Monocyte regulatory phenotypes and systemic proteomic signatures in helminth-tuberculosis coinfection

Background Chronic helminth infection is associated with altered anti-mycobacterial immunity, including impaired Th1 responses and expansion of regulatory immune populations. However, how helminth infection reshapes coordinated innate and adaptive immune pathways during active tuberculosis remains poorly understood. We therefore investigated systemic and cellular immune signatures associated with helminth infection, tuberculosis (TB), and helminth-TB coinfection. Methods Plasma and peripheral blood mononuclear cells were obtained from healthy Swedish controls, endemic Peruvian controls, individuals with helminth infection, active tuberculosis, and helminth-TB coinfection. Plasma proteins were quantified using high-throughput Olink proteomics, while circulating monocytes and CD4 + T-cell compartments were characterized via flow cytometry. Protein abundance, monocyte phenotypes, and CD4 + T-cell differentiation and activation marker expression were compared between study groups. Results Proteomic profiling revealed broad differences associated with active TB, whereas helminth infection alone was associated with relatively few differentially abundant proteins compared with endemic controls. Participants with helminth-TB coinfection exhibited 65 differentially abundant proteins compared with endemic controls, including 33 that met the significance threshold only in this comparison. These proteins were associated with immune regulation, leukocyte trafficking, vascular activation, and myeloid responses. Flow cytometric analysis revealed increased PD-L1 expression on intermediate monocytes in helminth-infected participants compared to endemic controls, while plasma CD274 abundance was highest in helminth-TB coinfection. Coinfected individuals also displayed increased IL-4 receptor expression on classical and intermediate monocytes compared to the endemic control group. Within the CD4 + T-cell compartment, helminth infection was associated with broad upregulation of PD-1 across naïve, central memory, effector memory, and effector subsets, whereas TB was associated with altered T-cell differentiation and increased TIM-3 expression. Helminth-TB coinfection combined these features and was further characterized by increased frequencies of CTLA-4 + , CD40L + , and CD28 + CD4 + T-cell populations. Conclusion Plasma proteomic and cellular profiling identified distinct immune signatures associated with TB, helminth infection, and their co-occurrence. Helminth-TB coinfection was associated with additional changes in immune regulation and cell-communication pathways, alongside concurrent activation-associated and inhibitory features across monocyte and CD4 + T-cell compartments. Together, these findings support an exploratory model in which active TB is associated with broad systemic inflammatory remodeling, while helminth exposure is associated with an additional regulatory overlay during coinfection.