Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.816
Filtrar
1.
Rev Soc Bras Med Trop ; 57: e007052024, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38808801

RESUMEN

BACKGROUND: Accurate diagnosis of paracoccidioidomycosis is crucial for improving patient outcomes. Paracoccidioides antibody detection by double immunodiffusion (DID) is a convenient diagnostic tool, but testing performance can vary based on certain factors. METHODS: We assessed DID performance using a commercially prepared Paracoccidioides reagents (IMMY, USA), involving 40 serum specimens, including 20 from patients with proven paracoccidioidomycosis and 20 from patients without the disease. The DID test demonstrated a sensitivity of 90% (95% CI=68%-99%) and a specificity of 100% (95% CI=83%-100%). CONCLUSIONS: Our findings suggest that DID using commercial reagents may provide a feasible tool with satisfactory testing performance for anti-Paracoccidioides antibody detection.


Asunto(s)
Anticuerpos Antifúngicos , Inmunodifusión , Paracoccidioides , Paracoccidioidomicosis , Sensibilidad y Especificidad , Humanos , Anticuerpos Antifúngicos/sangre , Paracoccidioidomicosis/diagnóstico , Paracoccidioidomicosis/inmunología , Paracoccidioides/inmunología , Juego de Reactivos para Diagnóstico , Femenino , Masculino
3.
Mikrochim Acta ; 191(5): 287, 2024 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-38671236

RESUMEN

To overcome the limitations of current methods for diagnosing paracoccidioidomycosis (PCM), it is critical to develop novel diagnostic strategies that can be implemented in low-resource settings and dramatically improve turnaround times. This study focused on the development of a portable molecular test to screen for Paracoccidioides spp. The proposed approach integrated double-tagging polymerase chain reaction (PCR) and a paper-based lateral flow assay (LFA) for readout, using carbon nanoparticles as a signal generation system. Primers tagged with biotin and digoxigenin were employed to conduct the double-tagging PCR, which can be conveniently carried out on portable thermocyclers. This method can generate billions of tagged DNA copies from a single target molecule, which can be rapidly detected by the LFA platform, providing results within minutes. Avidin-modified carbon nanoparticles served as a signal generation system, enabling detection in the immunochromatographic assay. The LFA demonstrated the capability to detect double-tagged amplicons as low as 0.21 ng or 0.10 ng, depending on whether the results were assessed visually or with a smartphone equipped with an image processor. These findings suggest that the proposed approach holds great promise as a point-of-care diagnostic tool for the early and accurate detection of PCM in low-resource settings. The diagnostic test is rapid and inexpensive, requires minimal handling and can be easily introduced into the general practitioner's armoury for ambulatory screening of infection. This innovative approach has the potential to make a substantial contribution to PCM diagnosis, ultimately reducing morbidity and mortality associated with this disease.


Asunto(s)
Carbono , ADN de Hongos , Nanopartículas , Paracoccidioides , Paracoccidioides/genética , Paracoccidioides/aislamiento & purificación , Carbono/química , Nanopartículas/química , ADN de Hongos/genética , ADN de Hongos/análisis , Paracoccidioidomicosis/diagnóstico , Paracoccidioidomicosis/microbiología , Humanos , Reacción en Cadena de la Polimerasa/métodos , Límite de Detección
4.
Med Mycol ; 62(5)2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38684477

RESUMEN

The epidemiological dynamics of paracoccidioidomycosis (PCM) has been changing over the years. We analyzed secondary public data from the Hospital Information System of the Brazilian Unified Health System (SIH/SUS), focusing on PCM-related hospitalizations and in-hospital deaths. In the period between 2010 and 2019, 396 hospitalizations and 30 deaths were related to PCM among 7 073 334 hospitalizations registered in Rio de Janeiro. We highlight the rising rates, reflecting the increase in the number of acute forms previously reported. Urgent public health policies are essential to prevent poor outcomes related to this neglected mycosis.


Epidemiology of paracoccidioidomycosis has been changing in endemic areas. We analyzed secondary data on hospitalizations in Rio de Janeiro, an important endemic area. There is a trend on increasing rates of hospitalizations and in-hospital deaths mainly in the Metropolitan belt.


