Identification of a protective antigen reveals the trade-off between iron acquisition and antigen exposure in a global fungal pathogen

Systemic infections caused by <i>Cryptococcus</i> claim over 161,000 lives annually, with global mortality rate close to 70% despite antifungal therapies. Currently, no vaccine is available. To develop an effective multivalent vaccine against this free-living opportunistic eukaryotic pathogen, it is critical to identify protective antigens. We previously discovered <i>ZNF2</i>^oe strains elicit protective host immune responses and increase the abundance of antigens present in the capsule, which is required for its immunoprotection. Capsule is a defining feature of <i>Cryptococcus</i> species and composed of polysaccharides and mannoproteins. Here, we found increased levels of exposed mannoproteins in <i>ZNF2</i>^oe cells. As mannoproteins are the primary components recognized by anticryptococcal cell-mediated immune responses and few have been characterized, we systemically screened all 49 predicted GPI-mannoproteins in <i>Cryptococcus neoformans</i> for enhanced host recognition. We identified those highly present in <i>ZNF2</i>^oe cells and found Cig1 to be a protective antigen against cryptococcosis either as a recombinant protein vaccine or an mRNA vaccine. Cig1 is induced by iron limitation and is highly expressed by this fungus in infected mice and in patients with cryptococcal meningitis. Remarkably, iron restriction by the host induces cryptococcal cells to express iron-uptake proteins including Cig1, which act as cryptococcal antigens and in turn enhance host detection. Our results highlight an arms race between the pathogen and the host centered on iron competition, and the trade-off between cryptococcal iron acquisition and antigen exposure. These findings demonstrate the potential of leveraging this host-pathogen interaction for vaccine development.