Talaromycosis-associated immune reconstitution inflammatory syndrome exhibits immune dysregulation in patients with acquired immunodeficiency syndrome

BACKGROUND: Talaromycosis (TSM) is a severe opportunistic fungal infection that mostly infects patients with acquired immunodeficiency syndrome (AIDS). After antiretroviral therapy (ART), AIDS patients with TSM may develop immune reconstitution inflammatory syndrome (IRIS), leading to the paradoxical worsening of clinical symptoms. However, the immunological characteristics of TSM-related IRIS (TSM-IRIS) in AIDS patients remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a longitudinal cohort study of AIDS patients with TSM and analyzed the immunological features using flow cytometry, transcriptomes, and multiplex cytokine assays at admission, ART initiation, and at 2, 4 weeks after ART initiation. Patients with TSM-IRIS displayed significantly higher baseline CD3 ⁺ T cells at admission and lower frequencies of PD-1 ⁺ CD4 ⁺ T cells at ART initiation than those without IRIS (non-IRIS). After ART initiation, TSM-IRIS was associated with dynamic transcriptomic changes involving inflammatory and immune-related pathway enrichment, along with sustained elevations of interleukin (IL)-17, IL-21, C-X-C motif chemokine ligand (CXCL) 5, and CXCL12. Transcriptomic analysis revealed the dynamic enrichment of pro-inflammatory pathways prior to and during the early phase of ART. CONCLUSION/SIGNIFICANCE: AIDS patients with TSM-IRIS exhibited an immune profile associated with enhanced T cell activation, characterized by accelerated immune reconstitution accompanied by heightened inflammatory activity during the early phase of ART, may potentially acting as the immune markers for prediction or diagnosis of TSM-IRIS in AIDS patients.