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Within host cells,\n                      <jats:italic toggle=\"yes\">Aph<\/jats:italic>\n                      proliferates in a membrane-bound vacuole (\n                      <jats:italic toggle=\"yes\">Aph<\/jats:italic>\n                      -vacuole) to which all required nutrients must be routed, including essential iron. Here, using a fluorescent labile iron-binding dye in live image analysis, we found that\n                      <jats:italic toggle=\"yes\">Aph<\/jats:italic>\n                      -vacuoles are enriched with labile iron. Furthermore, ferroportin (Fpn), the only known iron exporter on the plasma membrane of host cells, increasingly encircled the\n                      <jats:italic toggle=\"yes\">Aph<\/jats:italic>\n                      -vacuole post-invasion in a ring-like pattern. Fpn is regulated by the hormone hepcidin, which binds to Fpn and triggers its ubiquitination and internalization, thereby, inhibits iron availability to blood-borne pathogens. Fpn-GFP mutants deficient in ubiquitination (domain deletion or Y64H) did not encircle\n                      <jats:italic toggle=\"yes\">Aph-<\/jats:italic>\n                      vacuoles. Fpn-GFP (D181V) and Fpn-GFP (D39A) mutants that are deficient in iron binding and transport could encircle\n                      <jats:italic toggle=\"yes\">Aph-<\/jats:italic>\n                      vacuoles, but unlike Fpn-GFP (wild-type) did not increase labile iron in\n                      <jats:italic toggle=\"yes\">Aph<\/jats:italic>\n                      -vacuoles or\n                      <jats:italic toggle=\"yes\">Aph<\/jats:italic>\n                      growth. The gene encoding hepcidin is upregulated by inflammation. We found\n                      <jats:italic toggle=\"yes\">Aph<\/jats:italic>\n                      infection induced the expression of the hepcidin mRNA and protein, and strong IL-6, IL-1\u03b2, and TNF-\u03b1 mRNA expression by host cells. Altogether, these results suggest that\n                      <jats:italic toggle=\"yes\">Aph<\/jats:italic>\n                      induces the production of proinflammatory cytokines for the upregulation of hepcidin which triggers the Fpn endocytosis and encasement of\n                      <jats:italic toggle=\"yes\">Aph-<\/jats:italic>\n                      \u00advacuoles in a ubiquitination-dependent manner. Fpn internalization raises host cell cytoplasmic iron and may export iron into the vacuoles to enrich intravacuolar iron for the benefit of bacteria. This finding demonstrates pathogen manipulation of cellular iron export mechanisms and subversion of host hepcidin-Fpn iron nutritional immunity against pathogens.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Iron is an essential element for both humans and microorganisms, serving as a cofactor in key metabolic processes. Obligatory intracellular bacterium\n                        <jats:italic toggle=\"yes\">Anaplasma phagocytophilum<\/jats:italic>\n                        infects and proliferates within a membrane-bound vacuole (\n                        <jats:italic toggle=\"yes\">Aph-<\/jats:italic>\n                        vacuoles) of neutrophils and endothelial cells, competitively acquiring intracellular iron from the host. Upon exploration of cytoplasmic labile free iron levels and distribution in the\n                        <jats:italic toggle=\"yes\">A. phagocytophilum<\/jats:italic>\n                        -infected and uninfected host cells, we uncovered the unique ability of this bacterium to enrich intravacuolar iron. Ferroportin is the only cellular iron exporter of host cells, which is regulated by the hepatic hormone hepcidin. Herein, we investigate the role of ferroportin and endogenous hepcidin locally produced by infected host cells for iron enrichment in\n                        <jats:italic toggle=\"yes\">Aph-<\/jats:italic>\n                        vacuoles. Ultimately, this study provides new insights into the novel mechanisms of microbial manipulation of host cells to acquire the essential micronutrient iron and overcoming host nutritional immunity, which may facilitate more effective treatment and prevention.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01134-26","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:00:40Z","timestamp":1781524840000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["<i>Anaplasma phagocytophilum<\/i>\n                    subversion of host hepcidin-ferroportin iron nutritional immunity"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0779-2031","authenticated-orcid":false,"given":"Stephen 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