An immunoproteomic approach revealing peptides from Sporothrix brasiliensis that induce a cellular immune response in subcutaneous sporotrichosis

Abstract

Sporothrix brasiliensis is the most virulent fungus of the Sporothrix complex and is the main species recovered in the sporotrichosis zoonotic hyperendemic area in Rio de Janeiro. A vaccine against S. brasiliensis could improve the current sporotrichosis situation. Here, we show 3 peptides from S. brasiliensis immunogenic proteins that have a higher likelihood for engaging MHC-class II molecules. We investigated the efficiency of the peptides as vaccines for preventing subcutaneous sporotrichosis. In this study, we observed a decrease in lesion diameters in peptide-immunized mice, showing that the peptides could induce a protective immune response against subcutaneous sporotrichosis. ZR8 peptide is from the GP70 protein, the main antigen of the Sporothrix complex, and was the best potential vaccine candidate by increasing CD4+ T cells and higher levels of IFN-γ, IL-17A and IL-1β characterizing a strong cellular immune response. This immune environment induced a higher number of neutrophils in lesions that are associated with fungus clearance. These results indicated that the ZR8 peptide induces a protective immune response against subcutaneous sporotrichosis and is a vaccine candidate against S. brasiliensis infection.

Skin Mast Cells Contribute to Sporothrix schenckii Infection

“…To investigate the role of MCs in sporotrichosis, we used a modified mouse model with subcutaneous injections of S. schenckii into the foot pad of mouse (31,32). This model shows many features of skin sporotrichosis in patients including ulceration, scarring, and crusty lesions, as well as nodules at infected skin sites (23,33).…”

“…However, the major clinical manifestations in most cases of sporotrichosis occur in the skin, after traumatic inoculation or zoonotic transmission, and infections with S. schenckii primarily results in cutaneous sporotrichosis (fixed cutaneous, lymphocutaneous, or disseminated forms) (27). As of now, the role of MCs in sporotrichosis of the skin has not been investigated and, thus, remains to be characterized and defined (28)(29)(30)(31). Consequently, the purpose of the current study was to investigate the in vitro response of skin MCs to S. schenckii involvement in a murine model of experimental cutaneous sporotrichosis, and their role in human skin infections with Sporothrix.…”

Sporothrix brasiliensis induces a more severe disease associated with sustained Th17 and regulatory T cells responses than Sporothrix schenckii sensu stricto in mice

“…After a pioneer study that was conducted by Beurmann and Gougerot involving 250 cases of cutaneous sporotrichosis in France (Beurmann and Gougerot, 1912), the number of cases has decreased drastically in Europe, and currently, only sporadic cases have been recently reported in some countries such as Spain, Italy and Portugal (Carlos and Batista-Duharte, 2015). Sporothrix schenckii sensu lato, the etiologic agent of sporotrichosis, is a complex of at least four pathogenic species that include Sporothrix brasiliensis, S. schenckii sensu stricto, Sporothrix globosa, and Sporothrix luriei (de Beer et al, 2016). However, the two most important pathogenic species are both S. schenckii sensu stricto, which is responsible for human sporotrichosis worldwide and S. brasiliensis, which is the more virulent specie, involved in an expanding zoonosis transmitted by cats in Brazil (Arrillaga-Moncrieff et al, 2009;Castro et al, 2013;Della Terra et al, 2017).…”

Immunity and Treatment of Sporotrichosis

“…Several antigenic peptides in the CW of Sporothrix have been described, and these are able to induce (in vitro) proliferation in T cells sensitized with S. brasiliensis . Among them are the ZR3 peptide, which is a sequence of an importin protein, the ZR4 peptide that comes from a hypothetical protein, and the ZR8, which is a peptide of the Gp70 glycoprotein [ 59 ]. The mentioned glycoprotein has been reported as the major adhesin in the CW and as the immunodominant molecule in sporotrichosis [ 60 ].…”

“…ZR3, ZR4, and ZR8 all induce high cell proliferation, but only ZR3 is able to induce the systemic production of high levels of IL-17A and IFN-γ. However, ZR8 is able to promote higher levels of IFN-γ, IL-17A, IFN-β, and IL-1β with a higher number of neutrophils in the lesions, and increases CD4 + T cells in the lymph nodes (with increased levels of IFN-β) and spleen with a higher number of neutrophils in the lesions, suggesting a Th1/Th17 immune response profile [ 59 ]. It is well known that the main mechanism for antibody protection is opsonization of the pathogen by the Fc gamma receptor (FcγR) [ 61 ].…”