An Open Receptor-Binding Cavity of Hemagglutinin-Esterase-Fusion Glycoprotein from Newly-Identified Influenza D Virus: Basis for Its Broad Cell Tropism
Influenza viruses cause seasonal flu each year and pandemics or epidemic sporadically, posing a major threat to public health. Recently, a new influenza D virus (IDV) was isolated from pigs and cattle. Here, we reveal that the IDV utilizes 9-O-acetylated sialic acids as its receptor for virus entry. Then, we determined the crystal structures of hemagglutinin-esterase-fusion glycoprotein (HEF) of IDV both in its free form and in complex with the receptor and enzymatic substrate analogs. The IDV HEF shows an extremely similar structural fold as the human-infecting influenza C virus (ICV) HEF. However, IDV HEF has an open receptor-binding cavity to accommodate diverse extended glycan moieties. This structural difference provides an explanation for the phenomenon that the IDV has a broad cell tropism. As IDV HEF is structurally and functionally similar to ICV HEF, our findings highlight the potential threat of the virus to public health.
References
[1]
Bouvier NM, Palese P. The biology of influenza viruses. Vaccine. 2008;26 Suppl 4:D49–53. pmid:19230160; PubMed Central PMCID: PMC3074182. doi: 10.1016/j.vaccine.2008.07.039
[2]
Cohen M, Zhang X-Q, Senaati HP, Chen H-W, Varki NM, Schooley RT, et al. Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase. Virology Journal. 2013;10. doi: 10.1186/1743-422x-10-321 pmid:WOS:000327877500001.
[3]
Muraki Y, Hongo S. The molecular virology and reverse genetics of influenza C virus. Japanese journal of infectious diseases. 2010;63(3):157–65. pmid:20495266.
[4]
Muchmore EA, Varki A. Selective inactivation of influenza C esterase: a probe for detecting 9-O-acetylated sialic acids. Science. 1987;236(4806):1293–5. pmid:3589663. doi: 10.1126/science.3589663
[5]
Kauppila J, R？nkk？ E, Juvonen R, Saukkoriipi A, Saikku P, Bloigu A, et al. Influenza C virus infection in military recruits—symptoms and clinical manifestation. Journal of medical virology. 2014;86(5):879–85. doi: 10.1002/jmv.23756. pmid:24122799
[6]
Matsuzaki Y, Abiko C, Mizuta K, Sugawara K, Takashita E, Muraki Y, et al. A nationwide epidemic of influenza C virus infection in Japan in 2004. J Clin Microbiol. 2007;45(3):783–8. Epub 2007/01/12. doi: 10.1128/jcm.01555-06 pmid:17215347; PubMed Central PMCID: PMCPmc1829124.
[7]
Gouarin S, Vabret A, Dina J, Petitjean J, Brouard J, Cuvillon-Nimal D, et al. Study of influenza C virus infection in France. Journal of medical virology. 2008;80(8):1441–6. doi: 10.1002/jmv.21218 pmid:18551600.
[8]
Takayanagi M, Umehara N, Watanabe H, Kitamura T, Ohtake M, Nishimura H, et al. Acute encephalopathy associated with influenza C virus infection. The Pediatric infectious disease journal. 2009;28(6):554. doi: 10.1097/INF.0b013e3181a064b2 pmid:19483529.
[9]
Matsuzaki Y, Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, et al. Clinical features of influenza C virus infection in children. The Journal of infectious diseases. 2006;193(9):1229–35. Epub 2006/04/06. doi: 10.1086/502973 pmid:16586359.
[10]
Salez N, Melade J, Pascalis H, Aherfi S, Dellagi K, Charrel RN, et al. Influenza C virus high seroprevalence rates observed in 3 different population groups. The Journal of infection. 2014;69(2):182–9. Epub 2014/04/08. doi: 10.1016/j.jinf.2014.03.016 pmid:24704348.
