{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T00:13:39Z","timestamp":1793060019167,"version":"4.5.0"},"reference-count":93,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T00:00:00Z","timestamp":1729036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T00:00:00Z","timestamp":1729036800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"HHS | National Institutes of Health","award":["R37 AI072683,R01 AI139072"],"award-info":[{"award-number":["R37 AI072683,R01 AI139072"]}]},{"name":"HHS | National Institutes of Health","award":["F32 AI183749"],"award-info":[{"award-number":["F32 AI183749"]}]},{"name":"HHS | National Institutes of Health","award":["R21 AI159592"],"award-info":[{"award-number":["R21 AI159592"]}]},{"name":"Uconn | School of Medicine, University of Connecticut","award":["402238"],"award-info":[{"award-number":["402238"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2024,10,16]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Host-microbe interactions that facilitate entry into mammalian cells are essential for obligate intracellular bacterial survival and pathogenesis.\n              <jats:italic>Anaplasma phagocytophilum<\/jats:italic>\n              is an obligate intracellular bacterium that invades neutrophils to cause granulocytic anaplasmosis. The invasin-receptor pairs and signaling events that induce\n              <jats:italic>Anaplasma<\/jats:italic>\n              uptake are inadequately defined.\n              <jats:italic>A. phagocytophilum<\/jats:italic>\n              invasion protein A orchestrates entry via residues 9\u201321 (AipA\n              <jats:sub>9\u201321<\/jats:sub>\n              ) engaging an unknown receptor. Yeast two-hybrid screening suggested that AipA binds within C-terminal amino acids 851\u2013967 of CD13 (aminopeptidase N), a multifunctional protein that, when crosslinked, initiates Src kinase and Syk signaling that culminates in endocytosis. Co-immunoprecipitation validated the interaction and confirmed that it requires the AipA N-terminus. CD13 ectopic expression on non-phagocytic cells increased susceptibility to\n              <jats:italic>A. phagocytophilum<\/jats:italic>\n              infection. Antibody blocking and enzymatic inhibition experiments found that the microbe exploits CD13 but not its ectopeptidase activity to infect myeloid cells.\n              <jats:italic>A. phagocytophilum<\/jats:italic>\n              induces Src and Syk phosphorylation during invasion. Inhibitor treatment established that Src is key for\n              <jats:italic>A. phagocytophilum<\/jats:italic>\n              infection, while Syk is dispensable and oriented the pathogen-invoked signaling pathway by showing that Src is activated before Syk. Disrupting the AipA-CD13 interaction with AipA\n              <jats:sub>9\u201321<\/jats:sub>\n              or CD13\n              <jats:sub>781\u2013967<\/jats:sub>\n              antibody inhibited Src and Syk phosphorylation and also infection. CD13 crosslinking antibody that induces Src and Syk signaling restored infectivity of anti-AipA\n              <jats:sub>9\u201321<\/jats:sub>\n              -treated\n              <jats:italic>A. phagocytophilum<\/jats:italic>\n              . The bacterium poorly infected CD13 knockout mice, providing the first demonstration that CD13 is important for microbial infection\n              <jats:italic>in vivo<\/jats:italic>\n              . Overall,\n              <jats:italic>A. phagocytophilum<\/jats:italic>\n              AipA\n              <jats:sub>9\u201321<\/jats:sub>\n              binds CD13 to induce Src signaling that mediates uptake into host cells, and CD13 is critical for infection\n              <jats:italic>in vivo<\/jats:italic>\n              .\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Diverse microbes engage CD13 to infect host cells. Yet invasin-CD13 interactions, the signaling they invoke for pathogen entry, and the relevance of CD13 to infection\n              <jats:italic>in vivo<\/jats:italic>\n              are underexplored. Dissecting these concepts would advance fundamental understanding of a convergently evolved infection strategy and could have translational benefits.\n              <jats:italic>Anaplasma phagocytophilum<\/jats:italic>\n              infects neutrophils to cause granulocytic anaplasmosis, an emerging disease for which there is no vaccine and few therapeutic options. We found that\n              <jats:italic>A. phagocytophilum<\/jats:italic>\n              uses its surface protein and recently identified protective immunogen, AipA, to bind CD13 to elicit Src kinase signaling, which is critical for infection. We elucidated the AipA CD13 binding domain, which CD13 region AipA engages, and established that CD13 is key for\n              <jats:italic>A. phagocytophilum<\/jats:italic>\n              infection in vivo. Disrupting the AipA-CD13 interaction could be utilized to prevent granulocytic anaplasmosis and offers a model that could be applied to protect against multiple infectious diseases.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01561-24","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T13:02:56Z","timestamp":1727355776000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["<i>Anaplasma phagocytophilum<\/i>\n            invasin AipA interacts with CD13 to elicit Src kinase signaling that promotes infection"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6060-6918","authenticated-orcid":false,"given":"Mary Clark H.","family":"Lind","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, Virginia, 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