{ "abstract": "Malaria caused by Plasmodium falciparum (Pf) compromise innate immunity, yet the underlying mechanisms remain elusive. The immune dysregulation caused by the parasite may lead to bacterial superinfections and increase mortality. We reveal that Pf exploits extracellular vesicles (EVs) secreted by infected red blood cells (iRBC-EVs) to deliver host-derived miR451a to human neutrophils, impairing their antimicrobial defenses. Neutrophil phagocytosis of iRBC-EVs suppresses reactive oxygen species (ROS) production and compromised microbicidal activity against Salmonella typhimurium. Microfluidic assays show that miR451a transfer significantly disrupts neutrophil chemotaxis and swarming upon microbial challenge. Transcriptomic profiling indicates that EVs and miR451a reprogram neutrophil gene expression, notably upregulating ferroptosis-related genes, suggesting a role in further impairing immune responses. We have uncovered a novel mechanism of iRBC-EVs-induced neutrophil immune suppression and provide insights into increased susceptibility to bacterial superinfections in malaria. These findings have implications for therapeutic strategies aimed at mitigating bacterial superinfections and sepsis in malaria-endemic regions. Author summary: Malaria caused by Plasmodium falciparum not only leads to severe disease on its own but also increases the risk of dangerous secondary infections with bacteria and fungi, particularly in children. The biological reasons for this heightened vulnerability have remained poorly understood. In this study, we uncover a mechanism by which the malaria parasite suppresses a key arm of the human immune system: neutrophils, the body’s first responders to infection. We show that red blood cells infected with P. falciparum release small membrane-bound particles, called extracellular vesicles, that are taken up by neutrophils. These vesicles deliver a host-derived regulatory RNA molecule, miR-451a, into neutrophils, profoundly impairing their ability to migrate, coordinate collective responses, produce antimicrobial molecules, and kill invading microbes. As a result, neutrophils become less effective at controlling bacterial and fungal pathogens. We further demonstrate that this process reprograms neutrophil gene expression, including pathways linked to oxidative stress and cell death. Our findings reveal how malaria parasites exploit host molecules to weaken immune defenses, providing a mechanistic explanation for the increased susceptibility to secondary infections during malaria and highlighting extracellular vesicles as potential therapeutic targets.", "abstract_shown": true, "affiliations": [ "The Faculty of Science and Medicine, Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland", "Christine Kühne- Center for Allergy Research and Education (CK-CARE), Davos, Switzerland", "Department of Pathology & Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, United States of America", "Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden", "Department of Surgery, BioMEMS Resource Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America", "Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Stockholm, Sweden", "Department of Medical Biotechnology, University of Siena, Siena, Italy" ], "article_type": "Research Article", "arxiv": null, "author_total": 15, "authors": [ { "affs": [ 0 ], "name": "Kehinde Adebayo Babatunde" }, { "affs": [ 1 ], "name": "Mtakai Ngara" }, { "affs": [ 2 ], "name": "Paola Martinez Murillo" }, { "affs": [ 3 ], "name": "Bibin Subramanian" }, { "affs": [ 4 ], "name": "Alex Hopke" }, { "affs": [ 5 ], "name": "Simone Lucchesi" }, { "affs": [ 6 ], "name": "Maria Novedrati" }, { "name": "Giorgio Montesi" }, { "name": "Francesco Santoro" }, { "name": "Michael Hagemann-Jensen" }, { "name": "Rickard Sandberg" }, { "name": "Luis Filgueira" }, { "name": "Michael Walch" }, { "name": "Daniel Irimia" }, { "name": "Pierre-Yves Mantel" } ], "bibtex": "https://research.draconitic.com/paper/ap0zy7jpm3f1g.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014533", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014533", "id": "ap0zy7jpm3f1g", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014533", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2739|Malaria Research and Control" ], [ "plos", "/Biology and life sciences/Anatomy/Body fluids/Blood" ], [ "plos", "/Biology and life sciences/Cell biology/Cell motility/Chemotaxis" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Neutrophils" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Neutrophils" ], [ "plos", "/Biology and life sciences/Genetics/Gene expression" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Neutrophils" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota/Protozoans/Parasitic protozoans/Malarial parasites" ], [ "plos", "/Biology and life sciences/Physiology/Body fluids/Blood" ], [ "plos", "/Medicine and health sciences/Anatomy/Body fluids/Blood" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Neutrophils" ], [ "plos", "/Medicine and health sciences/Medical conditions/Parasitic diseases" ], [ "plos", "/Medicine and health sciences/Medical conditions/Parasitic diseases/Malaria" ], [ "plos", "/Medicine and health sciences/Medical conditions/Tropical diseases/Malaria" ], [ "plos", "/Physical sciences/Mathematics/Statistics/Statistical methods/Multivariate analysis/Principal component analysis" ], [ "plos", "/Research and analysis methods/Mathematical and statistical techniques/Statistical methods/Multivariate analysis/Principal component analysis" ] ], "openalex": "W7204901975", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014533&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-01", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/ap0zy7jpm3f1g.ris", "sources": [ { "first_seen": "2026-10-30T12:18:02Z", "native_id": "10.1371/journal.ppat.1014533", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014533" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "Plasmodium falciparum subverts neutrophil function via host miR-451a loaded extracellular vesicles driving bacterial and fungal superinfection susceptibility", "title_text": "Plasmodium falciparum subverts neutrophil function via host miR-451a loaded extracellular vesicles driving bacterial and fungal superinfection susceptibility", "type": "peer-reviewed", "updated_at": "2026-10-30T12:18:02Z", "url": "https://research.draconitic.com/paper/ap0zy7jpm3f1g", "venue": "PLOS Pathogens", "versions": [] }