Congresso Brasileiro de Microbiologia 2023

Congresso Brasileiro de Microbiologia 2023

Resumo: 250-1

250-1

Structural and Metabolic effects of Lectin-Fc(IgG) proteins against C. albicans fungi

Autores:

Susana Ruiz Mendoza (UFRJ - UNIVERSIDADE FEDERAL DO RIO DE JANEIRO, PPG-II - Pós-Graduação em Imunologia e inflamação- IMPG, IMPG - Instituto de Microbiología Paulo de góes) ; Marina da Silva Pereira (UFRJ - UNIVERSIDADE FEDERAL DO RIO DE JANEIRO, PPG-II - Pós-Graduação em Imunologia e inflamação- IMPG, IMPG - Instituto de Microbiología Paulo de góes) ; Leandro Honorato (UFRJ - UNIVERSIDADE FEDERAL DO RIO DE JANEIRO, IMPG - Instituto de Microbiología Paulo de góes) ; Leonardo Nimrichter (UFRJ - UNIVERSIDADE FEDERAL DO RIO DE JANEIRO, IMPG - Instituto de Microbiología Paulo de góes, PPG-II - Pós-Graduação em Imunologia e inflamação- IMPG) ; Allan Jefferson Guimarães (UFF - Universidade Federal Fluminense, PPGMPA - Pos-Graduacão em Microbiologia e Parasitologia-UFF, PPG-II - Pós-Graduação em Imunologia e inflamação- IMPG, IMPG - Instituto de Microbiología Paulo de góes)

Resumo:

Human candidiasis is originated by an opportunistic fungal pathogen which is the fourth most leading cause of death in nosocomial infections, with a 60% mortality rate in systemic infections and are also responsible for chronic infections in the ICU in patients, leading to important healthcare costs. C. albicans have a variety of virulence factors to colonize the human body such as morphogenesis, invasion, biofilm formation, and metabolic adaptations that facilitate its survival in distinct host environments. Numerous data related the currently capacity of C. albicans MDR (Multidrug-resistant) and support the urgent need to develop alternative antifungal therapies. In previous studies, our group develop three Lectin-Fc(IgG) proteins (WGA-Fc(IgG2a), Dectin-Fc(IgG2a) and Dectin-Fc(IgG2b)) able to recognize and bind to chitin oligomers and β-1,3-glucan on the fungal cell wall, demonstrating in vivo and in vitro antifungal capacities against Aspergillosis, Histoplasmosis, Cryptococcosis and Candidiasis models. This study aimed to demonstrate the effects of the treatment of these lectin-Fc proteins on C. albicans. Lectin-Fc(IgG) treatment diminished the β- glucans (WGA-Fc(IgG) p=0.0011), chitin (Dectin-Fc(IgG) p=0.0131 and WGA-Fc(IgG) p=0.0006) and Mannosylated components (p<0.0001 in both) on the fungal cell wall. These consistent with ultrastructural analysis that show C. albicans treated with Lectin-Fc(IgG) displayed a decreased dimension. Dectin-Fc(IgG) increased vacuolization and vesicle accumulation whereas WGA-Fc(IgG) displayed damage to the cytoplasm integrity. Treatment of C. albicans yeast with lectin-Fc also impacted the micronutrients pool such as iron, zinc, and calcium, decrease Ergosterol and lipid droplets; and increased reactive oxygen species (ROS) levels. Treatment resulted in differential protein expression of yeast, with molecular functions related to cellular metabolism and signal transduction, histones, ribosomal proteins, chaperones, and proteins related to pathogenicity. Protein cargo in Evs were also impacted, where the most vesicular proteins differences are in endopeptidase activity, cellular response to hydrogen peroxide, protein refolding and cytosol. BMDCs infected with C. albicans yeast treated with Lectin-Fc(IgG) proteins showed an enhance immune activation expressing costimulatory molecules MHC-II and CD40, and an incremented killing activity with less CFU growth. ELISA demonstrate an enhance cytokine expression (IL-6 IL-10 and TNF-α). These results altogether strongly suggested that therapeutic interventions with Lectin-Fc(IgG) proteins are an alternative strategy against fungal infections, altering the metabolic adaptations of the fungi and turning their cell wall more susceptible to recognize and killing by the host immune cells and the activity of antifungals.

Palavras-chave:

Lectin-Fc(IgG) proteins, chimeric proteins, antifungals, biopharmaceuticals, passive immunization

Agência de fomento:

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação Carlos Chagas de Amparo à Pesquisa no Estado do Rio de Janeiro (FAPERJ).