabolismo , Meningite/fisiopatologia , Camundongos , Camundongos Endogâmicos A , Polissacarídeos/metabolismo , Virulência
10.
BMC Infect Dis ; 20(1): 68, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964348

RESUMO

BACKGROUND: Cryptococcal meningitis (CCM) is a common and deadly disease among HIV-infected patients. Notable about CCM is its association with the immune reconstitution inflammatory syndrome (IRIS). Though it has been posited a switch from first to second-line antiretroviral therapy (ART) can induce CCM IRIS, a case presentation of CCM IRIS has not been published. CASE PRESENTATION: A 10-year-old, HIV-infected girl who initially presented with severe headache and new-onset seizures, with cerebrospinal fluid that returned antigen, India Ink, and culture positive for Cryptococcus neoformans. Notably, 8 weeks prior to seizures, she had switched from first line to second-line ART (abacavir-lamivudine-efavirenz to zidovudine-lamivudine-lopinavir/ritonavir) due to virologic failure, with a viral load of 224,000 copies/milliliter. At time of seizures and 8 weeks on second-line ART, her viral load had reduced to 262 copies/milliliter. Her hospital course was prolonged, as she had ongoing headaches and developed bilateral cranial nerve VI palsies despite clearance of Cryptococcus from cerebrospinal fluid on antifungal therapy and therapeutic lumbar punctures. However, symptoms stabilized, and she was discharged with oral fluconazole. Cranial nerve palsies resolved 10 weeks post discharge and she has remained disease free. CONCLUSIONS: We describe a case of CCM IRIS in a 10-year-old HIV infected child after changing to second-line ART. This case provides evidence that screening for cryptococcal antigenaemia prior to switch from first-line to second-line ART could be an important measure to prevent cryptococcal disease.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Cryptococcus neoformans/isolamento & purificação , HIV/efeitos dos fármacos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Lamivudina/uso terapêutico , Lopinavir/uso terapêutico , Meningite Criptocócica/diagnóstico , Ritonavir/uso terapêutico , Zidovudina/uso terapêutico , Infecções Oportunistas Relacionadas com a AIDS/complicações , Antifúngicos/uso terapêutico , Antígenos de Fungos/sangue , Benzoxazinas/uso terapêutico , Criança , Didesoxinucleosídeos/uso terapêutico , Combinação de Medicamentos , Feminino , Fluconazol/uso terapêutico , HIV/isolamento & purificação , Humanos , Síndrome Inflamatória da Reconstituição Imune/etiologia , Lamivudina/efeitos adversos , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/etiologia , Ritonavir/efeitos adversos , Resultado do Tratamento , Carga Viral , Zidovudina/efeitos adversos
11.
J Med Microbiol ; 69(1): 72-81, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31750814

RESUMO

Introduction. Limited data regarding the epidemiology and susceptibility profiles of cryptococcosis are available in the Middle East.Aim. Our study aimed to evaluate the molecular diversity, mating types and antifungal susceptibility pattern of Cryptococcus species (n=14) isolated from 320 suspected patients with cryptococcosis.Methodology. The URA5 gene was subjected to restriction fragment length polymorphism and sequence analysis. In addition, in vitro antifungal susceptibility testing was performed by Clinical and Laboratory Standards Institute (CLSI) M27-A4 and M59 guidelines.Results. Overall, 14 (4.4 %) patients were confirmed as cryptococcosis. Based on molecular type, 85.7 and 14.3 % of the isolates were C. neoformans VN I and VN II, respectively. Phylogenetic analysis of URA5 gene sequences revealed clustering of VN I and VN II isolates into two distinct clades with a substantial difference within each molecular type. Voriconazole and 5-fluorocytosine, respectively, had the lowest (0.031 µg ml-1) and highest (8 µg ml-1) MICs. The epidemiological cutoff values (ECVs) for amphotericin B, fluconazole, voriconazole and 5-fluorocytosine encompassed ≥97 % of all 14 C. neoformans VN I species. However, according to the CLSI document M59, ECVs for itraconazole (7; 50 % of the isolates) and for posaconazole (1; 7.1 % of the isolate), were one log2 dilution higher than the wild type range. Combinations of amphotericin B with 5-fluorocytosine, amphotericin B with fluconazole and fluconazole with 5-fluorocytosine exhibited synergistic effects against 37, 31 and 12.5 % of the isolates, respectively.Conclusion. Our findings may significantly contribute to the development of management strategies for patients at a higher risk of cryptococcosis, particularly HIV-positive individuals.


