Abstract
As there are more than 6 million human deaths due to mycoses each year, there is an urgent need to develop fungal vaccines. Moreover, given the similarities among pathogenic fungi, it may be possible to create a multi-fungi vaccine. In this study, we combined immunoproteomic and immunopeptidomic methods, for which we have adapted a technique based on co-immunoprecipitation (Co-IP) that made it possible to map Histoplasma capsulatum epitopes for the first time in a natural context using murine dendritic cells (DCs) and macrophages (Mφ). Although polysaccharide epitopes exist, this research focused on mapping protein epitopes as these are more immunogenic. We used different algorithms to screen proteins and peptides identified by two-dimensional electrophoresis (2-D) and Co-IP. Seventeen proteins were revealed by 2-D gels, and 45 and 24 peptides from distinct proteins were presented by DCs and Mφ, respectively. We then determined which epitopes were restricted to MHC-I and II from humans and mice and showed high promiscuity, but lacked identity with human proteins. The 4 most promising peptides were synthesized, and the peptides with and without incorporation into glucan particles induced CD4+ and CD8+ T cell proliferation and produced a Th1 and Th17 response marked by the secretion of high levels of IFN-γ, IL-17 and IL-2. These epitopes were from heat shock protein 60, enolase, and the ATP-dependent molecular chaperone HSC82, and they each have a high degree of identity with proteins expressed by other medically important pathogenic fungi. Thus, the epitopes described in this study have the potential for use in the development of vaccines that could result in cross-protection among fungal species.
Highlights
Invasive fungal infections remain a major public health problem and there are no licensed vaccines to combat any human mycosis
Techniques based on proteomics and bioinformatics have enabled the scientific community to map metabolic pathways and discover targets for the development of new drugs, therapies, and biological markers for diagnosis [38]
The first was based on immunoproteomics, in which the combination of 2-D gel and immunoblot allowed the identification of antigenic proteins of H. capsulatum
Summary
Invasive fungal infections remain a major public health problem and there are no licensed vaccines to combat any human mycosis. The continued increase in numbers of immunocompromised individuals, such as transplant and implant recipients, people living with the human immunodeficiency virus (HIV), cancer patients, and individuals receiving immunosuppressants, has worried the scientific community, since these individuals are highly susceptible to and more frequently develop serious fungal infections [2]. The fungal cell wall and plasma membrane are composed of polysaccharides and a variety of proteins conserved between species. These conserved proteins can potentially be utilized to develop a single vaccine to protect against different types of mycoses [3]. An example of a “pan-fungal” vaccine candidate was reported by Wuthrich et al [4], demonstrating that calnexin, an conserved antigen present on the surface of the fungal cell and a 13-mer peptide derived from this protein induced the expansion of CD4+ T cells
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