Intranasal Vaccine Using P10 Peptide Complexed within Chitosan Polymeric Nanoparticles as Experimental Therapy for Paracoccidioidomycosis in Murine Model

Santos, Samuel Rodrigues Dos; Silva, Francenya Kelley Lopes da; Dias, Lucas Dos Santos; Souza, Ana Camila Oliveira; Araujo, Marcelo Valdemir de; Silva, Leandro Buffoni Roque da; Travassos, Luiz R.; Amaral, André Corrêa; Taborda, Carlos Pelleschi

doi:10.3390/jof6030160

Cited by 15 publications

(19 citation statements)

References 49 publications

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“…Hence, there is an urgent need to identify new therapeutic approaches to combat this complex disease. One of the most promising treatment innovations for PCM is the inclusion of the peptide P10 in therapy, which is highlighted by P10's ability to be used both early in or after disease in immunologically normal or compromised mice (21)(22)(23)(24)26). However, P10 does not sufficiently correspond to sequences in PLGp43.…”

Section: Discussionmentioning

confidence: 99%

“…Administration of P10 either before or after the establishment of PB PCM produces a therapeutically protective effect in both immunosuppressed and immunocompetent mice (21)(22)(23)(24). P10 requires concomitant administration of adjuvant for efficacy although diverse adjuvants produce a therapeutic effect with the peptide (25), including delivery as a P10-nanoparticle (26). However, these protection experiments have been carried out using the PB (Pb18) isolate.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Potentially Therapeutic Immunogenic Peptides From Paracoccidioides lutzii Species

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Potentially Therapeutic Immunogenic Peptides From Paracoccidioides lutzii Species

et al. 2021

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“…Currently, all the available antifungal agents are toxic to humans, because of the similarities between mammal cells and fungi. Regarding PCM treatment, extended periods of antifungal therapies, infection relapses, and constant medical monitoring highlight the urgency for the development of new therapeutic alternatives, mainly strategies based on the enhancing of the immune responses ( 46 , 47 ). Moreover, the research for therapeutic approaches that aim to improve the immune system of hosts suffering of impaired immune responses is a challenge that must be pursued in order to enhance the effectiveness of the available antifungal therapies ( 4 , 48 ).…”

Section: Discussionmentioning

confidence: 99%

Antibody- Based Immunotherapy Combined With Antimycotic Drug TMP- SMX to Treat Infection With Paracoccidioides brasiliensis

et al. 2021

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Monoclonal antibodies (mAbs) are promising alternatives to treat infectious diseases, especially given their potential for applications in combination therapies with antimicrobial drugs to enhance the antifungal efficacy. Protection mediated by mAbs used to treat experimental paracoccidioidomycosis (PCM) has been demonstrated previously. Our aim in the present work was to characterize a monoclonal antibody (mAbF1.4) raised against a cell wall glycoconjugate fraction of Paracoccidioides spp. and to analyze its efficacy combined with trimethoprim-sulfamethoxazole (TMP/SMX) as treatment for experimental PCM. We demonstrated that the epitope recognized by mAbF1.4 is consistent with branched glucose residues present on a cell wall β-glucan polymer. In vitro, mAbF1.4 increased the phagocytic capacity and nitric oxide concentration induced by the macrophage cell line J774.1A, and this resulted in a significant reduction in the viability of the opsonophagocytized yeasts. In vivo, we detected a significant reduction in pulmonary fungal burdens of mice treated with mAbF1.4 in association with TMP/SMX, which correlated with increased pulmonary concentrations (determined by ELISA) of IFN- γ, TNF-α, IL-10 and IL-17. In parallel, we observed a decrease in IL-4, suggesting that the treatment was associated with a mixed Th1-Th17 type immune response. Histopathology of lung segments from mice receiving the combination therapy showed a significant reduction in granulomas, which were well-defined, and improved maintenance of lung architecture. These findings demonstrate that mAbF1.4 + TMP/SMX therapy is a promising approach to combat PCM as well as decrease disease sequelae and highlights the potential benefits of immune mediators in PCM combined immunotherapy.

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“…Different strategies to improve PCM therapy are under development, many using the benefits promoted by nanotechnology ( Table 1 ), whether carrying molecules that act as immunomodulatory boosts such as the peptide P10 [ 187 , 188 ], a DNA vaccine [ 189 ] or the scFv fraction from a recombinant antibody [ 190 ]. These carriers may also carry conventional drugs, such as amphotericin B [ 191 , 192 ] and itraconazole [ 191 ].…”

Section: Nanotechnology As An Approach For Alternative Therapiesmentioning

confidence: 99%

“…The intranasal administration route was also chosen to evaluate a nanostructured formulation for the P10 peptide considering the mucosa present in the nasal route. Thus, polymeric nanoparticles were prepared with chitosan [ 188 ], Chitosan is a natural cationic polymer, biocompatible, biodegradable and mucoadhesive, which can interact electrostatically with the anionic mucin present in the airway [ 197 ]. The results indicated a 20-fold reduction in the amount of peptide needed to present an efficient protective immune response in animals.…”

Section: Nanotechnology As An Approach For Alternative Therapiesmentioning

confidence: 99%

One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy

Kioshima

Mendonca

Teixeira

et al. 2021

JoF

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Paracoccidioidomycosis (PCM) is a notable fungal infection restricted to Latin America. Since the first description of the disease by Lutz up to the present day, Brazilian researchers have contributed to the understanding of the life cycle of this pathogen and provided the possibility of new targets for antifungal therapy based on the structural and functional genomics of Paracoccidioides. In this context, in silico approaches have selected molecules that act on specific targets, such as the thioredoxin system, with promising antifungal activity against Paracoccidioides. Some of these are already in advanced development stages. In addition, the application of nanostructured systems has addressed issues related to the high toxicity of conventional PCM therapy. Thus, the contribution of molecular biology and biotechnology to the advances achieved is unquestionable. However, it is still necessary to transcend the boundaries of synthetic chemistry, pharmaco-technics, and pharmacodynamics, aiming to turn promising molecules into newly available drugs for the treatment of fungal diseases.

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Intranasal Vaccine Using P10 Peptide Complexed within Chitosan Polymeric Nanoparticles as Experimental Therapy for Paracoccidioidomycosis in Murine Model

Cited by 15 publications

References 49 publications

Identification of Potentially Therapeutic Immunogenic Peptides From Paracoccidioides lutzii Species

Identification of Potentially Therapeutic Immunogenic Peptides From Paracoccidioides lutzii Species

Antibody- Based Immunotherapy Combined With Antimycotic Drug TMP- SMX to Treat Infection With Paracoccidioides brasiliensis

One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy

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