Asunto(s)
Mortalidad Hospitalaria , Hospitalización , Paracoccidioidomicosis , Brasil/epidemiología , Humanos , Paracoccidioidomicosis/epidemiología , Paracoccidioidomicosis/mortalidad , Hospitalización/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Femenino , Adulto , Anciano , Adolescente , Adulto Joven , Niño , Preescolar , Anciano de 80 o más Años
5.
Rev Soc Bras Med Trop ; 57: e008042024, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38537002

RESUMEN

Cutaneous involvement in paracoccidioidomycosis (PCM) can exhibit a highly polymorphic spectrum. The infiltrative pattern corresponds to up to 26.6% of observed skin lesions, including sarcoid-like plaques, a rare presentation of cutaneous lesions in PCM. This clinical expression is almost exclusively cutaneous, and its histology reveals a tuberculoid granuloma with a scarcity of fungi, leading to misdiagnosis as other granulomatous diseases. Here, we report a rare form of chronic multifocal paracoccidioidomycosis manifesting as sarcoid-like skin lesions misdiagnosed as granulomatous rosacea in a patient with severe systemic disease.


Asunto(s)
Paracoccidioidomicosis , Sarcoidosis , Humanos , Paracoccidioidomicosis/complicaciones , Paracoccidioidomicosis/diagnóstico , Sarcoidosis/complicaciones , Sarcoidosis/diagnóstico , Piel/patología , Diagnóstico Diferencial , Errores Diagnósticos
6.
Front Immunol ; 15: 1347318, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38500881

RESUMEN

Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged.


Asunto(s)
Paracoccidioidomicosis , Ratones , Animales , Antígeno CTLA-4 , Receptor de Muerte Celular Programada 1 , Ratones Endogámicos C57BL , Gravedad del Paciente , Inmunoglobulina G
7.
PLoS One ; 19(3): e0300364, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38512915

RESUMEN

Paracoccidioides fungi are thermodimorphic microorganisms that cause paracoccidioidomycosis (PCM), an autochthonous disease from Latin America, with most cases in Brazil. Humans become infected by inhaling conidia or mycelial fragments that transform into yeast at body temperature. These fungi cause chronic-granulomatous inflammation, which may promote fibrosis and parenchyma destruction in the lungs. In response to stress imposed by the host, fungi Paracoccidioides spp. increase the expression of heat shock proteins (HSP), which protect them by sustaining cellular proteostasis. Our group has studied the role of HSP60 in PCM, and previous data show that the recombinant HSP60 (rHSP60) has a deleterious effect when used in a single dose as therapy for experimental PCM. Here, we investigated the mechanism by which rHSP60 could worsen the disease. We found that rHSP60 caused the viability loss of splenic or lymph node cells from both immunized and non-immunized mice, including in splenic T lymphocytes under polyclonal stimulation with concanavalin A, probably by undergoing apoptosis. Among analyzed splenic cells, lymphocytes were indeed the main cells to die. When we investigated the death mechanisms, remarkably, we found that there was no viability loss in rHSP60-stimulated splenic cells from mice deficient in Toll-like receptor 4, TRIF adapter protein, and TNF receptor 1(TNFR1), as well as rHSP60-stimulated WT cells incubated with anti-TNF antibody. Besides, caspase-8 inhibitor IETD-CHO blocked the rHSP60 effect on splenic cells, suggesting that rHSP60 induces the extrinsic apoptosis pathway dependent on signaling via TLR4/TRIF and TNFR1.


