ABSTRACT Fungal pathogens are underappreciated causes of significant morbidity and mortality worldwide. In previous studies, we determined that a heat-killed, Cryptococcus neoformans fbp1-deficient strain (HK-fbp1) is a potent vaccine candidate. We determined that vaccination with HK-fbp1 confers protective immunity against lethal Cryptococcosis in an interferon γ (IFNγ)-dependent manner. In this study, we set out to uncover cellular sources and relevant targets of the protective effects of IFNγ in response to the HK-fbp1 vaccine. We found that early IFNγ production peaks at day 3 and that monocytes and neutrophils are important sources of this cytokine after vaccination. Neutralization of IFNγ at day 3 results in impaired CCR2 + monocyte recruitment and reduced differentiation into monocyte-derived dendritic cells (Mo-DC). In turn, depletion of CCR2 + cells prior to immunization results in impaired activation of IFNγ-producing CD4 and CD8 T cells. Thus, monocytes are important targets of innate IFNγ and help promote further IFNγ production by lymphocytes. We employed monocyte-fate mapper and conditional STAT1 knockout mice to uncover that STAT1 activation in CD11c + cells, including alveolar macrophages, Mo-DCs, and monocyte-derived macrophages (Mo-Mac) is essential for HK-fbp1 vaccine-induced protection. Altogether, our aggregate findings suggest critical roles for innate cells as orchestrators of vaccine-induced protection against Cryptococcus infection. IMPORTANCE The number of patients susceptible to invasive fungal infections across the world continues to rise at an alarming pace yet current antifungal drugs are often inadequate. Immune-based interventions and novel antifungal vaccines hold the promise of significantly improving patient outcomes. In previous studies, we identified a Cryptococcus neoformans mutant strain (Fbp1-deficient) as a potent, heat-inactivated vaccine candidate capable of inducing homologous and heterologous antifungal protection. In this study, we used a combination of methods together with a cohort of conditional knockout mouse strains to interrogate the roles of innate cells in the orchestration of vaccine-induced antifungal protection. We uncovered novel roles for neutrophils and monocytes as coordinators of a STAT1-dependent cascade of responses that mediate vaccine-induced protection against invasive cryptococcosis. This new knowledge will help guide the future development of much-needed antifungal vaccines.

31 Dec 2023·Expert Review of Vaccines

Vaccine development for pathogenic fungi: current status and future directions

Review

Author: Taborda, Carlos P. ; Zamith-Miranda, Daniel ; Figueiredo, Julia M. ; Chechi, Jéssica L. ; Nosanchuk, Joshua D. ; Valdez, Alessandro F. ; Camara, Aline C. ; da Costa, Felipe A. C. ; de Souza, Cássia M.

INTRODUCTIONFungal infections are caused by a broad range of pathogenic fungi that are found worldwide with different geographic distributions, incidences, and mortality rates. Considering that there are relatively few approved medications available for combating fungal diseases and no vaccine formulation commercially available, multiple groups are searching for new antifungal drugs, examining drugs for repurposing and developing antifungal vaccines, in order to control deaths, sequels, and the spread of these complex infections.AREAS COVEREDThis review provides a summary of advances in fungal vaccine studies and the different approaches under development, such as subunit vaccines, whole organism vaccines, and DNA vaccines, as well as studies that optimize the use of adjuvants. We conducted a literature search of the PubMed with terms: fungal vaccines and genus of fungal pathogens (Cryptococcus spp. Candida spp. Coccidioides spp. Aspergillus spp. Sporothrix spp. Histoplasma spp. Paracoccidioides spp. Pneumocystis spp. and the Mucorales order), a total of 177 articles were collected from database.EXPERT OPINIONProblems regarding the immune response development in an immunocompromised organism, the similarity between fungal and mammalian cells, and the lack of attention by health organizations to fungal infections are closely related to the fact that, at present, there are no fungal vaccines available for clinical use.

01 May 2023·Journal of Medical Mycology

Fungal melanin-induced metabolic reprogramming in macrophages is crucial for inflammation

Review

Author: Wu, Yifan ; Sang, Hong ; He, Yifan ; Kong, Qingtao ; Chen, Qiying ; Liu, Fang

The overuse of antifungal and immunosuppressant drugs and the higher frequency of organ transplantation has resulted in mycosis being increasingly intractable, and there is a great need for the development of new therapies. Melanin is an important virulence factor that can inhibit the inflammatory response in the host and facilitate fungal survival by several methods. However, a recent study showed that the Akt/mTOR/HIF1α axis in macrophages was activated after melanin-binding proteins recognised the DHN melanin of Aspergillus fumigatus, with a resulting metabolic shift towards glycolysis (i.e., metabolic reprogramming). As a result, antimicrobial compounds (e.g., inflammatory mediators and reactive oxygen species) were increased to fight the fungal invasion. Actually, DHN melanin from other fungi and DOPA melanin can induce inflammation and stimulate the production of melanin-binding antibodies. In addition, DOPA melanin contains conserved repeating units that are similar to those of DHN melanin. Therefore, we evaluated the associated evidence to propose an interesting and reasonable hypothesis that melanin promotes inflammation by metabolic reprogramming, which could provide a research direction for antifungal therapy. It suggests that regulating the metabolism of immune cells can guide the inflammatory response against fungi, despite the presence of immunosuppressant melanin. Since the biochemical molecules of glycolysis are clearly described, regulating glycolysis in macrophages may be easier than inventing new antifungal drugs. Further clarification of our hypothesis may strengthen the candidacy of melanin for future antifungal vaccines.

100 Deals associated with Antifungal vaccine (Immunitor USA)

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Indication	Highest Phase	Country/Location	Organization	Date
Mycoses	Phase 2	US	Immunitor USA Inc.	25 Oct 2010

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