This competing renewal exploits a conserved fungal antigen to vaccinate against the three major systemic my- coses of North America, Blastomycocis, Coccidiodomycosis and Histoplasmosis, and elucidate the mechanics that underpin vaccine induced CD4 T cell memory immunity elicited against these pulmonary fungal infections. While host resistance against respiratory pathogens is thought to reside with lung tissue-resident memory cells (Trm) and mucosal immunity, our strong preliminary data unexpectedly reveal that systemic vaccination elicits a population of migratory T cells that confer protection, whereas Trm elicited at the lung mucosa do not protect. We have discovered a novel fungal ligand for dectin-2, Blastomyces endoglucanase 2 (Bl-Eng2), that is an ad- juvant and an immune-dominant antigen that confers vaccine immunity. We have also developed MHCII: pep- tide tetramers to enable in vivo tracking of Eng2-specific migratory and lung-resident CD4 T cells. Importantly, Eng2 is conserved Blastomyces, Coccidiodes and Histoplasma, the agents of endemic mycoses. We propose to identify Eng2 T cell epitopes that confer protection against the endemic mycoses and uncover correlates of protective immunity during the systemic vaccine priming and effector phases. We hypothesize that migratory T cells confer vaccine immunity by homing to lung via CX3CR1 and CXCR3 mediated chemotaxis.
We aim to: 1. Elucidate the role of migratory T cells and their homing receptors in vaccine resistance. We will use adoptive transfer, parabiosis and SIPR1 blockade of T egress from the SLO to identify the functional and phenotypic features of protective CD4 T cells and determine the roles of CX3CR1 and CXCR3 in migration. 2. Pinpoint priming events that elicit protective, migratory T cells. We will identify accessory cells that transport Eng2 to the lymph nodes, display peptide and prime nave T cells, and define by fate mapping of T cells whether phenotypes are irreversibly set locally in draining LN or display plasticitity on recall to lung. 3. Identify Eng2 T cell epitopes that protect mice against infection and are recognized by humans. We will use an immunoinformatic algorithm to identify Eng2 T cell epitopes that protect C57BL6 and ?humanized? HLA-DR4 mice against the endemic mycoses and are recognized by humans recovered from the diseases. Our work will exploit a conserved fungal antigen to vaccinate against multiple systemic mycoses. We will use this vaccine to unveil conceptually new insight about how antifungal CD4 T cells are ideally primed systemi- cally, and divine the mechanics by which they migrate to resist pulmonary infection. Our work will challenge emerging views about a critical role for Trm in the generation of mucosal resistance to respiratory infection.
Systemic fungal infections represent a significant and growing public health problem. In the United States, invasive fungal infections are now one of the 10 leading causes of death (7th) even ahead of mortality due to tuberculosis. Our work tackles the significant unmet need of developing vaccines against fungal pathogens that cause disease in humans.
Showing the most recent 10 out of 71 publications
