{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T05:11:10Z","timestamp":1777957870695,"version":"3.51.4"},"reference-count":146,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      In co-endemic regions, hosts are concurrently infected by related apicomplexan hemoparasites,\n                      <jats:italic>Plasmodium<\/jats:italic>\n                      and the zoonotic pathogen\n                      <jats:italic>Babesia<\/jats:italic>\n                      . This study investigates how\n                      <jats:italic>Plasmodium berghei<\/jats:italic>\n                      XAT-\n                      <jats:italic>Babesia rodhaini<\/jats:italic>\n                      co-infection modulates host immunity, dissecting the contributions of innate and adaptive immune cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Disease progression was assessed by survival, parasitemia, body weight, and hematological parameters. Splenic histopathology and qPCR were used to evaluate tissue damage and parasite burden. Immune responses were analyzed by cytokine, antibody measurement, and flow cytometry. Adaptive immunity was examined using SCID mice, and the roles of innate effectors were determined through selective depletion of NK cells and macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>P<\/jats:italic>\n                      .\n                      <jats:italic>berghei<\/jats:italic>\n                      XAT infection elicited robust, heterologous protection significantly reducing parasitemia and splenic damage. This was linked with potent pro-inflammatory cytokines (IFN-\u03b3, IL-12p70, and TNF-\u03b1), balanced by increased IL-10 levels, alongside increased ROS\/NO production. While co-infected SCID mice, and NK depletion retained protection, macrophage depletion eliminated cross-protection and altered microbicidal cytokine and ROS\/NO profiles. Flow cytometry confirmed expansion of the splenic macrophages in protected mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings demonstrate that cross-protection is mediated by a macrophage-driven innate response. Protection was associated with IFN-\u03b3-driven pro-inflammatory responses and ROS\/NO production, balanced by IL-10 to limit immunopathology. This \u201cprotective homeostasis\u201d highlights macrophage-targeted immunomodulation as a promising strategy for multivalent vaccines against apicomplexan parasites. Future research is warranted to elucidate macrophage activation and polarization dynamics underlying this protection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1805513","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T04:16:58Z","timestamp":1777954618000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunity beyond borders: non-lethal Plasmodium confers cross-protection against lethal Babesia via macrophage activation"],"prefix":"10.3389","volume":"17","author":[{"given":"Iqra","family":"Zafar","sequence":"first","affiliation":[{"name":"National Research Centre for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine","place":["Obihiro, Hokkaido, Japan"]},{"name":"Laboratory of Sustainable Animal Environment, Graduate School of Agricultural Science, Tohoku University","place":["Osaki, Miyagi, 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