Assuntos
Antifúngicos/farmacologia , Criptococose/epidemiologia , Criptococose/microbiologia , Cryptococcus gattii/classificação , Cryptococcus gattii/efeitos dos fármacos , Cryptococcus neoformans/classificação , Cryptococcus neoformans/efeitos dos fármacos , Adulto , Cryptococcus gattii/genética , Cryptococcus gattii/isolamento & purificação , Cryptococcus neoformans/genética , Cryptococcus neoformans/isolamento & purificação , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Epidemiologia Molecular , Tipagem Molecular , Técnicas de Tipagem Micológica , Polimorfismo de Fragmento de Restrição
12.
Braz J Infect Dis ; 24(1): 7-12, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31870760

RESUMO

BACKGROUND: This study aims to explore the epidemiology, clinical profile and strain characteristics of cryptococcosis from 2013 to 2017 in a major teaching hospital in China. METHODS: Trends in antifungal drug susceptibility of 217 consecutive non-repetitive cryptococcal isolates collected from patients of an university hospital in China were analyzed between 2013 and 2017. Of those, 98 isolates were conserved for identification by internal transcribed spacer (ITS) sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) system. Multilocus sequence typing (MLST) was used to designate molecular types. Clinical characteristics of the 98 patients with cryptococcosis during the period of 2013-2017 were retrospectively evaluated. RESULTS: There was a trend for gradual increase in the MIC range of fluconazole was from 2013 to 2017. The conserved 98 clinical cryptococcal isolates included 97 C. neoformans and one C. gattii, and 90 (91.8%) isolates belonged to ST5 genotype VNI. Out of the 98 patients with cryptococcosis, 28 (28.6%) were HIV-infected and 32 (32.7%) had no underlying diseases. HIV-infected patients had higher mortality than HIV-uninfected patients (28.6% vs 14.3%, p=0.147). CONCLUSIONS: Most of the patients with cryptococcosis were not HIV-infected in this study, while patients with HIV had a higher mortality. Reduced susceptibility to fluconazole was observed among C. neoformans isolates, most of them belonged to ST5 genotype VNI having an impact on the effective dose of fluconazole.


Assuntos
Criptococose/epidemiologia , Criptococose/microbiologia , Hospitais Universitários/estatística & dados numéricos , Adulto , Antifúngicos/uso terapêutico , China/epidemiologia , Estudos Transversais , Criptococose/tratamento farmacológico , Cryptococcus gattii/efeitos dos fármacos , Cryptococcus gattii/genética , Cryptococcus gattii/isolamento & purificação , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/genética , Cryptococcus neoformans/isolamento & purificação , Feminino , Genótipo , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Tempo
13.
Chem Biodivers ; 17(2): e1900624, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31863703

RESUMO

In search for new fungicidal and free radical scavenging agents, we synthesized a focused library of 2-chloroquinoline based monocarbonyl analogs of curcumin (MACs). The synthesized MACs were evaluated for in vitro antifungal and antioxidant activity. The antifungal activity was evaluated against five different fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, and Cryptococcus neoformans, respectively. Most of the synthesized MACs displayed promising antifungal activity compared to the standard drug Miconazole. Furthermore, molecular docking study on a crucial fungal enzyme sterol 14α-demethylase (CYP51) could provide insight into the plausible mechanism of antifungal activity. MACs were also screened for in vitro radical scavenging activity using butylated hydroxytoluene (BHT) as a standard. Almost all MACs exhibited better antioxidant activity compared to BHT.


Assuntos
Antifúngicos/síntese química , Antioxidantes/química , Curcumina/análogos & derivados , Proteínas Fúngicas/metabolismo , Simulação de Acoplamento Molecular , Quinolinas/química , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Domínio Catalítico , Cryptococcus neoformans/efeitos dos fármacos , Curcumina/metabolismo , Curcumina/farmacologia , Proteínas Fúngicas/química , Testes de Sensibilidade Microbiana , Esterol 14-Desmetilase/química , Esterol 14-Desmetilase/metabolismo
14.
Infect Immun ; 88(3)2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-31871099

