Alterations in hemagglutinin receptor-binding specificity accompany the emergence of highly pathogenic avian influenza viruses.
Highly pathogenic avian influenza viruses (HPAIVs) of hemagglutinin H5 and H7 subtypes emerge after introduction of low-pathogenic avian influenza viruses (LPAIVs) from wild birds into poultry flocks, followed by subsequent circulation and evolution. The acquisition of multiple basic amino acids at the endoproteolytical cleavage site of the hemagglutinin (HA) is a molecular indicator for high pathogenicity, at least for infections of gallinaceous poultry. Apart from the well-studied significance of the multibasic HA cleavage site, there is only limited knowledge on other alterations in the HA and neuraminidase (NA) molecules associated with changes in tropism during the emergence of HPAIVs from LPAIVs. We hypothesized that changes in tropism may require alterations of the sialyloligosaccharide specificities of HA and NA. To test this hypothesis, we compared a number of LPAIVs and HPAIVs for their HA-mediated binding and NA-mediated desialylation of a set of synthetic receptor analogs, namely, α2-3-sialylated oligosaccharides. NA substrate specificity correlated with structural groups of NAs and did not correlate with pathogenic potential of the virus. In contrast, all HPAIVs differed from LPAIVs by a higher HA receptor-binding affinity toward the trisaccharides Neu5Acα2-3Galβ1-4GlcNAcβ (3'SLN) and Neu5Acα2-3Galβ1-3GlcNAcβ (SiaLe(c)) and by the ability to discriminate between the nonfucosylated and fucosylated sialyloligosaccharides 3'SLN and Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ (SiaLe(x)), respectively. These results suggest that alteration of the receptor-binding specificity accompanies emergence of the HPAIVs from their low-pathogenic precursors.


OBJECTIVE
Here, we have found for the first time correlations of receptor-binding properties of the HA with a highly pathogenic phenotype of poultry viruses. Our study suggests that enhanced receptor-binding affinity of HPAIVs for a typical "poultry-like" receptor, 3'SLN, is provided by substitutions in the receptor-binding site of HA which appeared in HA of LPAIVs in the course of transmission of LPAIVs from wild waterfowl into poultry flocks, with subsequent adaptation in poultry. The identification of LPAIVs with receptor characteristics of HPAIVs argues that the sialic acid-binding specificity of the HA may be used as a novel phenotypic marker of HPAIVs.
Robert Koch Institute, Division for Influenza Viruses and Other Respiratory Viruses, Berlin, Germany HeiderA@rki.de.
Alla
A
Heider
A. N. Belozersky Institute of Physical-Chemical Biology of Lomonosov Moscow State University, Moscow, Russia.
Larisa
L
Mochalova
Institute of Diagnostic Virology, Friedrich Loeffler Institute, Greifswald-Insel Riems, Germany.
Timm
T
Harder
Shemyakin Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
Alexander
A
Tuzikov
Shemyakin Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
Nicolai
N
Bovin
Robert Koch Institute, Division for Influenza Viruses and Other Respiratory Viruses, Berlin, Germany.
Thorsten
T
Wolff
Institute of Virology, Philipps University, Marburg, Germany.
Mikhail
M
Matrosovich
Robert Koch Institute, Division for Influenza Viruses and Other Respiratory Viruses, Berlin, Germany.
Brunhilde
B
Schweiger
D000595:Amino Acid Sequence; D000818:Animals; D000835:Animals, Wild / Q000821:virology; D046090:Anseriformes / Q000821:virology; D002240:Carbohydrate Sequence; D005814:Genes, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009980:Influenza A virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D005585:Influenza in Birds / Q000821:virology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009439:Neuraminidase / Q000378:metabolism; D009844:Oligosaccharides / Q000378:metabolism; D010802:Phylogeny; D011200:Poultry / Q000821:virology; D011485:Protein Binding; D011991:Receptors, Virus / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014774:Virulence / Q000502:physiology
D019267:Hemagglutinin Glycoproteins, Influenza Virus; D009844:Oligosaccharides; D011991:Receptors, Virus; C109963:hemagglutinin, avian influenza A virus; C016735:sialooligosaccharides; D009439:Neuraminidase