Asunto(s)
Paracoccidioides , Paracoccidioidomicosis , Humanos , Ratones , Animales , Receptor Toll-Like 4 , Receptores Tipo I de Factores de Necrosis Tumoral , Inhibidores del Factor de Necrosis Tumoral , Paracoccidioidomicosis/microbiología , Factor de Necrosis Tumoral alfa , Inflamación , Linfocitos/patología , Proteínas Adaptadoras del Transporte Vesicular
8.
Am J Trop Med Hyg ; 110(5): 961-964, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38531110

RESUMEN

Co-occurrence of paracoccidioidomycosis and strongyloidiasis in immunosuppressed patients, particularly those infected with human T-lymphotropic virus type 1/2, is infrequent. We describe the case of a Peruvian farmer from the central jungle with human T-lymphotropic virus type 1/2 infection, with 2 months of illness characterized by respiratory and gastrointestinal symptoms associated with fever, weight loss, and enlarged lymph nodes. Strongyloides stercoralis and Paracoccidioides brasiliensis were isolated in sputum and bronchoalveolar lavage samples, respectively. The clinical evolution was favorable after the patient received ivermectin and amphotericin B. We hypothesize that autoinfestation by S. stercoralis in human T-lymphotropic virus type 1/2-infected patients may contribute to the disseminated presentation of Paracoccidioides spp. Understanding epidemiological context is crucial for suspecting opportunistic regional infections, particularly those that may coexist in immunosuppressed patients.


Asunto(s)
Infecciones por HTLV-I , Ivermectina , Paracoccidioidomicosis , Strongyloides stercoralis , Estrongiloidiasis , Humanos , Paracoccidioidomicosis/tratamiento farmacológico , Paracoccidioidomicosis/complicaciones , Paracoccidioidomicosis/diagnóstico , Estrongiloidiasis/tratamiento farmacológico , Estrongiloidiasis/complicaciones , Estrongiloidiasis/diagnóstico , Masculino , Infecciones por HTLV-I/complicaciones , Animales , Ivermectina/uso terapéutico , Strongyloides stercoralis/aislamiento & purificación , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Paracoccidioides/aislamiento & purificación , Coinfección , Infecciones por HTLV-II/complicaciones , Huésped Inmunocomprometido , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Adulto
9.
Virulence ; 15(1): 2329573, 2024 12.
Artículo en Inglés | MEDLINE | ID: mdl-38511558

RESUMEN

Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that transport several biomolecules and are involved in important mechanisms and functions related to the pathophysiology of fungal diseases. EVs from Paracoccidioides brasiliensis, the main causative agent of Paracoccidioidomycosis (PCM), modulate the immune response of macrophages. In this study, we assessed the EVs proteome from a virulent P. brasiliensis isolated from granulomatous lesions and compared their immunomodulatory ability with EVs isolated from the fungus before the animal passage (control EVs) when challenging macrophages and dendritic cells (DCs). Proteome showed that virulent EVs have a higher abundance of virulence factors such as GP43, protein 14-3-3, GAPDH, as well as virulence factors never described in PCM, such as aspartyl aminopeptidase and a SidJ analogue compared with control EVs. Virulent extracellular vesicles induced higher expression of TLR4 and Dectin-1 than control EVs in macrophages and dendritic cells (DCs). In opposition, a lower TLR2 expression was induced by virulent EVs. Additionally, virulent EVs induced lower expression of CD80, CD86 and TNF-α, but promoted a higher expression of IL-6 and IL-10, suggesting that EVs isolated from virulent P. brasiliensis-yeast promote a milder DCs and macrophage maturation. Herein, we showed that EVs from virulent fungi stimulated a higher frequency of Th1/Tc1, Th17, and Treg cells, which gives new insights into fungal extracellular vesicles. Taken together, our results suggest that P. brasiliensis utilizes its EVs as virulence bags that manipulate the immune system in its favour, creating a milder immune response and helping with fungal evasion from the immune system.


Asunto(s)
Vesículas Extracelulares , Lectinas Tipo C , Paracoccidioides , Paracoccidioidomicosis , Animales , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Proteoma , Paracoccidioidomicosis/microbiología , Vesículas Extracelulares/metabolismo , Factores de Virulencia
10.
Microb Pathog ; 188: 106537, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38211834