RESUMO

Cryptococcosis is an infectious disease caused by two fungal species, Cryptococcus neoformans and Cryptococcus gattii While C. neoformans affects mainly immunocompromised patients, C. gattii infects both immunocompetent and immunocompromised individuals. Laccase is an important virulence factor that contributes to the virulence of C. neoformans by promoting pulmonary growth and dissemination to the brain. The presence of laccase in C. neoformans can shift the host immune response toward a nonprotective Th2-type response. However, the role of laccase in the immune response against C. gattii remains unclear. In this study, we characterized laccase activity in C. neoformans and C. gattii isolates from Thailand and investigated whether C. gattii that is deficient in laccase might modulate immune responses during infection. C. gattii was found to have higher laccase activity than C. neoformans, indicating the importance of laccase in the pathogenesis of C. gattii infection. The expression of laccase promoted intracellular proliferation in macrophages and inhibited in vitro fungal clearance. Mice infected with a lac1Δ mutant strain of C. gattii had reduced lung burdens at the early but not the late stage of infection. Without affecting type-1 and type-2 responses, the deficiency of laccase in C. gattii induced cryptococcus-specific interleukin-17 (IL-17) cytokine, neutrophil accumulation, and expression of the neutrophil-associated cytokine gene Csf3 and chemokine genes Cxcl1, Cxcl2, and Cxcl5 in vivo, as well as enhanced neutrophil-mediated phagocytosis and killing in vitro Thus, our data suggest that laccase constitutes an important virulence factor of C. gattii that plays roles in attenuating Th17-type immunity, neutrophil recruitment, and function during the early stage of infection.


Assuntos
Criptococose , Cryptococcus gattii/imunologia , Cryptococcus neoformans/imunologia , Lacase/metabolismo , Animais , Proliferação de Células , Quimiocinas/metabolismo , Criptococose/imunologia , Criptococose/metabolismo , Cryptococcus gattii/patogenicidade , Cryptococcus neoformans/patogenicidade , Citocinas/metabolismo , Macrófagos/imunologia , Camundongos , Neutrófilos/metabolismo , Virulência/imunologia , Fatores de Virulência/metabolismo
15.
An Bras Dermatol ; 94(6): 744-746, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31789256

RESUMO

This report describes a case of unusual deep skin ulcers with tortuous sinus tract formation in an immunocompetent woman. She was initially diagnosed with a Staphylococcus aureus skin infection and histopathologically diagnosed with pyoderma gangrenosum. However, culture from the deep end of ribbon gauze inserted into the subcutaneous sinus tract revealed shiny, light-yellow mucoid colonies, which were identified as Cryptococcus neoformans var. grubii. She was treated with fluconazole for nine months and completely healed. Cryptococcosis is an opportunistic infection caused by variants of C. neoformans species. Cutaneous manifestations of cryptococcosis are quite divergent, rarely occurring as deep skin ulcers with sinus formation.


Assuntos
Criptococose/patologia , Cryptococcus neoformans/isolamento & purificação , Dermatomicoses/patologia , Imunocompetência , Úlcera Cutânea/microbiologia , Úlcera Cutânea/patologia , Adulto , Antifúngicos/uso terapêutico , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Dermatomicoses/tratamento farmacológico , Dermatomicoses/microbiologia , Feminino , Fluconazol/uso terapêutico , Humanos , Hospedeiro Imunocomprometido , Úlcera Cutânea/tratamento farmacológico
16.
BMC Infect Dis ; 19(1): 1051, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830905

RESUMO

BACKGROUND: Cryptococcal prostatitis is a rare clinical disease and has never been reported in China. CASE PRESENTATION: We report on a male HIV-infected patient with pulmonary and prostate cryptococcosis that was misdiagnosed (as tuberculosis) and delayed diagnosed. Although the patients accepted anti-fungal treatment and anti-retroviral treatment finally, the physician's mistakes reflect the rarity of this condition in China. CONCLUSION: Cryptococcal prostatitis is a rare disease that unusually presents in immunodeficient patients. Physicians should have a heightened awareness of this particular infection in the immunodeficient population.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Criptococose/diagnóstico , Cryptococcus neoformans/isolamento & purificação , Pneumonia por Pneumocystis/diagnóstico , Prostatite/diagnóstico , Retenção Urinária/diagnóstico , Retenção Urinária/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , China , Criptococose/complicações , Criptococose/tratamento farmacológico , Diagnóstico Tardio , Erros de Diagnóstico , Fluconazol/administração & dosagem , Fluconazol/uso terapêutico , Flucitosina/administração & dosagem , Flucitosina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/microbiologia , Prostatite/tratamento farmacológico , Prostatite/microbiologia , Resultado do Tratamento , Voriconazol/administração & dosagem , Voriconazol/uso terapêutico
17.
mBio ; 10(6)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848271

