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Frontiers in Immunology 2023Previous studies on paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America, revealed that host immunity is tightly regulated by several...
Previous studies on paracoccidioidomycosis (PCM), the most prevalent systemic mycosis in Latin America, revealed that host immunity is tightly regulated by several suppressive mechanisms mediated by tolerogenic plasmacytoid dendritic cells, the enzyme 2,3 indoleamine dioxygenase (IDO-1), and regulatory T-cells (Tregs). IDO-1 orchestrates local and systemic immunosuppressive effects through the recruitment and activation of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells possessing a potent ability to suppress T-cell responses. However, the involvement of MDSCs in PCM remains uninvestigated. The presence, phenotype, and immunosuppressive activity of MDSCs were evaluated at 96 h, 2 weeks, and 8 weeks of pulmonary infection in C57BL/6 mice. Disease severity and immune responses were assessed in MDSC-depleted and nondepleted mice using an anti-Gr1 antibody. Both monocytic-like MDSCs (M-MDSCs) and polymorphonuclear-like MDSCs (PMN-MDSCs) massively infiltrated the lungs during infection. Partial reduction of MDSC frequency led to a robust Th1/Th17 lymphocyte response, resulting in regressive disease with a reduced fungal burden on target organs, diminishing lung pathology, and reducing mortality ratio compared with control IgG2b-treated mice. The suppressive activity of MDSCs on CD4 and CD8 T-lymphocytes and Th1/Th17 cells was also demonstrated using coculture experiments. Conversely, adoptive transfer of MDSCs to recipient -infected mice resulted in a more severe disease. Taken together, our data showed that the increased influx of MDSCs into the lungs was linked to more severe disease and impaired Th1 and Th17 protective responses. However, protective immunity was rescued by anti-Gr1 treatment, resulting in a less severe disease and controlled tissue pathology. In conclusion, MDSCs have emerged as potential target cells for the adjuvant therapy of PCM.
Topics: Mice; Animals; Paracoccidioidomycosis; Myeloid-Derived Suppressor Cells; Th17 Cells; Mice, Inbred C57BL; Lung
PubMed: 36776848
DOI: 10.3389/fimmu.2023.1039244 -
Infection and Drug Resistance 2018Human fungal infections remain a major challenge in medicine. Only a limited number of antifungal drugs are available, which are often related to severe adverse effects.... (Review)
Review
Human fungal infections remain a major challenge in medicine. Only a limited number of antifungal drugs are available, which are often related to severe adverse effects. In addition, there is an increased emergence related to resistant strains, which makes imperative to understand the host-pathogen interactions as well as to develop alternative treatments. Host innate and adaptive immunity play a crucial role controlling fungal infections; therefore, vaccines are a viable tool to prevent and treat fungal pathogens. Innate immunity is triggered by the interaction between the cell surface pattern recognition receptors (PRRs) and the pathogen-associated molecular patterns (PAMPs). Such an initial immunological response is yet little understood in fungal infections, in part due to the complexity and plasticity of the fungal cell walls. Described host cell-fungus interactions and antigenic molecules are addressed in this paper. Furthermore, antigens found in the cell wall and capsule, including peptides, glycoproteins, glycolipids, and glycans, have been used to trigger specific immune responses, and an increased production of antibodies has been observed when attached to immunogenic molecules. The recent biotechnological advances have allowed the development of vaccines against viral and bacterial pathogens with positive results; therefore, this technology has been applied to develop anti-fungal vaccines. Passive immunization has also emerged as an appealing alternative to treat disseminated mycosis, especially in immunocompromised patients. Those approaches have a long way to be seen in clinical cases. However, all studies discussed here open the possibility to have access to new therapies to be applied alone or in combination with current antifungal drugs. Herein, the state of the art of fungal vaccine developments is discussed in this review, highlighting new advances against , , and spp.
PubMed: 30013373
DOI: 10.2147/IDR.S170337 -
Anais Brasileiros de Dermatologia 2021Paracoccidioidomycosis is an endemic systemic mycosis caused by Paracoccidioides brasiliensis complex and P. lutzii. It is a rare disease in non-HIV-induced...