RESUMEN

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by Paracoccidioides spp. The interaction mediated by the presence of adhesins on the fungal surface and receptors in the extracellular matrix of the host, as well as the biofilm formation, is essential in its pathogenesis. Adhesins such as gp43, enolase, GAPDH (glyceraldehyde-3-phosphate dehydrogenase), and 14-3-3 have been demonstrated in the Paracoccidioides brasiliensis (Pb18) strain and recognized as necessary in the fungus-host interaction. The Pb 18 strain silenced to 14-3-3 showed changes in morphology, virulence, and adhesion capacity. The study aimed to evaluate the role of adhesin 14-3-3 in P. brasiliensis biofilm formation and the differential expression of genes related to adhesins, comparing planktonic and biofilm forms. The presence of biofilm was also verified in sutures in vitro and in vivo. The silenced strain (Pb14-3-3 aRNA) was compared with the wild type Pb18, determining the differential metabolic activity between the strains by the XTT reduction assay; the biomass by violet crystal and the polysaccharides by safranin, even as morphological differences by microscopic techniques. Differential gene expression for adhesins was also analyzed, comparing the relative expression of these in planktonic and biofilm forms at different times. The results suggested that the silencing of 14-3-3 protein altered the ability to form biofilm and its metabolism. The quantity of biomass was similar in both strains; however, the formation of exopolymeric substances and polysaccharide material was lower in the silenced strain. Our results showed increased expression of enolase, GAPDH, and 14-3-3 genes in the first periods of biofilm formation in the Pb18 strain. In contrast, the silenced strain showed a lower expression of these genes, indicating that gene silencing can influence the expression of other genes and be involved in the biofilm formation of P. brasiliensis. In vitro and in vivo assays using sutures confirmed this yeast's ability to form biofilm and may be implicated in the pathogenesis of paracoccidioidomycosis.


Asunto(s)
Paracoccidioides , Paracoccidioidomicosis , Paracoccidioides/genética , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Gliceraldehído-3-Fosfato Deshidrogenasas , Biopelículas , Adhesinas Bacterianas/metabolismo , Fosfopiruvato Hidratasa/genética
11.
N Engl J Med ; 390(4): 357, 2024 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-38265647
12.
Braz J Microbiol ; 55(1): 837-842, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38238556

RESUMEN

Paracoccidioidomycosis is an infection with the potential for environmental dissemination, especially in regions of hot and humid climate, where human cases have been recorded in the Southwestern Amazon of Brazil, specifically in the state of Acre. Despite studies providing information about the presence of these fungi in soil and animal samples, such as armadillos, further investigations are still needed to determine the epidemiological distribution of the genus Paracoccidioides. The aim of this study was to detect the occurrence of Paracoccidioides fungi in the Southwestern Amazon. To achieve this, 60 soil samples were collected from armadillo burrows on rural properties in the in the municipalities of Acrelândia, Bujari, Plácido de Castro, Rio Branco, Sena Madureira, and Senador Guiomard, located in the state of Acre, Brazil. Fungal DNA was extracted from these samples using the DNEASY® PowerSoil kit-Quiagen, followed by Nested PCR technique with ITS4 and ITS5 as external primers, and PBITS-E and PBITS-R as internal primers. DNA amplification products of about 380 bp compatible with Paracoccidioides spp. were detected in six samples (10%), being sequenced and identified as P. brasiliensis. These findings indicate that the soils of the Acre state could be considered a potential source for Paracoccidioides spp., suggesting that local infections are likely.


Asunto(s)
Paracoccidioides , Paracoccidioidomicosis , Animales , Humanos , Paracoccidioides/genética , Microbiología del Suelo , Hongos , Suelo , Paracoccidioidomicosis/epidemiología , Paracoccidioidomicosis/microbiología , Brasil/epidemiología
13.
Biochimie ; 218: 20-33, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37709188

RESUMEN

The pathogen Paracoccidioides lutzii (Pb01) is found in South America countries Colombia, Ecuador, Venezuela and Brazil, especially in the central, west, and north regions of the latter. It belongs to the Ajellomycetaceae family, Onygenales order, and is typically thermodimorphic, presenting yeast cells when it grows in animal tissues, but mycelia when in the environment, where it produces the infectious propagule. This fungus is one of the etiologic agents of Paracoccidioidomycosis (PCM), the most important endemic fungal infection in Latin America. Investigations on its genome have contributed to a better understanding about its metabolism and revealed the complexity of several metabolic glycolytic pathways. Glyceraldehyde-3-Phosphate Dehydrogenase from Paracoccidioides lutzii (PlGAPDH) is considered a moonlighting protein and participates in several biological processes of this pathogen. The enzyme was expressed and purified, as seen in SDS-PAGE gel, crystallized and had its three dimensional structure (3D) determined in complex with NAD+, a sulphate ion and d-galactonic acid, therefore, a type of 'GAA site'. It is the first GAPDH structure to show this chemical type in this site and how this protein can bind an acid derived from oxidation of a linear hexose.