RESUMO

Cryptococcus neoformans can cause fatal meningoencephalitis in patients with AIDS or other immunocompromising conditions. Current antifungals are suboptimal to treat this disease; therefore, novel targets and new therapies are needed. Previously, we have shown that chitosan is a critical component of the cryptococcal cell wall and is required for survival in the mammalian host and that chitosan deficiency results in rapid clearance from the mammalian host. We had also identified several specific proteins that were required for chitosan biosynthesis, and we hypothesize that screening for compounds that inhibit chitosan biosynthesis would identify additional genes/proteins that influence chitosan biosynthesis. To identify these compounds, we developed a robust and novel cell-based flow cytometry screening method to identify small-molecule inhibitors of chitosan production. We screened the ICCB Known Bioactives library and identified 8 compounds that reduced chitosan in C. neoformans We used flow cytometry-based counterscreens and confirmatory screens, followed by a biochemical secondary screen to refine our primary screening hits to 2 confirmed hits. One of the confirmed hits that reduced chitosan content was the aminoalkylindole BML-190, a known inverse agonist of mammalian cannabinoid receptors. We demonstrated that BML-190 likely targets the C. neoformans G-protein-coupled receptor Gpr4 and, via the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, contributes to an intracellular accumulation of cAMP that results in decreased chitosan. Our discovery suggests that this approach could be used to identify additional compounds and pathways that reduce chitosan biosynthesis and could lead to potential novel therapeutics against C. neoformans IMPORTANCE Cryptococcus neoformans is a fungal pathogen that kills ∼200,000 people every year. The cell wall is an essential organelle that protects fungi from the environment. Chitosan, the deacetylated form of chitin, has been shown to be an essential component of the cryptococcal cell wall during infection of a mammalian host. In this study, we screened a set of 480 compounds, which are known to have defined biological activities, for activity that reduced chitosan production in C. neoformans Two of these compounds were confirmed using an alternative method of measuring chitosan, and one of these was demonstrated to impact the cAMP signal transduction pathway. This work demonstrates that the cAMP pathway regulates chitosan biosynthesis in C. neoformans and validates that this screening approach could be used to find potential antifungal agents.


Assuntos
Quitosana/metabolismo , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Indometacina/análogos & derivados , Modelos Biológicos , Morfolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fenômenos Químicos , Descoberta de Drogas , Indometacina/química , Indometacina/farmacologia , Estrutura Molecular , Morfolinas/química , Receptores Acoplados a Proteínas-G/metabolismo
18.
mBio ; 10(6)2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31874916

RESUMO

Macrophages are well known for their phagocytic activity and their role in innate immune responses. Macrophages eat non-self particles, via a variety of mechanisms, and typically break down internalized cargo into small macromolecules. However, some pathogenic agents have the ability to evade this endosomal degradation through a nonlytic exocytosis process termed vomocytosis. This phenomenon has been most often studied for Cryptococcus neoformans, a yeast that causes roughly 180,000 deaths per year, primarily in immunocompromised (e.g., human immunodeficiency virus [HIV]) patients. Existing dogma purports that vomocytosis involves distinctive cellular pathways and intracellular physicochemical cues in the host cell during phagosomal maturation. Moreover, it has been observed that the immunological state of the individual and macrophage phenotype affect vomocytosis outcomes. Here we compile the current knowledge on the factors (with respect to the phagocytic cell) that promote vomocytosis of C. neoformans from macrophages.