Paracoccidioidomycosis is an endemic systemic mycosis caused by Paracoccidioides brasiliensis complex and P. lutzii. It is a rare disease in non-HIV-induced immunosuppressed individuals. In organ transplant recipients, it is more frequently associated with immunosuppression after kidney transplantation. In a liver transplant patient, only one case has been published in the literature to date. The present report comprises the case of a 47-year-old female patient with disseminated skin lesions associated with signs and symptoms of systemic involvement of paracoccidioidomycosis that manifested one year after liver transplantation and under an immunosuppression regimen with tacrolimus and mycophenolate mofetil.
Topics: Female; Humans; Kidney Transplantation; Liver Transplantation; Middle Aged; Paracoccidioides; Paracoccidioidomycosis; Transplant Recipients
PubMed: 33775484
DOI: 10.1016/j.abd.2020.07.011 -
Scientific Reports Jul 2020AhR is a ligand-activated transcription factor that plays an important role in the innate and adaptive immune responses. In infection models, it has been associated with...
AhR is a ligand-activated transcription factor that plays an important role in the innate and adaptive immune responses. In infection models, it has been associated with host responses that promote or inhibit disease progression. In pulmonary paracoccidioidomycosis, a primary fungal infection endemic in Latin America, immune protection is mediated by Th1/Th17 cells and disease severity with predominant Th2/Th9/Treg responses. Because of its important role at epithelial barriers, we evaluate the role of AhR in the outcome of a pulmonary model of paracoccidioidomycosis. AhR mice show increased fungal burdens, enhanced tissue pathology and mortality. During the infection, AhR mice have more pulmonary myeloid cells with activated phenotype and reduced numbers expressing indoleamine 2,3 dioxygenase 1. AhR-deficient lungs have altered production of cytokines and reduced numbers of innate lymphoid cells (NK, ILC3 and NCR IL-22). The lungs of AhR mice showed increased presence Th17 cells concomitant with reduced numbers of Th1, Th22 and Foxp3 Treg cells. Furthermore, treatment of infected WT mice with an AhR-specific antagonist (CH223191) reproduced the main findings obtained in AhR mice. Collectively our data demonstrate that in pulmonary paracoccidioidomycosis AhR controls fungal burden and excessive tissue inflammation and is a possible target for antifungal therapy.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Indoleamine-Pyrrole 2,3,-Dioxygenase; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Paracoccidioidomycosis; Receptors, Aryl Hydrocarbon; Th17 Cells
PubMed: 32647342
DOI: 10.1038/s41598-020-68322-6 -
Actas Dermo-sifiliograficas Dec 2016In the second part of this review on the deep mycoses, we describe the main systemic mycoses-paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, mucormycosis,... (Review)
Review
In the second part of this review on the deep mycoses, we describe the main systemic mycoses-paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, mucormycosis, and cryptococcosis-and their cutaneous manifestations. Skin lesions are only occasionally seen in deep systemic mycoses either directly, when the skin is the route of entry for the fungus, or indirectly, when the infection has spread from a deeper focus. These cutaneous signs are often the only clue to the presence of a potentially fatal infection. As with the subcutaneous mycoses, early diagnosis and treatment is important, but in this case, even more so.
Topics: Dermatomycoses; Humans; Mycoses
PubMed: 27499249
DOI: 10.1016/j.ad.2016.06.001 -
Journal of Fungi (Basel, Switzerland) Oct 2020is a genus of thermodimorphic fungi that causes paracoccidioidomycosis. When in the host, the fungus undergoes several challenges, including iron deprivation imposed by... (Review)
Review
is a genus of thermodimorphic fungi that causes paracoccidioidomycosis. When in the host, the fungus undergoes several challenges, including iron deprivation imposed by nutritional immunity. In response to the iron deprivation triggered by the host, the fungus responds in a ternary manner using mechanisms of high affinity and specificity for the uptake of Fe, namely non-classical reductive iron uptake pathway, uptake of host iron proteins, and biosynthesis and uptake of siderophores. This triple response resembles the rhythmic structure of a waltz, which features three beats per compass. Using this connotation, we have constructed this review summarizing relevant findings in this area of study and pointing out new discoveries and perspectives that may contribute to the expansion of this "little iron waltz".
