A novel mannan-specific chimeric antigen receptor M-CAR redirects T cells to interact with <i>Candida</i> spp. hyphae and <i>Rhizopus oryzae</i> spores

Invasive fungal infections (IFIs) are responsible for elevated rates of morbidity and mortality, causing around of 1.5 million deaths annually worldwide. One of the main causative agents of IFIs is <i>Candida albicans</i>, and non-albicans <i>Candida</i> species have emerged as a spreading global public health concernment. Furthermore, COVID-19 has contributed to a boost in the incidence of IFIs, such as mucormycosis, in which <i>Rhizopus oryzae</i> is the most prevalent causative agent. The effector host immune response against IFIs depends on the activity of T cells, which are susceptible to the regulatory effects triggered by fungal virulence factors. The fungal cell wall plays a crucial role as a virulence factor, and its remodeling compromises the development of a specific T-cell response. The redirection of Jurkat T cells to target <i>Candida</i> spp. by recognizing targets expressed on the fungal cell wall can be facilitated using chimeric antigen receptor (CAR) technology. This study generated an M-CAR that contains an scFv with specificity to α-1,6 mannose backbone of fungal mannan, and the expression of M-CAR on the surface of modified Jurkat cells triggered a strong activation against <i>Candida albicans</i> (hyphae form), <i>Candida tropicalis</i> (hyphae form), <i>Candida parapsilosis</i> (pseudohyphal form), and <i>Candida glabrata</i> (yeast form). Moreover, M-CAR Jurkat cells recognized <i>Rhizopus oryzae</i> spores, which induced high expression of cell activation markers. Thus, a novel Mannan-specific CAR enabled strong signal transduction in modified Jurkat cells in the presence of <i>Candida</i> spp. or <i>R. oryzae</i>.