Assuntos
Cálcio/metabolismo , Cryptococcus neoformans/imunologia , Macrófagos/microbiologia , Fagossomos/microbiologia , Fagossomos/fisiologia , Animais , Humanos , Concentração de Íons de Hidrogênio , Macrófagos/fisiologia , Camundongos , Fagocitose , Fenótipo
19.
Pan Afr Med J ; 33: 249, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31692764

RESUMO

Neuromeningeal cryptococcosis is a common and severe opportunistic fungal infection caused by the encapsulated yeast Cryptococcus neoformans. It commonly occurs in immunocompromised patients, in particular in subjects with advanced stage HIV while it is rare in immunocompetent patients. We report 40 cases of neuromeningeal cryptococcosis (NMC) diagnosed at the Mycology-Parasitology Department of the Ibn Sina hospital in Rabat, over a 21-year period (1993-2014). The diagnosis was based on nested-PCR-based assay for the detection of Cryptococcus neoformans after staining with China ink and culture on Sabouraud agar without actidione as well as on the identification of soluble cryptococcal antigens. Thirty-five patients had HIV infection, 2 patients were apparently immunocompetent and 3 were immunocompromised patients without HIV (30 men and 10 women). The average age of patients was 38 years; neuromeningeal cryptococcosis was indicative of HIV infection in 13 cases. In 22 cases it was a complication of AIDS. Twenty-seven patients of our series were treated with fluconazole monotherapy. Amphotericin B was used in 13 patients. Outcome was favorable in 13 patients (32.5%) while 3 patients had complications (7.5%). Eighteen patients died (45%) and 6 were lost to follow-up (15%). The tests to diagnose a Cryptococcus neoformans infection should be performed systematically in patients with neurological signs for early diagnosis.


Assuntos
Antifúngicos/administração & dosagem , Infecções por HIV/epidemiologia , Hospedeiro Imunocomprometido , Meningite Criptocócica/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Adulto , Idoso , Anfotericina B/administração & dosagem , Cryptococcus neoformans/isolamento & purificação , Feminino , Fluconazol/administração & dosagem , Infecções por HIV/complicações , Humanos , Masculino , Meningite Criptocócica/diagnóstico , Meningite Criptocócica/tratamento farmacológico , Pessoa de Meia-Idade , Marrocos , Adulto Jovem
20.
PLoS Negl Trop Dis ; 13(11): e0007812, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31738768

RESUMO

Genetic diversity analyses were performed by sero-genotyping and multi-locus sequence typing on 252 cryptococcal isolates from 13 HIV-positive Ivorian patients followed-up for cryptococcal meningitis. Antifungal susceptibility analyses were performed according to the CLSI M27A3 method. The majority (67.8%) of the isolates belonged to the Cryptococcus neoformans (serotype A) species complex, with 93% being VNI and 7% being VNII. Cryptococcus deuterogattii VGII (serotype B) represented 16.7% of the strains, while C. neoformans/C. deneoformans VNIII (serotype AD) hybrids accounted for 15.1% of the strains. One strain (0.4%) was not identifiable. Nine different sequence types (STs 5, 6, 23, 40, 93, 207, 311, and a new ST; 555) were identified in the C. neoformans population, while the C. deuterogattii population comprised the single ST 173. The distribution of the strains showed that, while the majority of patients (9/13) harboured a single sequence type, 4 patients showed mixed infections. These patients experienced up to 4 shifts in strain content either at the species and/or ST level during their follow-up. This evolution of diversity over time led to the co-existence of up to 3 different Cryptococcus species and 4 different ST within the same individual during the course of infection. Susceptibility testing showed that all strains were susceptible to amphotericin B while 3.6% of them had a none-wild type phenotype to 5-flucytosine. Concerning fluconazole, 2.9% of C.neoformans serotype A strains and 2.4% of C. deuterogattii had also respectively a none-wild type phenotype to this molecule. All C. neoformans x C. deneoformans serotype AD hybrids had however a wild type phenotype to fluconazole. The present study showed that mixed infections exist and could be of particular importance for care outcomes. Indeed, (i) the different Cryptococcus species are known to exhibit different virulence and different susceptibility patterns to antifungal drugs and (ii) the strains genetic diversity within the samples may influence the susceptibility to antifungal treatment.


Assuntos
Antifúngicos/uso terapêutico , Coinfecção , Cryptococcus/efeitos dos fármacos , Cryptococcus/genética , Variação Genética , Infecções por HIV/complicações , Meningite Criptocócica/complicações , Adulto , Anfotericina B/uso terapêutico , Coinfecção/microbiologia , Criptococose , Cryptococcus/isolamento & purificação , Cryptococcus neoformans/genética , Feminino , Fluconazol/uso terapêutico , Flucitosina/uso terapêutico , Seguimentos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Técnicas de Tipagem Micológica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA