Abstract
Candida albicans causes opportunistic systemic infections with high mortality (30%–50%). Despite significant nephrotoxicity, amphotericin (AmB) is still used for the treatment of this serious fungal infection. Therefore, alternative treatments are urgently needed. Dialyzable leukocyte extracts have been used successfully to treat patients with mucocutaneous candidiasis, but their effectiveness in systemic candidiasis has not been evaluated. In this study, low-dose AmB (0.1 mg/kg) plus 10 pg of murine dialyzable spleen extracts (mDSE) were tested in a systemic candidiasis mouse model. Survival, tissue fungal burden, kidney damage, kidney cytokines, and serum levels of IL-6 and hepcidin were evaluated. Our results showed that the combined treatment of low-dose AmB plus mDSE improved survival and reduced kidney fungal burden and histopathology; these effects correlated with increased kidney concentration of IFN-γ and TGF-β1, decreased levels of TNF-α, IL-6, and IL-10, as well as high levels of systemic IL-6 and hepcidin. Low-dose AmB and mDSE synergized to clear the infectious agent and reduced tissue damage, confirming the efficacy of a low dose of AmB, which might decrease the risk of drug toxicity. Further studies are necessary to explore these findings and its implications in future therapeutic approaches.
Highlights
Opportunistic mycoses are infections caused by saprophytic or commensal fungi in hosts in which the normal microbiota has been altered by antibiotic treatments, in hosts with disrupted anatomic barriers, or in immunosuppressed hosts [1]
We showed that experimental murine tuberculosis could be successfully treated with a combination of murine dialyzable spleen extracts and conventional chemotherapy [18]
We evaluated the effects of the combined treatment on survival, tissue fungal burden, tissue damage, kidney cytokines, and hepcidin and IL-6 serum levels
Summary
Opportunistic mycoses are infections caused by saprophytic or commensal fungi in hosts in which the normal microbiota has been altered by antibiotic treatments, in hosts with disrupted anatomic barriers, or in immunosuppressed hosts [1]. Candida albicans is an ubiquitous, dimorphic fungus that colonizes the skin, gastrointestinal tract, and oral and vaginal mucosa of immunocompetent individuals without causing disease [2], but it can cause opportunistic mucocutaneous and systemic infections (with a mortality of 30–50%), in hospitalized patients [1, 3, 4]. Neutrophils and macrophages play a central role in the immune response against C. albicans, and decreased. Neutrophils and macrophages are activated through several pattern-recognition receptors, including Toll-like receptor (TLR) 2, TLR4, TLR9, C-type lectin receptor, dectin-1, dectin-2, DC-SIGN, mincle, galectin-3, SCARF1/CD36, and NLRP3. Recognition of C. albicans by dectin-1 triggers CARD9 signalling, and mutations in CARD9 lead to chronic mucocutaneous candidiasis and invasive Candida infections in humans [6]. The proinflammatory cytokines TNF-α and IL-6 are critical for the immune response against C. albicans [5]
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