Asunto(s)
Paracoccidioides , Paracoccidioidomicosis , Animales , Paracoccidioides/genética , Paracoccidioidomicosis/epidemiología , Paracoccidioidomicosis/microbiología , Brasil/epidemiología , Azúcares
14.
Mycoses ; 67(1): e13662, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37837228

RESUMEN

BACKGROUND: Paracoccidioidomycosis is the most prevalent systemic mycosis in Latin America, with a high incidence in Brazil, Colombia and Venezuela, and constitutes a serious public health problem, a frequent cause of morbidity and disability for work. Some mechanisms of cell death are described as important tools in infectious processes. When apoptosis is blocked, RIPK (Receptor-interacting protein kinase) 3 dependent, a caspase-independent form of cell death, can limit the replication and spread of pathogens. Some molecules that mediate necroptosis include RIPK3 and have been extensively studied due to their signalling mechanism and pathological function. RIPK3 activates NLRP1 and NLRP3-mediated inflammasome formation. Caspase-1 has an important role in processing the cytokines ILß and IL18 to their active form. Such molecules are part of the inflammasome characterization, whose caspase-1-dependent activation promotes the death of pyroptotic cells and the secretion of proinflammatory cytokines. Knowledge about the mechanisms of pathogen-mediated cell death can be useful for understanding of the pathogenesis of infections and inflammatory conditions. OBJECTIVE: The objective of this work was to identify the mechanisms of programmed cell death and inflammasome components in human oral mucosal lesions of paracoccidioidomycosis through immunohistochemical methods and identification of RIPK-3, IL1ß, IL18, NLRP-1 and caspase-1. Thirty specimens were included, and a histopathological analysis of the lesions was performed using haematoxylin-eosin staining. RESULTS: Our results on in situ expression of inflammasome elements and programmed cell death showed increased expression of IL-1ß, NLRP-1, caspase-1 and RIPK-3. We suggest that inflammasome complex participate in the immunopathogenesis in paracoccidioidomycosis oral lesions in an interplay with RIPK3.


Asunto(s)
Inflamasomas , Paracoccidioidomicosis , Humanos , Interleucina-18 , Apoptosis/fisiología , Caspasa 1/metabolismo , Citocinas
15.
Artículo en Inglés | MEDLINE | ID: mdl-38055375

RESUMEN

Paracoccidioidomycosis (PCM) is a systemic fungal infection caused by Paracoccidioides spp. It can occur as an acute/subacute form (A/SAF), a chronic form (CF) and rarely as a mixed form combining the features of the two aforementioned forms in an immunocompromised patient. Here, we report a 56-year-old male patient with CF-PCM who presented with atypical manifestations, including the development of an initial esophageal ulcer, followed by central nervous system (CNS) lesions and cervical and abdominal lymphatic involvement concomitant with severe SARS-CoV-2 infection. He was HIV-negative and had no other signs of previous immunodeficiency. Biopsy of the ulcer confirmed its mycotic etiology. He was hospitalized for treatment of COVID-19 and required supplemental oxygen in the intensive unit. The patient recovered without the need for invasive ventilatory support. Investigation of the extent of disease during hospitalization revealed severe lymphatic involvement typical of A/SAF, although the patient`s long history of high-risk exposure to PCM, and lung involvement typical of the CF. Esophageal involvement is rare in non-immunosuppressed PCM patients. CNS involvement is also rare. We suggest that the immunological imbalance caused by the severe COVID-19 infection may have contributed to the patient developing atypical severe CF, which resembles the PCM mixed form of immunosuppressed patients. Severe COVID-19 infection is known to impair the cell-mediated immune response, including the antiviral response, through T-lymphopenia, decreased NK cell counts and T-cell exhaustion. We hypothesize that these alterations would also impair antifungal defenses. Our case highlights the potential influence of COVID-19 on the course of PCM. Fortunately, the patient was timely treated for both diseases, evolving favorably.


