Bat-derived influenza-like viruses H17N10 and H18N11
2014; Elsevier BV; Volume: 22; Issue: 4 Linguagem: Inglês
10.1016/j.tim.2014.01.010
ISSN1878-4380
AutoresYing Wu, Yan Wu, Boris Tefsen, Yi Shi, George F. Gao,
Tópico(s)Viral Infections and Outbreaks Research
Resumo•Bat-derived influenza-like virus hemagglutinin and neuraminidase lack canonical functions and structures.•Putative functional modules/domains in other bat-derived influenza-like proteins are conserved.•Potential genomic reassortments with canonical influenza virus cannot be ruled out and should be assessed. Shorebirds and waterfowls are believed to be the reservoir hosts for influenza viruses, whereas swine putatively act as mixing vessels. The recent identification of two influenza-like virus genomes (designated H17N10 and H18N11) from bats has challenged this notion. A crucial question concerns the role bats might play in influenza virus ecology. Structural and functional studies of the two major surface envelope proteins, hemagglutinin (HA) and neuraminidase (NA), demonstrate that neither has canonical HA or NA functions found in influenza viruses. However, putative functional modules and domains in other encoded proteins are conserved, and the N-terminal domain of the H17N10 polymerase subunit PA has a classical structure and function. Therefore, potential genomic reassortments of such influenza-like viruses with canonical influenza viruses cannot be excluded at this point and should be assessed. Shorebirds and waterfowls are believed to be the reservoir hosts for influenza viruses, whereas swine putatively act as mixing vessels. The recent identification of two influenza-like virus genomes (designated H17N10 and H18N11) from bats has challenged this notion. A crucial question concerns the role bats might play in influenza virus ecology. Structural and functional studies of the two major surface envelope proteins, hemagglutinin (HA) and neuraminidase (NA), demonstrate that neither has canonical HA or NA functions found in influenza viruses. However, putative functional modules and domains in other encoded proteins are conserved, and the N-terminal domain of the H17N10 polymerase subunit PA has a classical structure and function. Therefore, potential genomic reassortments of such influenza-like viruses with canonical influenza viruses cannot be excluded at this point and should be assessed. Influenza virus is a member of the Orthomyxoviridae family. There are three types of influenza virus based on its internal proteins of nucleoprotein and matrix protein, namely A, B, and C [1Palese P. Shaw M.L. Orthomyxoviridae: the viruses and their replication.in: Knipe D.M. Howley P.M. Fields Virology. 4th edn. Lippincott Williams & Wilkins, 2007: 1647-1690Google Scholar]. Among these, influenza A virus is the most prevalent pathogen for both humans and animals, causing the so-called seasonal flu. Influenza A virus was also the causative agent of four major pandemics, in other words the 1918 Spanish flu, 1957 Asian flu, 1968 Hong Kong flu, and the 2009 swine-origin pandemic flu (2009 pH1N1), as well as of the relatively milder pandemic, the 1977 Russian flu [2Cox N.J. Subbarao K. Global epidemiology of influenza: past and present.Annu. Rev. Med. 2000; 51: 407-421Crossref PubMed Scopus (637) Google Scholar, 3Kobasa D. et al.Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus.Nature. 2004; 431: 703-707Crossref PubMed Scopus (411) Google Scholar, 4Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team Emergence of a novel swine-origin influenza A (H1N1) virus in humans.N. Engl. J. Med. 2009; 360: 2605-2615Crossref PubMed Scopus (2762) Google Scholar]. For the origin, genesis and ecology of influenza viruses, migratory birds (shorebirds and waterfowls) are regarded as reservoir hosts, providing a large pool of virus gene segments that can contribute to novel reassortant viruses [5Webster R.G. et al.Evolution and ecology of influenza A viruses.Microbiol. Rev. 1992; 56: 152-179Crossref PubMed Google Scholar, 6Hale B.G. et al.Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein.Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 1954-1959Crossref PubMed Scopus (92) Google Scholar, 7Liu D. et al.Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses.Lancet. 2013; 381: 1926-1932Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar]. Meanwhile, swine are believed to be 'mixing vessels' or at least intermediate hosts that influenza A viruses can utilize to 'jump' from poultry to humans [5Webster R.G. et al.Evolution and ecology of influenza A viruses.Microbiol. Rev. 1992; 56: 152-179Crossref PubMed Google Scholar]. Influenza A virus is an enveloped negative-stranded RNA virus, with a segmented genome of 8 pieces, which encode a total of 14 proteins [8Liu X. et al.Insights into the roles of cyclophilin A during influenza virus infection.Viruses. 2013; 5: 182-191Crossref PubMed Scopus (28) Google Scholar]. There are three major envelope proteins embedded in the virus surface: hemagglutinin (HA), neuraminidase (NA), and matrix protein 2 (M2) [5Webster R.G. et al.Evolution and ecology of influenza A viruses.Microbiol. Rev. 1992; 56: 152-179Crossref PubMed Google Scholar]. HA is responsible for virus binding to susceptible cells, which harbor sialylated proteins (as virus receptors), eventually resulting in fusion to and entry into the cells. NA is a sialidase that enables mature viruses to be released from infected cells [5Webster R.G. et al.Evolution and ecology of influenza A viruses.Microbiol. Rev. 1992; 56: 152-179Crossref PubMed Google Scholar]. To date 16 HA subtypes and nine NA subtypes have been identified (Figure 1), and the different reassorted combinations are used to name the viruses, for example, the common seasonal flu viruses H1N1, H2N2, H3N2, and the sporadic human infections with H5N1 and the recent H7N9 [9Palese P. Influenza: old and new threats.Nat. Med. 2004; 10: S82-S87Crossref PubMed Scopus (506) Google Scholar, 10Beigel J.H. et al.Avian influenza A (H5N1) infection in humans.N. Engl. J. Med. 2005; 353: 1374-1385Crossref PubMed Scopus (1193) Google Scholar, 11Gao R. et al.Human infection with a novel avian-origin influenza A (H7N9) virus.N. Engl. J. Med. 2013; 368: 1888-1897Crossref PubMed Scopus (2022) Google Scholar]. In 2012, an astonishing story published in Proc. Natl. Acad. Sci. USA [12Tong S. et al.A distinct lineage of influenza A virus from bats.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 4269-4274Crossref PubMed Scopus (841) Google Scholar] caused some concerns because a new influenza virus genome (H17N10) was isolated from bats by next-generation sequencing (NGS). This raised a serious scientific and public health question as to the origin and evolution of influenza virus. If this genome can produce a real influenza virus that can cause human or animal infections, then the situation for influenza virus-caused diseases would be more complicated because bats are known to harbor many viruses and are regarded as a reservoir host for many human- and animal-infecting viruses, including the SARS (severe acute respiratory syndrome) coronavirus [13Shi Z. Emerging infectious diseases associated with bat viruses.Sci. China Life Sci. 2013; 56: 678-682Crossref PubMed Scopus (39) Google Scholar]. If this is the case, then our understanding of the influenza virus ecology will need to be rewritten. Therefore research on this NGS-identified novel genome is urgently needed for the sake of public health. Studies on the two surface envelope proteins, HA and NA (NA-like) [14Kowalinski E. et al.Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of influenza pH1N1 (2009) polymerase.PLoS Pathog. 2012; 8: e1002831Crossref PubMed Scopus (148) Google Scholar, 15Zhu X. et al.Crystal structures of two subtype N10 neuraminidase-like proteins from bat influenza A viruses reveal a diverged putative active site.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 18903-18908Crossref PubMed Scopus (106) Google Scholar, 16Sun X. et al.Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism.Cell Rep. 2013; 3: 769-778Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 17Zhu X. et al.Hemagglutinin homologue from H17N10 bat influenza virus exhibits divergent receptor-binding and pH-dependent fusion activities.