ABSTRACT
Bloodstream infections caused by Candida species are responsible for high morbidity and mortality, and diabetes mellitus (DM) is an important underlying disease in candidemia episodes. Although DM patients show an enhanced proinflammatory profile, they are highly susceptible to mycobacterial and mycotic infections. Attempting to understand this paradox, we investigated if imbalanced macrophage and dendritic cell (DC) activations could be associated to high incidence and/or severity of Candida albicans infection in the hypoinsulinemia-hyperglycemia (HH) milieu. HH alloxan-induced mice were infected with C. albicans and peritoneal aderent phagocytes were co-cultured with or without lipopolyssaccharide or heat-killed C. albicans, and the production of cytotoxic metabolites, cytokines, and chemokines was evaluated. We also evaluated the surface expression of MHC-II and CD86 in splenic DCs. Our findings showed that both uninfected and C. albicans-infected HH mice showed less production of CCL2 and reduced expression of CD86 by peritoneal phagocytes and splenic DCs, respectively.
Subject(s)
Candida albicans/immunology , Candidiasis/microbiology , Dendritic Cells/immunology , Diabetes Mellitus, Experimental/immunology , Macrophages/immunology , Alloxan/toxicity , Animals , B7-2 Antigen/metabolism , Brazil , Cells, Cultured , Chemokine CCL2/metabolism , Coculture Techniques , Dendritic Cells/metabolism , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/microbiology , Genes, MHC Class II/immunology , Macrophages/metabolism , Male , MiceABSTRACT
BACKGROUND: Paracoccidioidomycosis (PCM) is systemic mycosis caused by the thermal dimorphic fungus of genus Paracoccidioides, leading to either acute/subacute (AF) or chronic (CF) clinical forms. Numerous CF patients after treatment exhibit sequels, such as pulmonary and adrenal fibrosis. Monocytes are cells that are involved in the inflammatory response during active infection as well as in the fibrogenesis. These cells comprise a heterogeneous population with distinct phenotypic and functional activities. The scope of this study was to identify changes regarding functional and phenotypical aspects in monocytes comparing CF PCM patients on antifungal treatment versus non-treated patients (PMC-p). METHODS: Twenty-three CF PCM composed of 11 non-treated patients (NTG) and 12 patients in apparent cure (ACG) were studied. Sixteen healthy individuals were used as control group (CG). Monocyte subsets were determined by immunophenotyping based on CD14 and CD16 expression. Cellular function was measured in vitro with and without stimulation with lipopolysaccharide (LPS) and P. brasiliensis exoantigen (PbAg) for 24 hours. Independent samples were compared using unpaired t tests, dependent samples were analyzed by paired t-test. Groups of more than two independent samples were analyzed using an ANOVA, with Tukey's post-test. Significance was set up at p <0.05. RESULTS: Our results showed high counts of peripheral blood CD14+CD16+ and CD14+CD16++ monocytes in untreated PCM-p accompanied by intense production of pro-inflammatory cytokines (IL-1ß and TNF-α) and profibrotic growth factors (TGF-ß1 and bFGF) by monocytes challenged with P. brasiliensis antigens. After the introduction of antifungal therapy, the counts of CD14+CD16+ cells returned to baseline while CD14+CD16++ counts remained high. Interestingly, counts of CD14+CD16++ monocytes remained elevated even 52 ± 7 months after successful antifungal treatment. Furthermore, the ACG-patients showed preserved pro-inflammatory activity in the presence of specific antigen stimuli and high spontaneous production of TNF-α by monocytes. CONCLUSIONS: Infection with Paracoccidioides leads to initiation of a specific proinflammatory response by monocytes of PCM-p during active disease and in the apparent cure. A profibrotic profile by monocytes was observed only at admission. Furthermore, PCM-p with apparent cure showed high spontaneous production of TNF-α and high counts of CD14+CD16++ monocytes, probably induced by hypoxia duo to fibrotic sequelae.
Subject(s)
Antifungal Agents/therapeutic use , Monocytes/metabolism , Paracoccidioidomycosis/immunology , Adult , Antifungal Agents/pharmacology , Case-Control Studies , Cells, Cultured , Chronic Disease , Cytokines/metabolism , Female , GPI-Linked Proteins/metabolism , Humans , Immunophenotyping , Lipopolysaccharide Receptors/metabolism , Lipopolysaccharides/pharmacology , Male , Middle Aged , Monocytes/drug effects , Monocytes/immunology , Paracoccidioidomycosis/blood , Paracoccidioidomycosis/drug therapy , Phenotype , Receptors, IgG/metabolismABSTRACT
Recognizing the invasive potential of the dermatophytes and understanding the mechanisms involved in this process will help with disease diagnosis and with developing an appropriate treatment plan. In this report, we present the histopathological, microbiological and immunological features of a model of invasive dermatophytosis that is induced by subcutaneous infection of Trichophyton mentagrophytes in healthy adult Swiss mice. Using this model, we observed that the fungus rapidly spreads to the popliteal lymph nodes, spleen, liver and kidneys. Similar to the human disease, the lymph nodes were the most severely affected sites. The fungal infection evoked acute inflammation followed by a granulomatous reaction in the mice, which is similar to what is observed in patients. The mice were able to mount a Th1-polarized immune response and displayed IL-10-mediated immune regulation. We believe that the model described here will provide valuable information regarding the dermatophyte-host relationship and will yield new perspective for a better understanding of the immunological and pathological aspects of invasive dermatophytosis.