Asunto(s)
COVID-19 , Paracoccidioides , Paracoccidioidomicosis , Masculino , Humanos , Persona de Mediana Edad , Paracoccidioidomicosis/complicaciones , Paracoccidioidomicosis/diagnóstico , Úlcera , COVID-19/complicaciones , SARS-CoV-2 , Antifúngicos/uso terapéutico
16.
Med Mycol ; 61(11)2023 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-37960963

RESUMEN

Germline-encoded pattern recognition receptors, particularly C-type lectin receptors (CLRs), are essential for phagocytes to sense invading fungal cells. Among CLRs, Dectin-2 (encoded by Clec4n) plays a critical role in the antifungal immune response as it recognizes high-mannose polysaccharides on the fungal cell wall, triggering phagocyte functional activities and ultimately determining adaptive responses. Here, we assessed the role of Dectin-2 on the course of primary Paracoccidioides brasiliensis systemic infection in mice with Dectin-2-targeted deletion. Paracoccidioides brasiliensis constitutes the principal etiologic agent of paracoccidioidomycosis, the most prominent invasive mycosis in Latin American countries. The deficiency of Dectin-2 resulted in shortened survival rates, high lung fungal burden, and increased lung pathology in mice infected with P. brasiliensis. Consistently, dendritic cells (DCs) from mice lacking Dectin-2 infected ex vivo with P. brasiliensis showed impaired secretion of several proinflammatory and regulatory cytokines, including TNF-α, IL-1ß, IL-6, and IL-10. Additionally, when cocultured with splenic lymphocytes, DCs were less efficient in promoting a type 1 cytokine pattern secretion (i.e., IFN-γ). In macrophages, Dectin-2-mediated signaling was required to ensure phagocytosis and fungicidal activity associated with nitric oxide production. Overall, Dectin-2-mediated signaling is critical to promote host protection against P. brasiliensis infection, and its exploitation might lead to the development of new vaccines and immunotherapeutic approaches.


We report a critical role of the innate immune receptor Dectin-2 during Paracoccidioides brasiliensis infection. Fungal sensing by Dectin-2 improved the survival of mice and lowered fungal burden. Further, Dectin-2 was required for cytokine production, phagocytosis, and fungal killing by phagocytes.


Asunto(s)
Paracoccidioides , Paracoccidioidomicosis , Ratones , Animales , Fagocitos/patología , Lectinas Tipo C/metabolismo , Macrófagos , Paracoccidioidomicosis/veterinaria
17.
Future Med Chem ; 15(24): 2239-2255, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38014535

RESUMEN

Background: Paracoccidioidomycosis (PCM) is a systemic infection caused by Paracoccidioides spp. (Pb). PCM can be associated or clinically confused with tuberculosis (TB), another pulmonary infection, caused by Mycobacterium tuberculosis (Mtb). Futhermore, the long treatment time of TB and PCM and the cases of TB drug resistance impose difficulties for the cure of these diseases. Results: New 1,3,4-oxadiazoles containing the 4-methoxynaphthalene ring were synthesized and their antimicrobial activity was evaluated against Pb and Mtb. The derivative 6n (with 2-hydroxy-5-nitrophenyl subunit) is the most promising of the series. Conclusion: The 1,3,4-oxadiazole 6n can be used as a prototype drug candidate, with anti-Pb and anti-MTb activities, showing a broad-spectrum profile for the treatment of both pulmonary infections.