PubMed: 33053811
DOI: 10.3390/jof6040221 -
Journal of Ethnopharmacology Sep 2021Paracoccidioidomycosis (PCM) is a systemic mycosis with high prevalence in South America and especially in Brazil with severe clinical consequences that need broadened...
ETHNOPHARMACOLOGICAL RELEVANCE
Paracoccidioidomycosis (PCM) is a systemic mycosis with high prevalence in South America and especially in Brazil with severe clinical consequences that need broadened therapeutic options. Propolis is a natural resin from bees used in folk medicine for centuries with the first report in the ancient history of Egypt by Eberly papyrus, in Middle-Ages used to wash the newborn's umbilical cord and World War II as antiseptic or antibiotics. Nowadays it is a natural product worldwide consumed as food and traditionally used for oral and systemic diseases as an anti-inflammatory, antimicrobial, antifungal, and other diseases. Brazilian red propolis (BRP) is a new type of propolis with a distinguished chemical profile and biological activities from propolis (green) with pharmacological properties such as antimicrobial, anti-inflammatory, antioxidant, and others.
AIM OF STUDY
Thus, the main purpose of this study was to investigate the direct in vitro and ex vivo effect of BRP on Paracoccidioides brasiliensis.
MATERIAL AND METHODS
Antifungal activity of different concentrations of BRP on a virulent P. brasiliensis isolate (Pb18) was evaluated using the microdilution technique. Also, mice splenic cells co-cultured with Pb18 were treated with BRP at different times and concentrations (only Pb18 = negative control). Mice were inoculated with Pb18 and treated with different concentrations of BRP (50-500 mg/mL) in a subcutaneous air pouch. In this later experimental model, macroscopic characteristics of the air pouch were evaluated, and cellular exudate was collected and analyzed for cellular composition, mitochondrial activity, total protein reactive oxygen specimens (ROS), and nitric oxide production, as well as the number of viable fungal cells.
RESULTS
The in vitro experiments showed remarkable direct antifungal activity of BRP, mainly with the highest concentration employed (500 mg/mL), reducing the number of viable cells to 10% of the original inoculum after 72 h incubation. The splenocytes co-cultivation assays showed that BRP had no cytotoxic effect on these cells, on the contrary, exerted a stimulatory effect. This stimulation was also observed on the PMNs at the air pouch, as verified by production of ROS and total proteins and mitochondrial activity. This activation resulted in enhanced fungicidal activity, mainly with the 500 mg/mL concentration of BRP. An anti-inflammatory effect was also detected, as verified by the smaller volume of the BRP-treated air pouch as well as by an earlier shift from neutrophils to mononuclear cells present in the infection site.
CONCLUSION
Our results strongly suggest, for the first time in the literature, that Brazilian Red propolis has four protective mechanisms in experimental paracoccidioidomycosis: activating neutrophils, exerting a direct antifungal effect, preventing fungal dissemination, and controlling excessive inflammation process.
Topics: Animals; Antifungal Agents; Brazil; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Inflammation; Mice; Neutrophils; Paracoccidioides; Paracoccidioidomycosis; Propolis; Reactive Oxygen Species
PubMed: 33991639
DOI: 10.1016/j.jep.2021.114181 -
Diseases of Aquatic Organisms Jul 2017From 2003 to 2015, 360 free-ranging Atlantic bottlenose dolphins Tursiops truncatus inhabiting the Indian River Lagoon (IRL, n = 246), Florida, and coastal waters of... (Review)
Review
From 2003 to 2015, 360 free-ranging Atlantic bottlenose dolphins Tursiops truncatus inhabiting the Indian River Lagoon (IRL, n = 246), Florida, and coastal waters of Charleston (CHS, n = 114), South Carolina, USA, were captured, given comprehensive health examinations, and released as part of a multidisciplinary and multi-institutional study of individual and population health. The aim of this review is to summarize the substantial health data generated by this study and to examine morbidity between capture sites and over time. The IRL and CHS dolphin populations are affected by complex infectious and neoplastic diseases often associated with immunologic disturbances. We found evidence of infection with cetacean morbillivirus, dolphin papilloma and herpes viruses, Chlamydiaceae, a novel uncultivated strain of Paracoccidioides brasiliensis (recently identified as the causal agent of dolphin lobomycosis/lacaziasis), and other pathogens. This is the first long-term study documenting the various types, progression, seroprevalence, and pathologic interrelationships of infectious diseases in dolphins from the southeastern USA. Additionally, the study has demonstrated that the bottlenose dolphin is a valuable sentinel animal that may reflect environmental health concerns and parallel emerging public health issues.
