Exploring inflammation pathways in endemic fungal infections and potential novel treatment strategies

Author(s)

Brenda Kischkel

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2022-06-24

Examining board members

Carlos Pelleschi Taborda; Sandro Rogerio de Almeida; Mário Henrique de Barros; André Luis Souza dos Santos

• Advisor: Carlos Pelleschi Taborda

Abstract

In recent years the increase in the number of immunocompromised individuals has contributed to the high global incidence rates of fungal infections. Treatment for systemic mycoses is still limited due to drug toxicity and long treatment periods that do not protect against disease recurrence. An alternative to solve these problems is the development of vaccines and immunotherapies that can stimulate the immune system to resolve the disease and be linked to low-dose antifungal therapies (Chapter 3). Using bioinformatics tools, we selected epitopes with greater affinities for human leukocyte antigen class I (HLA-I) and class II (HLA-II) molecules and conserved among different fungal species. Ex vivo experiments have demonstrated that these epitopes have antigenic potential and may become possible candidates in the development of a pan-fungal peptide vaccine (Chapter 4). In addition, we also identified important cytokine signalling pathways in response to sporotrichosis and the peptidorhamnomannan from the fungal cell wall. We demonstrate that the IL-1 pathway is crucial for the immune response against sporotrichosis and can be targeted for personalized immunotherapies that aim to ameliorate and control the inflammatory response and tissue destruction (Chapter 5 and 7). Finally, we discuss the skin\'s immune response to fungal infections and suggest that the pathogenicity of infectious skin diseases such as sporotrichosis may also be related to trained immunity (Chapter 6). In conclusion, the set of data compiled in this work contributes to the development of new vaccine and therapeutic strategies against endemic mycoses. (AU)

• FAPESP's process: 18/26402-1 - Prospection of new epitopes with vaccine potential in the control of experimental infection by Histoplasma capsulatum
• Grantee: Brenda Kischkel
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)