{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T16:22:17Z","timestamp":1788884537043,"version":"build-2803163510"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,4,4]],"date-time":"2016-04-04T00:00:00Z","timestamp":1459728000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,4,4]],"date-time":"2016-04-04T00:00:00Z","timestamp":1459728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Plasmodium knowlesi<\/jats:italic> is a zoonotic parasite transmitted from macaques causing malaria in humans in Southeast Asia. <jats:italic>Plasmodium<\/jats:italic> parasites bind to red blood cell (RBC) surface receptors, many of which are sialylated. While macaques synthesize the sialic acid variant <jats:italic>N<\/jats:italic>-glycolylneuraminic acid (Neu5Gc), humans cannot because of a mutation in the enzyme CMAH that converts <jats:italic>N<\/jats:italic>-acetylneuraminic acid (Neu5Ac) to Neu5Gc. Here we reconstitute <jats:italic>CMAH<\/jats:italic> in human RBCs for the reintroduction of Neu5Gc, which results in enhancement of <jats:italic>P. knowlesi<\/jats:italic> invasion. We show that two <jats:italic>P. knowlesi<\/jats:italic> invasion ligands, PkDBP\u03b2 and PkDBP\u03b3, bind specifically to Neu5Gc-containing receptors. A human-adapted <jats:italic>P. knowlesi<\/jats:italic> line invades human RBCs independently of Neu5Gc, with duplication of the sialic acid-independent invasion ligand, PkDBP\u03b1 and loss of PkDBP\u03b3. Our results suggest that absence of Neu5Gc on human RBCs limits <jats:italic>P. knowlesi<\/jats:italic> invasion, but that parasites may evolve to invade human RBCs through the use of sialic acid-independent pathways.<\/jats:p>","DOI":"10.1038\/ncomms11187","type":"journal-article","created":{"date-parts":[[2016,4,4]],"date-time":"2016-04-04T09:14:19Z","timestamp":1459761259000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Ancient human sialic acid variant restricts an emerging zoonotic malaria parasite"],"prefix":"10.1038","volume":"7","author":[{"given":"Selasi","family":"Dankwa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caeul","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy K.","family":"Bei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rays H. Y.","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Abshire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh D.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Goldberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yovany","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Kono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacquin C.","family":"Niles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj T.","family":"Duraisingh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,4,4]]},"reference":[{"key":"BFncomms11187_CR1","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1016\/j.cell.2014.10.057","volume":"159","author":"L Deng","year":"2014","unstructured":"Deng, L. et al. Host adaptation of a bacterial toxin from the human pathogen Salmonella Typhi. Cell 159, 1290\u20131299 (2014).","journal-title":"Cell"},{"key":"BFncomms11187_CR2","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1038\/nature07428","volume":"456","author":"E Byres","year":"2008","unstructured":"Byres, E. et al. Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin. Nature 456, 648\u2013652 (2008).","journal-title":"Nature"},{"key":"BFncomms11187_CR3","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1111\/j.1365-2958.2007.05791.x","volume":"65","author":"J Iyer","year":"2007","unstructured":"Iyer, J., Gruner, A. C., Renia, L., Snounou, G. & Preiser, P. R. Invasion of host cells by malaria parasites: a tale of two protein families. Mol. Microbiol. 65, 231\u2013249 (2007).","journal-title":"Mol. Microbiol."},{"key":"BFncomms11187_CR4","doi-asserted-by":"publisher","first-page":"14739","DOI":"10.1073\/pnas.0908196106","volume":"106","author":"A Varki","year":"2009","unstructured":"Varki, A. & Gagneux, P. Human-specific evolution of sialic acid targets: explaining the malignant malaria mystery? Proc. Natl Acad. Sci. USA 106, 14739\u201314740 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms11187_CR5","doi-asserted-by":"publisher","first-page":"11825","DOI":"10.1128\/JVI.74.24.11825-11831.2000","volume":"74","author":"Y Suzuki","year":"2000","unstructured":"Suzuki, Y. et al. Sialic acid species as a determinant of the host range of influenza A viruses. J. Virol. 74, 11825\u201311831 (2000).","journal-title":"J. Virol."},{"key":"BFncomms11187_CR6","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1007\/s00018-005-5589-y","volume":"63","author":"F Lehmann","year":"2006","unstructured":"Lehmann, F., Tiralongo, E. & Tiralongo, J. Sialic acid-specific lectins: occurrence, specificity and function. Cell. Mol. Life Sci. 63, 1331\u20131354 (2006).","journal-title":"Cell. Mol. Life Sci."},{"key":"BFncomms11187_CR7","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1021\/cr000407m","volume":"102","author":"T Angata","year":"2002","unstructured":"Angata, T. & Varki, A. Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem. Rev. 102, 439\u2013469 (2002).","journal-title":"Chem. Rev."},{"key":"BFncomms11187_CR8","doi-asserted-by":"publisher","first-page":"11751","DOI":"10.1073\/pnas.95.20.11751","volume":"95","author":"HH Chou","year":"1998","unstructured":"Chou, H. H. et al. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc. Natl Acad. Sci. USA 95, 11751\u201311756 (1998).","journal-title":"Proc. Natl Acad. Sci. 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USA"},{"key":"BFncomms11187_CR11","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1534\/genetics.105.046995","volume":"172","author":"T Hayakawa","year":"2006","unstructured":"Hayakawa, T., Aki, I., Varki, A., Satta, Y. & Takahata, N. Fixation of the human-specific CMP-N-acetylneuraminic acid hydroxylase pseudogene and implications of haplotype diversity for human evolution. Genetics 172, 1139\u20131146 (2006).","journal-title":"Genetics"},{"key":"BFncomms11187_CR12","doi-asserted-by":"publisher","first-page":"8902","DOI":"10.1073\/pnas.1001649107","volume":"107","author":"B Wood","year":"2010","unstructured":"Wood, B. Colloquium paper: reconstructing human evolution: achievements, challenges and opportunities. Proc. Natl Acad. Sci. USA 107, (suppl 2): 8902\u20138909 (2010).","journal-title":"Proc. Natl Acad. Sci. 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J. 13, 390 (2014).","journal-title":"Malar. J."},{"key":"BFncomms11187_CR20","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1093\/cid\/cis902","volume":"56","author":"BE Barber","year":"2013","unstructured":"Barber, B. E. et al. A prospective comparative study of knowlesi, falciparum, and vivax malaria in Sabah, Malaysia: high proportion with severe disease from Plasmodium knowlesi and Plasmodium vivax but no mortality with early referral and artesunate therapy. Clin. Infect. Dis. 56, 383\u2013397 (2013).","journal-title":"Clin. Infect. Dis."},{"key":"BFncomms11187_CR21","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1038\/ncomms2612","volume":"4","author":"C Lim","year":"2013","unstructured":"Lim, C. et al. Expansion of host cellular niche can drive adaptation of a zoonotic malaria parasite to humans. Nat. Commun. 4, 1638 (2013).","journal-title":"Nat. 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