[11]
Brown IH, Harris PA, Alexander DJ. Serological studies of influenza viruses in pigs in Great Britain 1991–2. Epidemiology and infection. 1995;114(3):511–20. pmid:7781739; PubMed Central PMCID: PMC2271297. doi: 10.1017/s0950268800052225
[12]
Ohwada K, Kitame F, Sugawara K, Nishimura H, Homma M, Nakamura K. Distribution of the antibody to influenza C virus in dogs and pigs in Yamagata Prefecture, Japan. Microbiology and immunology. 1987;31(12):1173–80. pmid:2836710. doi: 10.1111/j.1348-0421.1987.tb01351.x
[13]
Yamaoka M, Hotta H, Itoh M, Homma M. Prevalence of antibody to influenza C virus among pigs in Hyogo Prefecture, Japan. The Journal of general virology. 1991;72 (Pt 3):711–4. Epub 1991/03/01. pmid:1848603. doi: 10.1099/0022-1317-72-3-711
[14]
Guo YJ, Jin FG, Wang P, Wang M, Zhu JM. Isolation of influenza C virus from pigs and experimental infection of pigs with influenza C virus. The Journal of general virology. 1983;64 (Pt 1):177–82. Epub 1983/01/01. doi: 10.1099/0022-1317-64-1-177 pmid:6296296.
[15]
Kimura H, Abiko C, Peng G, Muraki Y, Sugawara K, Hongo S, et al. Interspecies transmission of influenza C virus between humans and pigs. Virus research. 1997;48(1):71–9. . pmid:9140195
[16]
Yuanji G, Desselberger U. Genome analysis of influenza C viruses isolated in 1981/82 from pigs in China. The Journal of general virology. 1984;65 (Pt 11):1857–72. pmid:6502138. doi: 10.1099/0022-1317-65-11-1857
[17]
Manuguerra JC, Hannoun C. Natural infection of dogs by influenza C virus. Research in virology. 1992;143(3):199–204. Epub 1992/05/01. pmid:1325663. doi: 10.1016/s0923-2516(06)80104-4
[18]
Manuguerra JC, Hannoun C, Simon F, Villar E, Cabezas JA. Natural infection of dogs by influenza C virus: a serological survey in Spain. The new microbiologica. 1993;16(4):367–71. Epub 1993/10/01. pmid:8264427.
[19]
Horimoto T, Gen F, Murakami S, Iwatsuki-Horimoto K, Kato K, Akashi H, et al. Serological evidence of infection of dogs with human influenza viruses in Japan. The Veterinary record. 2014;174(4):96. doi: 10.1136/vr.101929 pmid:24336761.
[20]
Hause BM, Ducatez M, Collin EA, Ran Z, Liu R, Sheng Z, et al. Isolation of a novel swine influenza virus from Oklahoma in 2011 which is distantly related to human influenza C viruses. PLoS Pathog. 2013;9(2):e1003176. doi: 10.1371/journal.ppat.1003176 pmid:23408893; PubMed Central PMCID: PMC3567177.
[21]
Hause BM, Collin EA, Liu R, Huang B, Sheng Z, Lu W, et al. Characterization of a novel influenza virus in cattle and Swine: proposal for a new genus in the Orthomyxoviridae family. mBio. 2014;5(2):e00031–14. doi: 10.1128/mBio.00031-14 pmid:24595369; PubMed Central PMCID: PMC3958797.
[22]
Sheng Z, Ran Z, Wang D, Hoppe AD, Simonson R, Chakravarty S, et al. Genomic and evolutionary characterization of a novel influenza-C-like virus from swine. Archives of virology. 2014;159(2):249–55. doi: 10.1007/s00705-013-1815-3 pmid:23942954.
[23]
Collin EA, Sheng Z, Lang Y, Ma W, Hause BM, Li F. Cocirculation of two distinct genetic and antigenic lineages of proposed influenza D virus in cattle. Journal of virology. 2015;89(2):1036–42. doi: 10.1128/JVI.02718-14 pmid:25355894; PubMed Central PMCID: PMC4300623.
[24]
Sreenivasan C, Thomas M, Sheng Z, Hause BM, Collin EA, Knudsen DE, et al. Replication and transmission of novel bovine influenza D virus in guinea pig model. Journal of virology. 2015. doi: 10.1128/JVI.01630-15 pmid:26378161.
[25]
Jiang WM, Wang SC, Peng C, Yu JM, Zhuang QY, Hou GY, et al. Identification of a potential novel type of influenza virus in Bovine in China. Virus genes. 2014;49(3):493–6. doi: 10.1007/s11262-014-1107-3 pmid:25142163.
[26]
Ducatez MF, Pelletier C, Meyer G. Influenza D virus in cattle, France, 2011–2014. Emerging infectious diseases. 2015;21(2):368–71. doi: 10.3201/eid2102.141449 pmid:25628038; PubMed Central PMCID: PMC4313661.
[27]
Taylor JD, Fulton RW, Lehenbauer TW, Step DL, Confer AW. The epidemiology of bovine respiratory disease: what is the evidence for preventive measures? The Canadian veterinary journal La revue veterinaire canadienne. 2010;51(12):1351–9. Epub 2011/03/02. pmid:21358927; PubMed Central PMCID: PMCPmc2978987.
[28]
Grissett GP, White BJ, Larson RL. Structured literature review of responses of cattle to viral and bacterial pathogens causing bovine respiratory disease complex. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine. 2015;29(3):770–80. doi: 10.1111/jvim.12597 pmid:25929158.
[29]
Quast M, Sreenivasan C, Sexton G, Nedland H, Singrey A, Fawcett L, et al. Serological evidence for the presence of influenza D virus in small ruminants. Veterinary microbiology. 2015. .
[30]
Lu X, Qi J, Shi Y, Wang M, Smith DF, Heimburg-Molinaro J, et al. Structure and receptor binding specificity of hemagglutinin H13 from avian influenza A virus H13N6. J Virol. 2013;87(16):9077–85. doi: 10.1128/jvi.00235-13 pmid:WOS:000322535600024.
[31]
Lu X, Shi Y, Zhang W, Zhang Y, Qi J, Gao GF. Structure and receptor-binding properties of an airborne transmissible avian influenza A virus hemagglutinin H5 (VN1203mut). Protein & Cell. 2013;4(7):502–11. doi: 10.1007/s13238-013-3906-z pmid:WOS:000322393900004.
[32]
Zhang W, Shi Y, Qi JX, Gao F, Li Q, Fan Z, 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(10):5949–58. doi: 10.1128/Jvi.00545-13 pmid:WOS:000318155000054.
[33]
Zhang W, Shi Y, Lu X, Shu Y, Qi J, Gao GF. An airborne transmissible avian influenza H5 hemagglutinin seen at the atomic level. Science. 2013;340(6139):1463–7. doi: 10.1126/science.1236787 pmid:WOS:000320647000045.
[34]
Pleschka S, Klenk HD, Herrler G. The Catalytic Triad of the Influenza-C Virus Glycoprotein Hef Esterase—Characterization by Site-Directed Mutagenesis and Functional-Analysis. J Gen Virol. 1995;76:2529–37. doi: 10.1099/0022-1317-76-10-2529 pmid:WOS:A1995RY54500012.
[35]
Rosenthal PB, Zhang X, Formanowski F, Fitz W, Wong CH, Meier-Ewert H, et al. Structure of the haemagglutinin-esterase-fusion glycoprotein of influenza C virus. Nature. 1998;396(6706):92–6. doi: 10.1038/23974 pmid:9817207.
[36]
Padler-Karavani V, Song X, Yu H, Hurtado-Ziola N, Huang S, Muthana S, et al. Cross-comparison of protein recognition of sialic acid diversity on two novel sialoglycan microarrays. The Journal of biological chemistry. 2012;287(27):22593–608. doi: 10.1074/jbc.M112.359323 pmid:22549775; PubMed Central PMCID: PMCPMC3391140.
[37]
Wang Q, Tian X, Chen X, Ma J. Structural basis for receptor specificity of influenza B virus hemagglutinin. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(43):16874–9. Epub 2007/10/19. doi: 10.1073/pnas.0708363104 pmid:17942670; PubMed Central PMCID: PMCPmc2040455.
[38]
Shi Y, Zhang W, Wang F, Qi J, Wu Y, Song H, et al. Structures and receptor binding of hemagglutinins from human-infecting H7N9 influenza viruses. Science. 2013;342(6155):243–7. doi: 10.1126/science.1242917 pmid:WOS:000325475200044.
[39]
Langereis MA, Zeng Q, Gerwig GJ, Frey B, von Itzstein M, Kamerling JP, et al. Structural basis for ligand and substrate recognition by torovirus hemagglutinin esterases. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(37):15897–902. doi: 10.1073/pnas.0904266106 pmid:19721004; PubMed Central PMCID: PMC2747215.
[40]
Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: Molecular Evolutionary Genetics Analysis Version 6.0. Mol Biol Evol. 2013;30(12):2725–9. doi: 10.1093/molbev/mst197 pmid:WOS:000327793000019.
[41]
Zhu X, Larsen NA, Basran A, Bruce NC, Wilson IA. Observation of an arsenic adduct in an acetyl esterase crystal structure. The Journal of biological chemistry. 2003;278(3):2008–14. Epub 2002/11/08. doi: 10.1074/jbc.M210103200 pmid:12421810.
[42]
Herrler G, Multhaup G, Beyreuther K, Klenk HD. Serine-71 of the Glycoprotein Hef Is Located at the Active-Site of the Acetylesterase of Influenza-C Virus. Archives of virology. 1988;102(3–4):269–74. doi: 10.1007/Bf01310831 pmid:WOS:A1988R377200010.
[43]
Krojer T, Sawa J, Huber R, Clausen T. HtrA proteases have a conserved activation mechanism that can be triggered by distinct molecular cues. Nature structural & molecular biology. 2010;17(7):844–52. Epub 2010/06/29. doi: 10.1038/nsmb.1840 pmid:20581825.
[44]
Xue Y, Ha Y. Large lateral movement of transmembrane helix S5 is not required for substrate access to the active site of rhomboid intramembrane protease. The Journal of biological chemistry. 2013;288(23):16645–54. Epub 2013/04/24. doi: 10.1074/jbc.M112.438127 pmid:23609444; PubMed Central PMCID: PMCPmc3675599.
[45]
Wang M, Veit M. Hemagglutinin-esterase-fusion (HEF) protein of influenza C virus. Protein Cell. 2015. doi: 10.1007/s13238-015-0193-x pmid:26215728.
[46]
Sun X, Shi Y, Lu X, He J, Gao F, Yan J, et al. Bat-derived influenza hemagglutinin H17 does not bind canonical avian or human receptors and most likely uses a unique entry mechanism. Cell reports. 2013;3(3):769–78. doi: 10.1016/j.celrep.2013.01.025 pmid:23434510.
[47]
Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, et al. New world bats harbor diverse influenza A viruses. PLoS Pathog. 2013;9(10):e1003657. doi: 10.1371/journal.ppat.1003657 pmid:24130481; PubMed Central PMCID: PMC3794996.
[48]
Taylor RM. Studies on Survival of Influenza Virus Between Epidemics and Antigenic Variants of the Virus. Am J Public Health N. 1949;39(2):171–8. doi: 10.2105/Ajph.39.2.171 pmid:WOS:000206441500003.
[49]
Francis T, Quilligan JJ, Minuse E. Identification of Another Epidemic Respiratory Disease. Science. 1950;112(2913):495–7. doi: 10.1126/science.112.2913.495 pmid:WOS:A1950UA77200002.
[50]
Quilligan JJ, Minuse E, Francis T. Further Observations on the Jj and 1233 Influenza Viruses. Fed Proc. 1951;10(1):416–7. pmid:WOS:A1951UG29101413.
[51]
Crescenzo-Chaigne B, van der Werf S. Rescue of influenza c virus from recombinant DNA. J Virol. 2007;81(20):11282–9. doi: 10.1128/Jvi.00910-07 pmid:WOS:000250019400043.
[52]
Ferguson L, Eckard L, Epperson WB, Long L-P, Smith D, Huston C, et al. Influenza D virus infection in Mississippi beef cattle. Virology. 2015;486:28–34. . doi: 10.1016/j.virol.2015.08.030. pmid:26386554
[53]
Maenz B, Schwemmle M, Brunotte L. Adaptation of Avian Influenza A Virus Polymerase in Mammals To Overcome the Host Species Barrier. J Virol. 2013;87(13):7200–9. doi: 10.1128/jvi.00980-13 pmid:WOS:000320116500001.
