{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T11:01:55Z","timestamp":1780743715225,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,3]]},"group-title":"Immunology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  During blood-stage\n                  <jats:italic>Plasmodium<\/jats:italic>\n                  infection, effective immune control hinges on the IL12\u03b2-IFN-\u03b3 axis, yet how this pathway is transcriptionally tuned\n                  <jats:italic>in vivo<\/jats:italic>\n                  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\u03b2 production that drives IFN-\u03b3 mediated control of infection. Emerging evidence implicates cellular nucleic acid-binding protein (CNBP), a zinc-finger transcriptional regulator, in control of IL12\u03b2 gene expression in myeloid cells exposed to bacterial and viral infections.\n                <\/jats:p>\n                <jats:p>\n                  Here, we defined the contribution of CNBP in cytokine-driven immunity to\n                  <jats:italic>Plasmodium<\/jats:italic>\n                  infection including both\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  (the major cause of malaria), as well as\n                  <jats:italic>P. chabaudi<\/jats:italic>\n                  and\n                  <jats:italic>P. berghei<\/jats:italic>\n                  ANKA, two rodent species that model human disease. Upon exposure to\n                  <jats:italic>Plasmodium<\/jats:italic>\n                  -infected erythrocytes, CNBP rapidly translocated to the nucleus in mouse and human dendritic cells, bound IL12\u03b2 promoter, and was required for optimal IL12\u03b2 induction. Genetic ablation of CNBP in mice and siRNA knockdown of CNBP in human monocyte-derived dendritic cells markedly reduced IL12\u03b2 production and downstream IFN-\u03b3 responses, while TNF-\u03b1 and several other innate cytokines were largely unaffected.\n                  <jats:italic>In vivo<\/jats:italic>\n                  , hematopoietic-specific deletion of CNBP (using\n                  <jats:italic>\n                    vav-iCre; Cnbp\n                    <jats:sup>fl<\/jats:sup>\n                  <\/jats:italic>\n                  <jats:sup>\/fl<\/jats:sup>\n                  ) 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\u03b2-IFN-\u03b3 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.\n                <\/jats:p>\n                <jats:p>Collectively, these findings position CNBP as a pivotal modulator of the IL12\u03b2-IFN-\u03b3 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.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Author summary<\/jats:title>\n                  <jats:p>\n                    Malaria remains one of the world\u2019s deadliest infectious diseases, caused by the protozoan\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    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\u03b2-IFN-\u03b3 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\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    parasite. We found that CNBP rapidly responds to parasite exposure, translocates to the nucleus and drives IL12\u03b2 production in innate immune cells, and promotes downstream IFN-\u03b3 driven adaptive immune responses. Mice lacking CNBP in hematopoietic stem cells exhibited changes in transcription of key inflammatory genes; markedly reduced systemic IL12\u03b2 and IFN-\u03b3, 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.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.01.729202","type":"posted-content","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T03:30:32Z","timestamp":1780543832000},"source":"Crossref","is-referenced-by-count":0,"title":["Cellular nucleic acid-binding protein (CNBP) dependent cytokine programming shapes host defense against\n                  <i>Plasmodium<\/i>\n                  infection"],"prefix":"10.64898","author":[{"given":"Romana","family":"Rashid","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro","family":"de Souza Silva","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahid","family":"Banday","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"},{"name":"Frontier Research Institute of Interdisciplinary Sciences, IUST-Awantipora, Jammu and Kashmir, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R","family":"Caffrey","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn A","family":"Kurt-Jones","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2447-2358","authenticated-orcid":false,"given":"Douglas T","family":"Golenbock","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060603401459000_2026.06.01.729202v1.1","unstructured":"World Health Organization. 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