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 1458-1463Crossref PubMed Scopus (134) Google Scholar], demonstrate that neither protein has the corresponding canonical influenza virus functions or structures [18Garcia-Sastre A. The neuraminidase of bat influenza viruses is not a neuraminidase.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 18635-18636Crossref PubMed Scopus (25) Google Scholar]. Therefore the new genome does not represent a 'true' influenza virus, and it should be renamed influenza-like virus, at most. Whether or not the genomic segments will reassort with canonical influenza A virus genomes should be vigorously tested in the near future. Recently a similar virus genome, H18N11, was again identified by NGS, and neither HA nor NA have canonical structures or functions [19Tong S. et al.New world bats harbor diverse influenza A viruses.PLoS Pathog. 2013; 9: e1003657Crossref PubMed Scopus (1002) Google Scholar]. In this review we summarize recent work on the functions and structures of both HA and NA derived from H17N10 and H18N11. In addition, all influenza proteins are examined using bioinformatics, and proteins from the six internal genes of the H17N10/H18N11 genomes are shown to conserve known structural and functional modules or domains. We also further discuss our recent work on the N-terminal domain of the polymerase subunit PA. We believe that the functions and structures of all the encoded proteins should be examined in detail to understand these influenza-like viruses better. Moreover, their reassortment potential should be assessed by reverse genetics experiments. HA is the receptor binding protein of the influenza A virus, and is responsible for virus entry into host cells. Before the discovery of the H17 and H18 genes there were 16 subtypes of HA described, H1–H16. Based on their primary sequences, these HA molecules can be categorized into two groups (Figure 1): group 1 (H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18) and group 2 (H3, H4, H7, H10, H14, and H15) [12Tong S. et al.A distinct lineage of influenza A virus from bats.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 4269-4274Crossref PubMed Scopus (841) Google Scholar, 19Tong S. et al.New world bats harbor diverse influenza A viruses.PLoS Pathog. 2013; 9: e1003657Crossref PubMed Scopus (1002) Google Scholar, 20Air G.M. Sequence relationships among the hemagglutinin genes of 12 subtypes of influenza A virus.Proc. Natl. Acad. Sci. U.S.A. 1981; 78: 7639-7643Crossref PubMed Scopus (132) Google Scholar, 21Nobusawa E. et al.Comparison of complete amino acid sequences and receptor-binding properties among 13 serotypes of hemagglutinins of influenza A viruses.Virology. 1991; 182: 475-485Crossref PubMed Scopus (444) Google Scholar, 22Gamblin S.J. Skehel J.J. Influenza hemagglutinin and neuraminidase membrane glycoproteins.J. Biol. Chem. 2010; 285: 28403-28409Crossref PubMed Scopus (456) Google Scholar]. Bat-derived H17 and H18 should be placed into group 1 based on their primary sequences (Figure 1) [12Tong S. et al.A distinct lineage of influenza A virus from bats.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 4269-4274Crossref PubMed Scopus (841) Google Scholar, 16Sun X. et al.Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism.Cell Rep. 2013; 3: 769-778Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 17Zhu X. et al.Hemagglutinin homologue from H17N10 bat influenza virus exhibits divergent receptor-binding and pH-dependent fusion activities.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 1458-1463Crossref PubMed Scopus (134) Google Scholar, 19Tong S. et al.New world bats harbor diverse influenza A viruses.PLoS Pathog. 2013; 9: e1003657Crossref PubMed Scopus (1002) Google Scholar]. As expected from their primary sequences, the H17 and H18 structures resemble the structures of group 1 HAs rather than those of group 2. Previously solved HA structures demonstrate that there are group-specific features at sites where extensive conformational changes occur for HA activation, including the conformation of the interhelix loop and the rigid body orientation of the globular domain [22Gamblin S.J. Skehel J.J. Influenza hemagglutinin and neuraminidase membrane glycoproteins.J. Biol. Chem. 2010; 285: 28403-28409Crossref PubMed Scopus (456) Google Scholar]. Taking H17 as an example, it displays a similar interhelix loop conformation to the HAs from group 1, and this is consistent with the phylogenetic analysis. Superimposition with other solved HA structures by means of the long central α-helices of HA2 revealed that the globular domains fall into three subgroups [16Sun X. et al.Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism.Cell Rep. 2013; 3: 769-778Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 23Lu X. et al.Structure and receptor binding specificity of hemagglutinin H13 from avian influenza A virus H13N6.J. Virol. 2013; 87: 9077-9085Crossref PubMed Scopus (17) Google Scholar]: subgroup 1, including H1, H2, H5, and H9; subgroup 2, including H3, H7, and H14; and subgroup 3, consisting of H13, H16, H17 and H18. These differences may result from subtle variation in the interhelix loops among different HA subtypes and could signify different mechanisms during HA activation [16Sun X. et al.Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism.Cell Rep. 2013; 3: 769-778Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 23Lu X. et al.Structure and receptor binding specificity of hemagglutinin H13 from avian influenza A virus H13N6.J. Virol. 2013; 87: 9077-9085Crossref PubMed Scopus (17) Google Scholar]. Influenza A virus enters susceptible cells through endocytosis after binding to cell surface receptors [24Sauter N.K. et al.Hemagglutinins from two influenza virus variants bind to sialic acid derivatives with millimolar dissociation constants: a 500 MHz proton nuclear magnetic resonance study.Biochemistry. 1989; 28: 8388-8396Crossref PubMed Scopus (326) Google Scholar, 25Takemoto D.K. et al.A surface plasmon resonance assay for the binding of influenza virus hemagglutinin to its sialic acid receptor.Virology. 1996; 217: 452-458Crossref PubMed Scopus (107) Google Scholar, 26Gambaryan A.S. et al.Specification of receptor-binding phenotypes of influenza virus isolates from different hosts using synthetic sialylglycopolymers: non-egg-adapted human H1 and H3 influenza A and influenza B viruses share a common high binding affinity for 6′-sialyl(N-acetyllactosamine).Virology. 1997; 232: 345-350Crossref PubMed Scopus (244) Google Scholar]. The receptors for influenza A viruses are sialic acids (SA) linked to cell surface glycolipids or glycoproteins [24Sauter N.K. et al.Hemagglutinins from two influenza virus variants bind to sialic acid derivatives with millimolar dissociation constants: a 500 MHz proton nuclear magnetic resonance study.Biochemistry. 1989; 28: 8388-8396Crossref PubMed Scopus (326) Google Scholar, 25Takemoto D.K. et al.A surface plasmon resonance assay for the binding of influenza virus hemagglutinin to its sialic acid receptor.Virology. 1996; 217: 452-458Crossref PubMed Scopus (107) Google Scholar, 26Gambaryan A.S. et al.Specification of receptor-binding phenotypes of influenza virus isolates from different hosts using synthetic sialylglycopolymers: non-egg-adapted human H1 and H3 influenza A and influenza B viruses share a common high binding affinity for 6′-sialyl(N-acetyllactosamine).Virology. 1997; 232: 345-350Crossref PubMed Scopus (244) Google Scholar]. After entering the cells, the virus fuses with the endosomal membrane under low pH and subsequently the genetic material is released into the cell [22Gamblin S.J. Skehel J.J. Influenza hemagglutinin and neuraminidase membrane glycoproteins.J. Biol. Chem. 2010; 285: 28403-28409Crossref PubMed Scopus (456) Google Scholar, 27Bullough P.A. et al.Structure of influenza haemagglutinin at the pH of membrane fusion.Nature. 1994; 371: 37-43Crossref PubMed Scopus (1420) Google Scholar, 28Harrison S.C. Viral membrane fusion.Nat. Struct. Mol. Biol. 2008; 15: 690-698Crossref PubMed Scopus (982) Google Scholar, 29Skehel J.J. Wiley D.C. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin.Annu. Rev. Biochem. 2000; 69: 531-569Crossref PubMed Scopus (2300) Google Scholar, 30Wiley D.C. Skehel J.J. The structure and function of the hemagglutinin membrane glycoprotein of influenza virus.Annu. Rev. Biochem. 1987; 56: 365-394Crossref PubMed Scopus (1267) Google Scholar]. Avian- and human-adapted influenza A viruses harbor distinct HA molecules that have different capacities to bind specifically linked SA-moieties. In Figure 2, the configurations of the α-2,3-linked SA and α-2,6-linked SA are shown. The molecular basis of the interaction of these specific receptors with the virus-derived HA has been extensively studied [22Gamblin S.J. Skehel J.J. Influenza hemagglutinin and neuraminidase membrane glycoproteins.J. Biol. Chem. 2010; 285: 28403-28409Crossref PubMed Scopus (456) Google Scholar, 27Bullough P.A. et al.Structure of influenza haemagglutinin at the pH of membrane fusion.Nature. 1994; 371: 37-43Crossref PubMed Scopus (1420) Google Scholar, 28Harrison S.C. Viral membrane fusion.Nat. Struct. Mol. Biol. 2008; 15: 690-698Crossref PubMed Scopus (982) Google Scholar, 29Skehel J.J. Wiley D.C. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin.Annu. Rev. Biochem. 2000; 69: 531-569Crossref PubMed Scopus (2300) Google Scholar, 30Wiley D.C. Skehel J.J. The structure and function of the hemagglutinin membrane glycoprotein of influenza virus.Annu. Rev. Biochem. 1987; 56: 365-394Crossref PubMed Scopus (1267) Google Scholar]. In the trimeric structure of the HA, resolved as early as in 1981 in an outstanding collaborative work by Wilson, Wiley, and Skehel [31Wilson I.A. et al.Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution.Nature. 1981; 289: 366-373Crossref PubMed Scopus (2105) Google Scholar], the HA head domain of each monomer was shown to be responsible for SA binding. We now know that there are three secondary elements and one base element involved directly in SA binding. The three secondary elements (the 130-loop, the 190-helix, and the 220-loop, in H3 numbering) form the edge portion, and four conserved residues (Y98, W153, H183, and Y195) form the base portion. These two portions usually form a shallow cavity to accommodate sialylated glycans. Typically, the SA moiety of the sialylated glycan forms several conserved hydrogen bonds with the 130-loop and the base residue Y98, and the remaining glycan moieties interact with the 220-loop or 190-helix. Substitution of the residues in the three secondary elements is important for the HA protein to obtain avian or human SA receptor preference. Different HA subtypes use different substitutions to achieve this goal. For H2 and H3 HAs, Q226L and G228S substitutions in the 220-loop are responsible for the switch between avian and human receptor binding specificities [30Wiley D.C. Skehel J.J. The structure and function of the hemagglutinin membrane glycoprotein of influenza virus.Annu. Rev. Biochem. 1987; 56: 365-394Crossref PubMed Scopus (1267) Google Scholar, 32Liu J. et al.Structures of receptor complexes formed by hemagglutinins from the Asian Influenza pandemic of 1957.Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 17175-17180Crossref PubMed Scopus (157) Google Scholar] whereas, for H1 HA, different combinations of substitutions at residues 190 and 225 are important for the SA binding preference [33Zhang W. et al.Molecular basis of the receptor binding specificity switch of the hemagglutinins from both the 1918 and 2009 pandemic influenza A viruses by a D225G substitution.J. Virol. 2013; 87: 5949-5958Crossref PubMed Scopus (57) Google Scholar, 34Gamblin S.J. et al.The structure and receptor binding properties of the 1918 influenza hemagglutinin.Science. 2004; 303: 1838-1842Crossref PubMed Scopus (607) Google Scholar]. For H5 HA, a single Q226L substitution is enough to change the receptor binding preference [35Zhang W. et al.An airborne transmissible avian influenza H5 hemagglutinin seen at the atomic level.Science. 2013; 340: 1463-1467Crossref PubMed Scopus (103) Google Scholar, 36Xiong X. et al.Receptor binding by a ferret-transmissible H5 avian influenza virus.Nature. 2013; 497: 392-396Crossref PubMed Scopus (177) Google Scholar]. By contrast, for H7 HAs, Q226L substitution is not solely responsible for the acquisition of human receptor binding, and other amino acid substitutions also contribute to the receptor binding switch, especially G186 V substitution [37Shi Y. et al.Structures and receptor binding of hemagglutinins from human-infecting H7N9 influenza viruses.Science. 