Abstract
The development of vaccines against fungi and other intracellular microbes is impeded in part by a lack of suitable adjuvants. While most current vaccines against infectious diseases preferentially induce production of antibodies, cellular immunity is essential for the resolution of fungal infections. Microbes such as fungi and Mycobacterium tuberculosis require Th17 and Th1 cells for resistance, and engage the C-type lectin receptors including Dectin-2. Herein, we discovered a novel Dectin-2 ligand, the glycoprotein Blastomyces Eng2 (Bl-Eng2). Bl-Eng2 triggers robust signaling in Dectin-2 reporter cells and induces IL-6 in human PBMC and BMDC from wild type but not Dectin-2-/- and Card9-/- mice. The addition of Bl-Eng2 to a pan-fungal subunit vaccine primed large numbers of Ag-specific Th17 and Th1 cells, augmented activation and killing of fungi by myeloid effector cells, and protected mice from lethal fungal challenge, revealing Bl-Eng2’s potency as a vaccine adjuvant. Thus, ligation of Dectin-2 by Bl-Eng-2 could be harnessed as a novel adjuvant strategy to protect against infectious diseases requiring cellular immunity.
Highlights
Fungal disease remains a challenging clinical and public health problem
Ag-specific CD4+ T cells play the major role in fungal resistance [4,5], as evidenced by the high incidence of lifethreatening fungal infections in patients with impaired CD4+ T cells
B. dermatitidis vaccine yeast are bound by soluble Dectin-2 fusion protein and trigger NFAT signaling of Dectin-2 reporter cells [19]
Summary
Fungal disease remains a challenging clinical and public health problem. Despite medical advances, invasive fungal infections have skyrocketed over the last decade and pose a mounting health threat in immune-competent and -deficient hosts with worldwide mortality rates ranking 7th, even ahead of tuberculosis [1,2]. The development of safe, effective vaccines remains a major hurdle for fungi. Critical barriers to progress include the lack of defined fungal antigens (Ags) and suitable adjuvants that together exert protective immunity. Recent strides in our understanding of fungal immunity and discovery of fungal Ags have raised the prospect that vaccines against fungi can be developed to elicit lasting protective immunity if suitable adjuvants are available. Ag-specific CD4+ T cells play the major role in fungal resistance [4,5], as evidenced by the high incidence of lifethreatening fungal infections in patients with impaired CD4+ T cells. Since CD4+ T cells are germane to host defense against fungi, the challenge is how best to elicit these T cells
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