Asunto(s)
Antiinfecciosos , Mycobacterium tuberculosis , Paracoccidioidomicosis , Tuberculosis , Humanos , Oxadiazoles/farmacología , Plomo/uso terapéutico , Tuberculosis/tratamiento farmacológico , Paracoccidioidomicosis/tratamiento farmacológico , Paracoccidioidomicosis/microbiología , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico
18.
Front Cell Infect Microbiol ; 13: 1268959, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37868350

RESUMEN

Granulomas are important immunological structures in the host defense against the fungus Paracoccidioides brasiliensis, the main etiologic agent of Paracoccidioidomycosis (PCM), a granulomatous systemic mycosis endemic in Latin America. We have performed transcriptional and proteomic studies of yeasts present in the pulmonary granulomas of PCM aiming to identify relevant genes and proteins that act under stressing conditions. C57BL/6 mice were infected with 1x106 yeasts and after 8- and 12-weeks of infection, granulomatous lesions were obtained for extraction of fungal and murine RNAs and fungal proteins. Dual transcriptional profiling was done comparing lung cells and P. brasiliensis yeasts from granulomas with uninfected lung cells and the original yeast suspension used in the infection, respectively. Mouse transcripts indicated a lung malfunction, with low expression of genes related to muscle contraction and organization. In addition, an increased expression of transcripts related to the activity of neutrophils, eosinophils, macrophages, lymphocytes as well as an elevated expression of IL-1ß, TNF-α, IFN-γ, IL-17 transcripts were observed. The increased expression of transcripts for CTLA-4, PD-1 and arginase-1, provided evidence of immune regulatory mechanisms within the granulomatous lesions. Also, our results indicate iron as a key element for the granuloma to function, where a high number of transcripts related to fungal siderophores for iron uptake was observed, a mechanism of fungal virulence not previously described in granulomas. Furthermore, transcriptomics and proteomics analyzes indicated a low fungal activity within the granuloma, as demonstrated by the decreased expression of genes and proteins related to energy metabolism and cell cycle.


Asunto(s)
Paracoccidioides , Paracoccidioidomicosis , Animales , Ratones , Paracoccidioides/genética , Proteómica , Ratones Endogámicos C57BL , Hierro/metabolismo , Inmunidad , Granuloma
20.
PLoS Negl Trop Dis ; 17(9): e0011645, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37708219

RESUMEN

The occurrence of acute paracoccidioidomycosis (PCM) in urban areas of the Rio de Janeiro state, Brazil, has emerged in recent years. Therefore, young populations, including pregnant women, are at a higher risk of infection. Furthermore, young women undergoing itraconazole treatment for PCM have increased chances to get pregnant because this medication may reduce the effectiveness of contraceptives. Acute PCM is invasive, reaching abdominal organs, posing a maternal-fetal risk. PCM treatment in pregnant women is also challenging due to the teratogenicity associated with the currently available oral drugs. There are scarce studies on PCM and pregnancy, mainly consisting of case reports and experimental murine models that highlight the severity of this association. We conducted a database research at a PCM reference center in Rio de Janeiro state from 1980 to 2020. We included patients diagnosed with PCM who were pregnant shortly before, at admission, or at any moment of their PCM follow-up care. Data related to pregnancy, childbirth, and the newborn were obtained from the Brazilian official public databases. We also reviewed the epidemiological and clinical features of these patients. During the study period, we identified 18 pregnant patients, with a median age of 26 years (range: 16-38). Among these cases, six (33.3%) were detected in the last 5 years, and 14 (77.8%) presented acute PCM, supporting the recent shift in the epidemiological profile towards acute PCM. Most pregnancies occurred during PCM treatment (n = 11, 61.1%), which led to challenges in the therapeutic management. Maternal-fetal complications occurred in some of these cases, including vaginal bleeding (n = 1), preeclampsia (n = 1), prematurity (n = 2), low birth weight (n = 4), and fetal deaths (n = 2). PCM during pregnancy presents a significant public health concern in the context of the emergence of acute PCM in urban areas.


Asunto(s)
Paracoccidioidomicosis , Humanos , Femenino , Animales , Ratones , Embarazo , Adolescente , Adulto Joven , Adulto , Paracoccidioidomicosis/tratamiento farmacológico , Paracoccidioidomicosis/epidemiología , Brasil/epidemiología , Estudios de Cohortes , Itraconazol , Bases de Datos Factuales
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA