Identification of Potentially Therapeutic Immunogenic Peptides From Paracoccidioides lutzii Species

Abstract

Paracoccidioidomycosis (PCM) is an endemic mycosis in Latin America caused by the thermodimorphic fungi of the genus Paracoccidioides spp. Paracoccidioides lutzii (PL) is one of the 5 species that constitute the Paracoccidioides genus. PL expresses low amounts of glycoprotein (Gp) 43 (PLGp43) and PLGp43 displays few epitopes in common with the P. brasiliensis (PB) immunodominant antigen PBGp43, which is commonly used for serological diagnosis of PCM. This difference in structure between the glycoproteins markedly reduces the efficiency of serological diagnosis in patients infected with PL. We previously demonstrated that peptide 10 (P10) from the PBGp43 induces protective immune responses in in vitro and in vivo models of PB PCM. Since, P10 has proven to be a promising therapeutic to combat PB, we sought to identify peptides in PL that could similarly be applied for the treatment of PCM. PL yeast cell proteins were isolated from PL: dendritic cell co-cultures and subjected to immunoproteomics. This approach identified 18 PL peptides that demonstrated in silico predictions for immunogenicity. Eight of the most promising peptides were synthesized and applied to lymphocytes obtained from peptide-immunized or PL-infected mice as well as to in vitro cultures with peptides or dendritic cells pulsed the peptides. The peptides LBR5, LBR6 and LBR8 efficiently promoted CD4+ and CD8+ T cell proliferation and dendritic cells pulsed with LBR1, LBR3, LBR7 or LBR8 stimulated CD4+ T cell proliferation. We observed increases of IFN-γ in the supernatants from primed T cells for the conditions with peptides without or with dendritic cells, although IL-2 levels only increased in response to LBR8. These novel immunogenic peptides derived from PL will be employed to develop new peptide vaccine approaches and the proteins from which they are derived can be used to develop new diagnostic assays for PL and possibly other Paracoccidioides spp. These findings identify and characterize new peptides with a promising therapeutic profile for future against this important neglected systemic mycosis.

Targeting the P10 Peptide in Maturing Dendritic Cells via the DEC205 Receptor In Vivo: A New Therapeutic Strategy against Paracoccidioidomycosis

“…There is a consensus that the therapeutic vaccine instead of the prophylactic one would be the best way to control PCM. Several works have demonstrated that a therapeutic vaccine to boost the cellular immune response seems relevant not only to reduce the time of treatment but also to prevent relapses and improve the prognosis of anergic cases [30][31][32]. P10 has previously been well characterized as an epitope for CD4 + T cells [16], and many studies have shown the ability of this peptide to generate a protective immune response against P. brasiliensis in different preparations (Freund's complete adjuvant, Salmonella enterica flagellin FliC) [16,20].…”

“…P10 is a major immunoprotective antigen that is being harnessed in vaccine development, and so far, it is the only candidate for vaccination in PCM. The administration of P10 either before or after the establishment of PCM produces a therapeutically protective effect in both immunosuppressed and immunocompetent mice [32]. P10 requires concomitant administration of adjuvant for efficacy, although diverse adjuvants produce a therapeutic effect with the peptide [31], including delivery as a P10-nanoparticle [30].…”

Paracoccidioidomicose em um adulto imunocompetente no Sul de Minas Gerais: Relato de caso

“…Na fase inicial da imunidade inata são recrutadas células de defesa informando às células hospedeiras que há uma infecção presente e que a imunidade adquirida deve ser ativada. A imunidade humoral, representada por anticorpos específicos, também é discutida (Silva, et al, 2021;Burger, 2021).…”

Cerebrospinal fluid: a target of some fungi and an overview

“…In addition, the peptide 10 (P10) from the PBGp43 has been explored as a therapeutic, since it can induce protective immune responses in in vitro and in vivo models due its ability to increase proliferation of cells T CD4 + Th1 and the expression of high levels of INF-γ and IL-2. 40 …”