Topics: Animals; Bottle-Nosed Dolphin; Communicable Diseases; Environmental Monitoring; Risk Assessment; Southeastern United States
PubMed: 28737159
DOI: 10.3354/dao03142 -
PloS One 2023Paracoccidioidomycosis (PCM) is caused by Paracoccidioides spp.; during infection, some host mechanisms limit the availability of iron, thereby reducing its...
Paracoccidioidomycosis (PCM) is caused by Paracoccidioides spp.; during infection, some host mechanisms limit the availability of iron, thereby reducing its reproduction. However, Paracoccidioides spp. can evade the immune defense and, even under limited iron conditions, use this mineral for growth and dissemination. This study evaluated the iron metabolism of 39 patients who were diagnosed with chronic PCM from 2013 to 2021. The forms of iron before treatment and at the time of clinical cure were evaluated based on the following: serum ferritin levels (storage iron); total iron-binding capacity (TIBC) and transferrin saturation (TSAT) level (transport iron); red blood cell (RBC), hemoglobin (Hb), hematocrit (HCT), and soluble transferrin receptor (sTfR) levels; and sTfR/log ferritin ratio (functional iron). The mean age of the patients was 54.5 years (±6.7 years). Most patients were men (97.4%), rural workers (92.1%), and smokers (84.6%); furthermore, most had moderate disease severity (66.7%). After achieving clinical cure, we observed that serum ferritin levels decreased, and parameters of functional iron increased. The extent of alteration in these parameters were more pronounced in severe cases than in to mild or moderate cases. Furthermore, moderate correlations were observed between C-reactive protein and the Hb (r = -0.500; p = 0.002), RBC (r = -0.461; p = 0.005), HCT (r = -0.514; p = 0.001), and iron levels (r = -0.491; p = 0.002). However, it is possible to infer that PCM interferes with functional and storage iron because improvements in these parameters after treatment as well as associations with disease severity were observed. PCM can lead to anemia of inflammation, which can be differentiated from iron deficiency anemia by a careful investigation of the iron form parameters.
Topics: Male; Humans; Middle Aged; Female; Iron; Paracoccidioidomycosis; Ferritins; Anemia; Hemoglobins; Receptors, Transferrin; Iron Metabolism Disorders; Anemia, Iron-Deficiency
PubMed: 37347744
DOI: 10.1371/journal.pone.0282218 -
Cureus Oct 2021Paracoccidioidomycosis (PCM) is an endemic fungal infection in Latin America, which manifests as an acute or chronic form and is more frequent in adult males. It is...
Paracoccidioidomycosis (PCM) is an endemic fungal infection in Latin America, which manifests as an acute or chronic form and is more frequent in adult males. It is caused by or , which are thermodimorphic fungi. The disease can present as a severe and disseminated form involving the lungs, skin, lymph nodes, spleen, liver, and lymphoid organs of the gastrointestinal tract. Most of the primary infections are subclinical, and the cell-mediated immune response contains the infection. It is rare in transplant patients, and there are few cases described in the literature. In solid organ transplant patients, it usually results from the reactivation of a latent infection, manifesting itself after a few years of transplantation with frequent pulmonary and skin involvement. PCM is an endemic infection in Brazil; however, as it is not classified as a notifiable disease, there is no accurate database on its incidence, and case reports are important sources of information. Clinical disease in kidney transplant patients is rare and has a high mortality rate. In this scope, the present clinical case reports the challenges of the clinical management of disseminated PCM caused by in a kidney transplant recipient who used immunosuppressive drugs and was treated with Itraconazole.
PubMed: 34820246
DOI: 10.7759/cureus.19007