Alterations in Hemagglutinin Receptor-Binding Specificity Accompany the Emergence of Highly Pathogenic Avian Influenza Viruses

Abstract

Highly pathogenic avian influenza viruses (HPAIVs) of hemagglutinin H5 and H7 subtypes emerge after introduction of lowpathogenic 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, ␣2-3-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 Neu5Ac␣2-3Gal␤1-4GlcNAc␤ (3=SLN) and Neu5Ac␣2-3Gal␤1-3GlcNAc␤ (SiaLe c ) and by the ability to discriminate between the nonfucosylated and fucosylated sialyloligosaccharides 3=SLN and Neu5Ac␣2-3Gal␤1-4(Fuc␣1-3)GlcNAc␤ (SiaLe x ), respectively. These results suggest that alteration of the receptor-binding specificity accompanies emergence of the HPAIVs from their low-pathogenic precursors. A vian influenza is a highly contagious infection with influenza A viruses, with a worldwide occurrence in aquatic wild bird populations which represent the major natural hosts of these viruses. Influenza A viruses are classified into subtypes according to their surface glycoproteins: 18 hemagglutinin (HA) and 11 neuraminidase (NA) antigenic subtypes have been identified (1, 2, 3). Avian influenza viruses (AIVs) are subdivided into groups of high and low pathogenicity. The presence of multiple basic amino acids at the endoproteolytical cleavage site of the HA is a molecular indicator for high pathogenicity, at least for infections of gallinaceous poultry (4,5,6,7,8). Influenza viruses of HA subtypes H5, H7, and H9 are commonly identified in terrestrial gallinaceous poultry (9, 10). Only low-pathogenic AIVs (LPAIVs) of subtypes H5 and H7 naturally evolve into highly pathogenic AIVs (HPAIVs), which cause severe infections with high rates of mortality in poultry (11,12,13,14) and can also be transmitted from birds to humans (15,16,17,18).The two viral glycoproteins, HA and NA, expressed on the surface of influenza virions play an important role in determining the pathogenic properties of the virus. Influenza virus infection is initiated by interactions between the viral HA and sialic acid-containing oligosaccharides on target cells. The NA cleaves off the terminal si...

Amino acid residues at positions 222 and 227 of the hemagglutinin together with the neuraminidase determine binding of H5 avian influenza viruses to sialyl Lewis X

“…Previous studies suggested that the functional balance between HA (receptor binding) and NA (receptor destroying) contributes to pathogenicity and host range of influenza A viruses [28]. Nevertheless, the mechanism by which NA contributes to virus–glycan interaction has not been extensively studied because analyses on interaction of NA with modified α2,3 sialosides are still limited [29]. …”

Influence of single amino acid substitutions in the hemagglutinin on the antigenic and receptor-binding properties of influenza virus B/Florida/04/2006 of Yamagata-like evolutionary lineage

“…It is necessary to point out that it is very important to monitor the receptor-binding characteristics of the circulating and emerging influenza A and B viruses because the repertoire of HA receptors defines tissue tropism and, consequently, virulence of the virus [5,6]. Thus, the patients infected with the influenza B virus strains that bind not only to the SAa2-6Gal-chains but also SAa2-3Gal ones (avian type) are prone to developing pneumonia and more often have the symptoms of gastrointestinal tract damage [11].…”

“…It is known that the avian influenza A viruses have an affinity predominantly for hydrocarbons with the a2-3 glycoside bond between SA and the neighboring galactose (GA) residue while the human influenza A viruses interact mostly with the SAa2-6Gal chains [1][2][3][4]. The receptor-binding specificity of the influenza A viruses had been studied in detail and it is considered to be one of the factors that influence virus pathogenicity [5,6]. As regards the receptor-binding specificity of influenza B viruses, there is rather limited data available [7][8][9].…”

Влияние Единичных Аминокислотных Замен В Гемагглютинине Вируса Гриппа В/Флорида/04/2006 Ямагатской Эволюционной Линии На Антигенные И Рецепторсвязывающие Свойства

“…Аминокислотный остаток в позиции 242 (замена Ser на Arg) также может влиять на репер-туар рецепторов вируса гриппа B/Флорида/04/2006. Необходимо подчеркнуть, что очень важно осу-ществлять мониторинг рецепторсвязывающих ха-рактеристик циркулирующих и вновь появляющих-ся штаммов вирусов гриппа как А, так и В, поскольку структура рецепторов вируса определяет его ткане-вой тропизм, а значит, и вирулентный фенотип [5,6]. Так, уже показано, что пациенты, инфицированные штаммами вируса гриппа В, которые связываются не только с SAα2-6Gal-звеньями, но и с сиалозидами «птичьего» типа (SAα2-3Gal), более склонны к раз-витию бронхопневмонии и чаще имели симптомы поражения желудочно-кишечного тракта [11].…”

“…Известно, что вирусы гриппа А птиц преимуще-ственно имеют сродство к углеводам с α2-3 гликозид-ной связью между SA и соседним остатком галактозы (Gal), тогда как вирусы гриппа А человека взаимодей-ствуют преимущественно с SAα2-6Gal-цепями [1][2][3][4]. Рецепторсвязывающая специфичность вирусов грип-па A детально изучена и считается одним из факто-ров патогенности [5,6]. Что касается вирусов гриппа В, то данных по рецепторсвязывающей специфично-сти НА этих вирусов крайне мало [7][8][9].…”