Endoglucanase 2 (Eng2), a shared immunodominant antigen in dimorphic fungi that elicits immunity during infection
Uju J. Okaa, Cleison Ledesma Taira, Lucas dos Santos Dias, Hannah Dobson, Gregory C. Kujoth, Althea Campuzano, E. Jane Homan, George R. Thompson, Chiung-Yu Hung, George S. Deepe Jr, Marcel Wüthrich, Bruce S. Klein
Uju J. Okaa, Cleison Ledesma Taira, Lucas dos Santos Dias, Hannah Dobson, Gregory C. Kujoth, Althea Campuzano, E. Jane Homan, George R. Thompson, Chiung-Yu Hung, George S. Deepe Jr, Marcel Wüthrich, Bruce S. Klein
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Research Article Immunology Infectious disease

Endoglucanase 2 (Eng2), a shared immunodominant antigen in dimorphic fungi that elicits immunity during infection

Abstract

We describe here a shared surface and cell wall protein, endoglucanase 2 (Eng2), expressed on the etiological agents that cause the endemic systemic mycoses of North America — Blastomyces, Coccidioides, and Histoplasma. We demonstrate that, despite sequence variation of the protein across these related fungi, exposure to Eng2 vaccinated and protected inbred and humanized HLA-DR4 strains of mice against lethal experimental infections with these fungi by eliciting adaptive immunity mediated by CD4+ T cells. We also show that CD4+ T cell precursors against Eng2 were detectable in naive individuals and that patients who had recovered from these infections evinced a memory and recall CD4+ T cell response to Eng2 and its immunodominant epitopes that we have mapped. We created and cataloged new tools and information, such as immunodominant peptide epitopes of Eng2 from each fungus recognized by inbred mice and humans, and we engineered peptide–MHC II tetramers to track T cells in inbred and HLA-DR4–humanized mice. These tools and tetramers will be useful for those who study these infections in mice and humans. Last, because most patients demonstrated immune memory and recall responses against Eng2, our work offers tools for the diagnosis of this collection of infectious diseases across North America.

Authors

Uju J. Okaa, Cleison Ledesma Taira, Lucas dos Santos Dias, Hannah Dobson, Gregory C. Kujoth, Althea Campuzano, E. Jane Homan, George R. Thompson, Chiung-Yu Hung, George S. Deepe Jr, Marcel Wüthrich, Bruce S. Klein

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Figure 7

Response of CD4+ T cell–naive participants to predicted epitopes.

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Response of CD4+ T cell–naive participants to predicted epitopes. (A) Sc...
(A) Schematic of antigen-priming strategy using Sanofi’s MIMIC System as described in Methods. (B) Naive CD4+ T cells from 16 healthy donors were primed and restimulated with full length Eng2 protein homologs from C. posadasii, B. dermatitidis, and H. capsulatum using the MIMIC System. Data are expressed as the SI, which is the ratio of cytokines produced by cells that were primed and restimulated versus cultured in medium alone. Ag, antigen. (C) Boolean analysis of the multifunctional cytokine response depicted in B, illustrating the fraction of activated donor CD4+ T cells that produced more than 1 cytokine following Eng2 stimulation (color). “Function” denotes the number of cytokine products. (D) Response of donor-derived naive CD4+ T cells to priming with protein (top row) or peptide pool (bottom row) and restimulation with individual peptides or protein in the MIMIC System. Data variation is displayed as box-and-whisker plots with variation as noted in Methods. (E) Heatmap of responses to peptides P1–P4 with different Th profiles according to individual HLA haplotype among the naive study cohort. Peptide sequences are provided in Supplemental Table 1.