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J. Biol. Chem., Vol. 278, Issue 48, 48245-48250, November 28, 2003

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Human-specific Regulation of 2–6-linked Sialic Acids^*

Pascal Gagneux, Monica Cheriyan, Nancy Hurtado-Ziola, Els C. M. Brinkman van der Linden, Dan Anderson¶, Harold McClure¶, Ajit Varki, and Nissi M. Varki||

From the Glycobiology Research and Training Center, Departments of Medicine and Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093-0687 and ^¶Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329

Many microbial pathogens and toxins recognize animal cells via cell surface sialic acids (Sias) that are 2–3- or 2–8-linked to the underlying glycan chain. Human influenza A/B viruses are unusual in preferring 2–6-linked Sias, undergoing a switch from 2–3 linkage preference during adaptation from animals to humans. This correlates with the expression of 2–6-linked Sias on ciliated human airway epithelial target cells and of 2–3-linked Sias on secreted soluble airway mucins, which are unable to inhibit virus binding. Given several known differences in Sia biology between humans and apes, we asked whether this pattern of airway epithelial Sia linkages is also human-specific. Indeed, we show that since the last common ancestor with apes, humans underwent a concerted bidirectional switch in 2–6-linked Sia expression between airway epithelial cell surfaces and secreted mucins. This can explain why the chimpanzee appears relatively resistant to experimental infection with human Influenza viruses. Other tissues showed additional examples of human-specific increases or decreases in 2–6-linked Sia expression and only one example of a change specific to certain great apes. Furthermore, while human and great ape leukocytes both express 2–6-linked Sias, only human erythrocytes have markedly up-regulated expression. These cell type-specific changes in 2–6-Sia expression during human evolution represent another example of a human-specific change in Sia biology. Because the data set involves multiple great apes, we can also conclude that Sia linkage expression patterns can be conserved during millions of years of evolution within some vertebrate taxa while undergoing sudden major changes in other closely related ones.

Received for publication, September 4, 2003 , and in revised form, September 18, 2003.

^* This work was supported in part by U. S. Public Health Service Grant R01-GM323373, Yerkes National Institutes of Health Base Grant RR00165, American Lung Association Research Training Fellowship Award RT043N, and National Institutes of Health Training Grant 5T32DK07202 (to P. G.) and by the G. Harold and Leila Y. Mathers Charitable Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Tables A and B.

Present address: Center for Research on Endangered Species, The San Diego Zoo, P.O. Box 120551, San Diego, CA 92112.

Present address: Neose Technologies, Inc., 6330 Nancy Ridge, San Diego, CA 92121.

^|| To whom correspondence should be addressed. Tel.: 858-534-4933; Fax: 858-534-5611; E-mail: nvarki{at}ucsd.edu.

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