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 IL12{beta}-IFN-{gamma} 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-12{beta} production that drives IFN-{gamma} mediated control of infection. Emerging evidence implicates cellular nucleic acid-binding protein (CNBP), a zinc-finger transcriptional regulator, in control of IL12{beta} 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 IL12{beta} promoter, and was required for optimal IL12{beta} induction. Genetic ablation of CNBP in mice and siRNA knockdown of CNBP in human monocyte-derived dendritic cells markedly reduced IL12{beta} production and downstream IFN-{gamma} responses, while TNF- and several other innate cytokines were largely unaffected. In vivo, hematopoietic-specific deletion of CNBP (using vav-iCre; Cnbpfl/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 IL12{beta}-IFN-{gamma} 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 IL12{beta}-IFN-{gamma} 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. Author summaryMalaria remains one of the worlds deadliest infectious diseases, caused by the protozoan Plasmodium that trigger complex immune responses in infected hosts. Effective host defense requires a tightly regulated inflammatory response: too weak and the parasite proliferates unchecked; too strong and the host suffers harmful immunopathology. Central to this balance is the IL12{beta}-IFN-{gamma} signaling axis. In this study, we investigated the role of a transcriptional regulator, known as Cellular Nucleic acid-Binding Protein (CNBP), in shaping the immune response against the Plasmodium parasite. We found that CNBP rapidly responds to parasite exposure, translocates to the nucleus and drives IL12{beta} production in innate immune cells, and promotes downstream IFN-{gamma} driven adaptive immune responses. Mice lacking CNBP in hematopoietic stem cells exhibited changes in transcription of key inflammatory genes; markedly reduced systemic IL12{beta} and IFN-{gamma}, leading to significantly elevated peripheral blood parasitemia and altered immune cell composition. Paradoxically, the absence of CNBP delayed mortality in a lethal infection model and reduced inflammatory responses that are associated with cytokine storm-mediated immunopathology. These findings identify CNBP as a key regulator that fine-tunes protective immunity and inflammatory pathology during malaria, highlighting its potential as a therapeutic target to optimize host defense while limiting harmful inflammation.