Immunophenotyping of apparently immunocompetent hosts with cryptococcosis reveals IL-17 deficiency as a unifying susceptibility factor

Introduction We describe the immunophenotyping and genetic analysis of HIV-uninfected apparently immunocompetent adults presenting with disseminated cryptococcosis. Cryptococci are environmentally ubiquitous fungi that may cause disseminated infection including meningitis. Cryptococcosis occurs predominantly in immunocompromised hosts and most commonly in the context of human immunodeficiency virus (HIV) infection. In apparently immunocompetent patients, cryptococcal disease is rare, often diagnosed later and associated with higher mortality. The immunologic work-up and management of this patient group is challenging and poorly studied. Methods Between 2015-2021, eight apparently immunocompetent adults at the time of diagnosis with cryptococcosis underwent extensive diagnostic immunological work-up including T-/B-cell subsets, immunoglobulins, T-cell proliferation and phenotyping, serum-specific antibody responses, mannose binding lectin, measurement of selected cytokines, anti-cytokine autoantibodies and targeted genetic next-generation sequencing. Results The production of interleukin (IL)-17 following phytohaemagglutinin (PHA) stimulation was significantly reduced in all eight patients with cryptococcosis compared to healthy controls (median IL-17 concentration in whole blood stimulation assay 88.1pg/mL in patients; 452.1pg/mL in controls, p=0.0047). In 5/5 patients tested, the percentage of CD4+ T-cells positive for IL-17, including memory CD4+CD45RO+ IL-17+ T-cells, after stimulation with staphylococcal enterotoxin B (SEB) was significantly reduced (<=0.4% cells). Reduced IgM+ memory B-cells were noted in 4/5 tested. 4/8 patients were found to have CD4 lymphopaenia. One patient with Cryptococcus gattii infection had autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). No underlying genetic causes were identified. Conclusion Patients had several immunological risk factors, but reduced IL-17 production was a striking feature across the cohort – a phenotype that may facilitate tailored immunotherapeutic approaches.