A two-amino acid substitution in the 1918 influenza virus hemagglutinin abolishes transmission of the pandemic virus

Authors: TUMPEY, TERRENCE - CDC, ATLANTA, GA; MAINES, TARONNA - CDC, ATLANTA, GA; VAN HOEVEN, NEAL - CDC, ATLANTA, GA; GLASER, LAUREL - MT SINAI SCHOOL MEDICINE; SOLORZANO, ALICIA - MT SINAI SCHOOL MEDICINE; PAPPAS, CLAUDIA - CDC, ATLANTA, GA; COX, NANCY - CDC, ATLANTA, GA; Swayne, David; PALESE, PETER - MT SINAI SCHOOL MEDICINE; KATZ, JACQUELINE - CDC, ATLANTA, GA; GARCIA-SASTRE, ADOLFO - MT SINAI SCHOOL MEDICINE

Submitted to: Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/13/2006
Publication Date: 2/2/2007
Citation: Tumpey, T.M., Maines, T.R., Van Hoeven, N., Glaser, L., Solorzano, A., Pappas, C., Cox, N.J., Swayne, D.E., Palese, P., Katz, J.M., Garcia-Sastre, A. 2007. A two-amino acid change in the hemagglutinin of the 1918 influenza virus abolishes transmission. Science. 315(5812):655-659.

Interpretive Summary: The 1918 human influenza pandemic was a catastrophic series of outbreaks that spread across the globe. In this animal model study, we report how a modest change in the virus altered human-to-human transmission of the virus. By changing the virus hemagglutinin to bind to bird cells or a combination of bird and human cells, the transmission stopped between ferrets, a model for human influenza infection, but did not prevent virus growth or death in ferrets if given the virus directly in the nasal cavity. However, when the hemagglutinin was changed to bind only human cells, efficient ferret-to-ferret transmission occurred. These findings identify an essential role of hemagglutinin receptor specificity for the transmission of influenza viruses in mammals.

Technical Abstract: The 1918 influenza pandemic was a catastrophic series of virus outbreaks that spread across the globe. Herein we show that only a modest change in the 1918 influenza hemagglutinin receptor binding site alters the transmissibility of this pandemic virus. Two amino acid mutations that cause a switch from the human alpha2,6 to the avian alpha2,3 sialic acid receptor binding preference resulted in a virus incapable of respiratory droplet transmission between ferrets, but that maintained its lethality and replication efficiency in the upper respiratory tract. Furthermore, poor transmission of a 1918 virus with dual alpha2,6/alpha2,3 specificity suggests that a predominant human alpha2,6 sialic acid binding preference is essential for optimal transmission of this pandemic virus. These findings identify an essential role of hemagglutinin receptor specificity for the transmission of influenza viruses in mammals.