Cellular nucleic acid-binding protein (CNBP) dependent cytokine programming shapes host defense against Plasmodium infection.

During blood-stage Plasmodium infection, effective immune control hinges on the IL12β-IFN-γ axis, yet how this pathway is transcriptionally tuned in vivo remains incompletely defined. Innate sensing of parasite-derived ligands by pattern-recognition receptors, including Toll like receptors, in dendritic cells and macrophages induces IL-12β production that drives IFN-γ mediated control of infection. Emerging evidence implicates cellular nucleic acid-binding protein (CNBP), a zinc-finger transcriptional regulator, in control of IL12β gene expression in myeloid cells exposed to bacterial and viral infections. Here, we defined the contribution of CNBP in cytokine-driven immunity to Plasmodium infection including both P. falciparum (the major cause of malaria), as well as P. chabaudi and P. berghei ANKA, two rodent species that model human disease. Upon exposure to Plasmodium-infected erythrocytes, CNBP rapidly translocated to the nucleus in mouse and human dendritic cells, bound IL12β promoter, and was required for optimal IL12β induction. Genetic ablation of CNBP in mice and siRNA knockdown of CNBP in human monocyte-derived dendritic cells markedly reduced IL12β production and downstream IFN-γ responses, while TNF-α and several other innate cytokines were largely unaffected. In vivo, hematopoietic-specific deletion of CNBP (using vav-iCre; Cnbp fl/fl) resulted in elevated peak parasitemia, impaired parasite clearance, and relapse after initial resolution. Consistent with these outcomes, spleens from mice lacking CNBP in hematopoietic cells exhibited reduced inflammatory remodeling, altered T-cell composition, and transcriptional reprogramming characterized by selective regulation of IL12β-IFN-γ transcripts alongside upregulation of distinct cytotoxic genes. Paradoxically, mice lacking CNBP in hematopoietic cells showed delayed mortality in the lethal infection model, underscoring its context-dependent contributions to host protection and inflammatory pathology. Collectively, these findings position CNBP as a pivotal modulator of the IL12β-IFN-γ axis during malaria, extending its functional repertoire beyond microbial contexts, with potential as a therapeutic target to fine-tune immune responses for enhanced protection with limited immunopathology.