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      Sporothrix schenckii Cell Wall Proteins-Stimulated BMDCs Are Able to Induce a Th1-Prone Cytokine Profile In Vitro

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          Abstract

          Sporotrichosis is a subcutaneous mycosis affecting humans and other animals. The disease can be acquired by accidental inoculation of the fungus through the skin or through the respiratory system. Sporotrichosis can also be transmitted through bites or scratches by infected cats and more rarely by other animals (zoonotic transmission). Conventional antifungal therapy is especially inefficient in immunocompromised patients, who tend to develop the most severe forms of the disease, thus prompting the search for alternative therapies. Given their antigen-presenting properties, dendritic cells (DCs) have been used in both prophylactic and therapeutic vaccination strategies. Hence, this study aims to assess the use of DCs as a prophylactic tool in sporotrichosis by evaluating the immune profile induced by Sporothrix schenckii cell wall proteins (SsCWP)-stimulated, bone-marrow-derived DCs (BMDCs). Mouse BMDCs were stimulated with SsCWP for 24 h and analyzed for the surface expression of costimulatory molecules and TLR-4, as well as for the secretion of proinflammatory cytokines and IL-10. Following that, activated BMDCs were cocultured with splenocytes for 72 h and had the same cytokines measured in the supernatant. SsCWP-stimulated BMDCs showed higher expression of CD80, CD86, and CD40, but not TLR-4, and higher secretion of IL-6, IL-17A, and TNF. On the other hand, higher levels of IFN-γ, IL-10, and IL-2 were found in the supernatants of the coculture as compared with the BMDCs alone; TNF secretion was almost completely abrogated, whereas IL-6 was only partially inhibited and IL-17A was unaffected. Our results thus suggest that SsCWP-stimulated BMDCs are able to induce a Th1-prone cytokine profile which is known to be protective against other fungal diseases. This result could lead to studies which evaluate the development of prophylactic and/or therapeutic DC-based tools against sporotrichosis.

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          Most cited references31

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          Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17.

          The C-type lectin dectin-1 binds to yeast and signals through the kinase Syk and the adaptor CARD9 to induce production of interleukin 10 (IL-10) and IL-2 in dendritic cells (DCs). However, whether this pathway promotes full DC activation remains unclear. Here we show that dectin-1-Syk-CARD9 signaling induced DC maturation and the secretion of proinflammatory cytokines, including IL-6, tumor necrosis factor and IL-23, but little IL-12. Dectin-1-activated DCs 'instructed' the differentiation of CD4+ IL-17-producing effector T cells (T(H)-17 cells) in vitro, and a dectin-1 agonist acted as an adjuvant promoting the differentiation of T(H)-17 and T helper type 1 cells in vivo. Infection with Candida albicans induced CARD9-dependent T(H)-17 responses to the organism. Our data indicate that signaling through Syk and CARD9 can couple innate to adaptive immunity independently of Toll-like receptor signals and that CARD9 is required for the development of T(H)-17 responses to some pathogens.
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            Global epidemiology of sporotrichosis.

            Sporotrichosis is an endemic mycosis caused by the dimorphic fungus Sporothrix schenckii sensu lato. It has gained importance in recent years due to its worldwide prevalence, recognition of multiple cryptic species within the originally described species, and its distinctive ecology, distribution, and epidemiology across the globe. In this review, we describe the current knowledge of the taxonomy, ecology, prevalence, molecular epidemiology, and outbreaks due to S. schenckii sensu lato. Despite its omnipresence in the environment, this fungus has remarkably diverse modes of infection and distribution patterns across the world. We have delved into the nuances of how sporotrichosis is intimately linked to different forms of human activities, habitats, lifestyles, and environmental and zoonotic interactions. The purpose of this review is to stimulate discussion about the peculiarities of this unique fungal pathogen and increase the awareness of clinicians and microbiologists, especially in regions of high endemicity, to its emergence and evolving presentations and to kindle further research into understanding the unorthodox mechanisms by which this fungus afflicts different human populations.
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              Toll-dependent selection of microbial antigens for presentation by dendritic cells.

              Dendritic cells constitutively sample the tissue microenvironment and phagocytose both microbial and host apoptotic cells. This leads to the induction of immunity against invading pathogens or tolerance to peripheral self antigens, respectively. The outcome of antigen presentation by dendritic cells depends on their activation status, such that Toll-like receptor (TLR)-induced dendritic cell activation makes them immunogenic, whereas steady-state presentation of self antigens leads to tolerance. TLR-inducible expression of co-stimulatory signals is one of the mechanisms of self/non-self discrimination. However, it is unclear whether or how the inducible expression of co-stimulatory signals would distinguish between self antigens and microbial antigens when both are encountered by dendritic cells during infection. Here we describe a new mechanism of antigen selection in dendritic cells for presentation by major histocompatibility complex class II molecules (MHC II) that is based on the origin of the antigen. We show that the efficiency of presenting antigens from phagocytosed cargo is dependent on the presence of TLR ligands within the cargo. Furthermore, we show that the generation of peptide-MHC class II complexes is controlled by TLRs in a strictly phagosome-autonomous manner.
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                Author and article information

                Journal
                J Fungi (Basel)
                J Fungi (Basel)
                jof
                Journal of Fungi
                MDPI
                2309-608X
                02 September 2018
                September 2018
                : 4
                : 3
                : 106
                Affiliations
                Department of Clinical Analysis, School of Pharmaceutical Sciences, Araraquara, São Paulo State University (UNESP), Rodovia Araraquara-Jaú-Km 1, Araraquara 14800-903, SP, Brazil; caquinello@ 123456hotmail.com (C.Q.); gigabreath@ 123456hotmail.com (L.S.F.); bepicolli@ 123456yahoo.com.br (I.P.); ma_luizaloesch@ 123456hotmail.com (M.L.L.); deivysleandro@ 123456gmail.com (D.L.P.); batistaduhartea@ 123456gmail.com (A.B.-D.)
                Author notes
                [* ]Correspondence: carlosiz@ 123456fcfar.unesp.br ; Tel.: +55-16-33015713
                Author information
                https://orcid.org/0000-0002-1875-0518
                Article
                jof-04-00106
                10.3390/jof4030106
                6162427
                30200530
                8b8c9fd9-46a3-486a-b432-17c30cbb5ca6
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 August 2018
                : 31 August 2018
                Categories
                Article

                sporothrix schenckii,bone-marrow-derived dendritic cells,vaccine,sporotrichosis

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