2013; 342: 243-247Crossref PubMed Scopus (226) Google Scholar, 38Xiong X. et al.Receptor binding by an H7N9 influenza virus from humans.Nature. 2013; 499: 496-499Crossref PubMed Scopus (267) Google Scholar]. Multiple lines of evidence, including surface plasmon resonance (SPR) experiments, MDCK cell binding assays, and glycan microarray analysis, revealed that the bat-derived H17 and H18 do not bind to canonical human or avian receptors [16Sun X. et al.Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism.Cell Rep. 2013; 3: 769-778Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 17Zhu X. et al.Hemagglutinin homologue from H17N10 bat influenza virus exhibits divergent receptor-binding and pH-dependent fusion activities.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 1458-1463Crossref PubMed Scopus (134) Google Scholar, 19Tong S. et al.New world bats harbor diverse influenza A viruses.PLoS Pathog. 2013; 9: e1003657Crossref PubMed Scopus (1002) Google Scholar]. This lack of canonical receptor binding is likely due to specific structural features in the putative receptor binding sites of H17 and H18 HA. In the H17 and H18 structures (Figure 3) there is no obvious cavity to accommodate the sialylated glycans, due to strong interactions among three secondary elements (130-loop, 190-helix, and 220-loop) through a hydrogen bond and salt bridge network formed by residues D136, Q190, H226, and D228 [16Sun X. et al.Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism.Cell Rep. 2013; 3: 769-778Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 19Tong S. et al.New world bats harbor diverse influenza A viruses.PLoS Pathog. 2013; 9: e1003657Crossref PubMed Scopus (1002) Google Scholar]. Furthermore, the negatively charged D136 in the 130-loop (all canonical influenza HAs have an uncharged threonine or serine at this position) could result in a charge conflict with the negatively charged carboxyl group of SA, which is unfavorable for SA receptor binding [16Sun X. et al.Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism.Cell Rep. 2013; 3: 769-778Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 19Tong S. et al.New world bats harbor diverse influenza A viruses.PLoS Pathog. 2013; 9: e1003657Crossref PubMed Scopus (1002) Google Scholar]. Moreover, residue 98 (usually a conserved tyrosine) in the base of the receptor binding site is a phenylalanine in H17 and H18, and this could also affect SA receptor binding capacity. Thus, these five key residues likely contribute to the lack of SA receptor binding by H17 and H18 and make the putative binding cavity a much smaller, pseudo-binding site (a 'closed' site) (Figure 3). The possibility remains that we may have not detected the binding of H17 and H18 to canonical human or avian receptors using the soluble protein in vitro because it is plausible that a stronger interaction may occur through receptor clustering in vivo. It is also possible that H17 and H18 may bind to canonical influenza receptors very weakly, below the level of our detection (which is a limitation of the available methods). However, together with the extensive amino acid changes in the receptor binding site of H17 and H18 protein, it is likely that the putative bat influenza virus has acquired a different receptor, possibly protein-based. There are many examples of closely related viruses that switch between protein and SA receptors, for example, paramyxoviruses. The most common type of the paramyxovirus attachment protein recognizes SA receptors. It is called hemagglutinin–neuraminidase (HN) and is found on viruses such as Newcastle disease virus (NDV) and human parainfluenza virus 3 (hPIV3), and recognizes SA receptors. The structures of the globular heads of HN proteins display a conserved β-sheet propeller motif, which was identified originally in influenza virus NA, and an SA binding site located in the central cavity of the proteins [39Lawrence M.C. et al.Structure of the haemagglutinin–neuraminidase from human parainfluenza virus type III.J. Mol. Biol. 2004; 335: 1343-1357Crossref PubMed Scopus (198) Google Scholar, 40Yuan P. et al.Structure of the Newcastle disease virus hemagglutinin–neuraminidase (HN) ectodomain reveals a four-helix bundle stalk.Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 14920-14925Crossref PubMed Scopus (144) Google Scholar]. Unlike HN, the hemagglutinin (H) of measles virus (MV), which also belongs to the Paramyxoviridae family, possesses an inactivated SA receptor binding site and recognizes specific proteins, such as signal lymphocyte-activating molecule (SLAM), CD46, and nectin-4 [41Naniche D. et al.Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus.J. Virol. 1993; 67: 6025-6032Crossref PubMed Google Scholar, 42Tatsuo H. et al.SLAM (CDw150) is a cellular receptor for measles virus.Nature. 2000; 406: 893-897Crossref PubMed Scopus (887) Google Scholar, 43Muhlebach M.D. et al.Adherens junction protein nectin-4 is the epithelial receptor for measles virus.Nature. 2011; 480: 530-533PubMed Google Scholar]. The structure of the globular heads of H protein still reveals a conserved β-sheet propeller motif, and the specific protein receptors bind to the side part of H protein with different orientations [44Zhang X. et al.Structure of measles virus hemagglutinin bound to its epithelial receptor nectin-4.Nat. Struct. Mol. Biol. 2013; 20: 67-72Crossref PubMed Scopus (76) Google Scholar]. In particular, the immunoglobulin (Ig)-like SLAM molecule binds to the H protein mainly through interactions between two β-sheets. Interestingly, the bat-derived influenza-like virus H17/H18 and N10/N11 proteins have similar Ig-like fold elements [14Kowalinski E. et al.Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of influenza pH1N1 (2009) polymerase.PLoS Pathog. 2012; 8: e1002831Crossref PubMed Scopus (148) Google Scholar, 15Zhu X. et al.Crystal structures of two subtype N10 neuraminidase-like proteins from bat influenza A viruses reveal a diverged putative active site.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 18903-18908Crossref PubMed Scopus (106) Google Scholar, 16Sun X. et al.Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism.Cell Rep. 2013; 3: 769-778Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 17Zhu X. et al.Hemagglutinin homologue from H17N10 bat influenza virus exhibits divergent receptor-binding and pH-dependent fusion activities.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 1458-1463Crossref PubMed Scopus (134) Google Scholar, 19Tong S. et al.New world bats harbor diverse influenza A viruses.PLoS Pathog. 2013; 9: e1003657Crossref PubMed Scopus (1002) Google Scholar], which possibly provide the β-sheets that could interact with putative protein-based receptors. If the H17 and H18 protein should lose its trimerization state and expose its Ig-like fold element, it might be able to bind a specific protein receptor. In this case, the bat-derived influenza-like virus would abrogate the need for an active N10 and N11. This hypothesis or notion needs further experimental work to be confirmed or rejected. Thus, the bat-derived H17 and H18 are unique among the characterized HAs and might use a different entry mechanism. NA is the second virus-surface envelope protein and is a sialidase, responsible for cleavage of SA from glycans on the host cell surface to release the emerging progeny virus, prevent virus aggregation, and help virus migration [45Palese P. et al.Characterization of temperature sensitive influenza virus mutants defective in neuraminidase.Virology. 1974; 61: 397-410Crossref PubMed Scopus (655) Google Scholar, 46Liu C. et al.Influenza type A virus neuraminidase does not play a role in viral entry, replication, assembly, or budding.J. Virol. 1995; 69: 1099-1106Crossref PubMed Google Scholar]. Therefore it has an opposite function from HA, SA-binding versus SA-releasing. If bat-derived HA does not bind SA, consequently it would have no need for a sialidase to help release the virus particles. There are nine subtypes (N1–N9) of NA identified so far, before the discovery of the NA-like N10 or N11 genes from bat. Similarly to HA, NA has also been classified into two groups, group
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