Antifungal immunotherapy and immunomodulation: A double-hitter approach to deal with invasive fungal infections

In recent years, the incidence of life-threatening fungal infections has dramatically increased. Despite significant developments in antifungal chemotherapy, its efficacy remains limited by the inability to sterilize infected organs and the tendency to induce resistance and cause side effects. In response to these challenges, it is now recognized that several aspects of antifungal immunity can be modulated to better deal with fungal infections. Extensive work was carried out on the development and testing of preventive and therapeutic antifungal vaccines. The potential use of cytokines, adoptive T-cell transfer, monoclonal antibodies (MoAb) and antimicrobial peptides (AMP) as solo or adjunctive therapies is also receiving much attention. Although each of these immune-based treatment strategies has many advantages and some shortcomings, none on its own, has proven satisfactorily effective to deal with invasive fungal infections. Appropriate combinations that optimize the advantages and minimize the disadvantages of immune-based antifungals are still lacking mainly due to the immense difficulty in sorting out candidate combinations given the long list of choices. In this review, immune-based antifungals are divided into two general categories on the basis of the intended target being the host (immunomodulation through vaccines, cytokines, adoptive T-cell transfer or MoAb) or the pathogen (immunotherapy through MoAb or AMP). Potential advantages and disadvantages of immunotherapy and immunomodulation are tentatively discussed so as to facilitate the design of future studies that aim at devising more potent immune-based antifungal treatment combinations.