[54]
Gora IM, Rozek W, Zmudzinski JF. Influenza virus proteins as factors involved in interspecies transmission. Polish Journal of Veterinary Sciences. 2014;17(4):765–74. doi: 10.2478/pjvs-2014-0112 pmid:WOS:000346882600028.
[55]
Kuiken T, Holmes EC, McCauley J, Rimmelzwaan GF, Williams CS, Grenfell BT. Host species barriers to influenza virus infections. Science. 2006;312(5772):394–7. doi: 10.1126/science.1122818 pmid:WOS:000236941800038.
[56]
Ortiz EJ, Kochel TJ, Capuano AW, Setterquist SF, Gray GC. Avian influenza and poultry workers, Peru, 2006. Influenza and other respiratory viruses. 2007;1(2):65–9. doi: 10.1111/j.1750-2659.2007.00009.x pmid:WOS:000207069700005.
[57]
Kayali G, Ortiz EJ, Chorazy ML, Gray GC. Evidence of Previous Avian Influenza Infection among US Turkey Workers. Zoonoses Public Hlth. 2010;57(4):265–72. doi: 10.1111/j.1863-2378.2009.01231.x pmid:WOS:000277416200006.
[58]
Lu X, Shi Y, Gao F, Xiao H, Wang M, Qi J, et al. Insights into avian influenza virus pathogenicity: the hemagglutinin precursor HA0 of subtype H16 has an alpha-helix structure in its cleavage site with inefficient HA1/HA2 cleavage. Journal of virology. 2012;86(23):12861–70. doi: 10.1128/JVI.01606-12 pmid:22993148; PubMed Central PMCID: PMCPMC3497694.
[59]
Otwinowski Z, Minor W. Processing of X-ray diffraction data collected in oscillation mode. Method Enzymol. 1997;276:307–26. doi: 10.1016/S0076-6879(97)76066-X pmid:WOS:A1997BH42P00020.
[60]
Read RJ. Pushing the boundaries of molecular replacement with maximum likelihood. Acta Crystallogr D. 2001;57:1373–82. doi: 10.1107/S0907444901012471 pmid:WOS:000171202700004.
[61]
Bailey S. The Ccp4 Suite—Programs for Protein Crystallography. Acta Crystallographica Section D 1994;50:760–3. pmid:WOS:A1994PK56800011. doi: 10.1107/s0907444994003112
[62]
Emsley P, Cowtan K. Coot: model-building tools for molecular graphics. Acta Crystallogr D. 2004;60:2126–32. doi: 10.1107/S0907444904019158 pmid:WOS:000225360500002.
[63]
Murshudov GN, Vagin AA, Dodson EJ. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D. 1997;53:240–55. doi: 10.1107/S0907444996012255 pmid:WOS:A1997XB25600002.
[64]
Adams PD, Afonine PV, Bunkóczi G, Chen VB, Davis IW, Echols N, et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallographica Section D. 2010;66(2):213–21. doi: 10.1107/S0907444909052925.
[65]
Morris AL, Macarthur MW, Hutchinson EG, Thornton JM. Stereochemical quality of protein-structure coordinates. Proteins-Structure Function and Genetics. 1992;12(4):345–64. doi: 10.1002/prot.340120407 pmid:WOS:A1992HJ85200006.
[66]
Killian M. Hemagglutination Assay for Influenza Virus. In: Spackman E, editor. Animal Influenza Virus. Methods in Molecular Biology. 1161: Springer New York; 2014. p. 3–9.
[67]
Langereis MA, Zeng QH, Heesters B, Huizinga EG, de Groot RJ. The Murine Coronavirus Hemagglutinin-esterase Receptor-binding Site: A Major Shift in Ligand Specificity through Modest Changes in Architecture. Plos Pathog. 2012;8(1). ARTN e1002492 doi: 10.1371/journal.ppat.1002492 pmid:WOS:000300767100036.
[68]
Klein A, Krishna M, Varki NM, Varki A. 9-O-acetylated sialic acids have widespread but selective expression: analysis using a chimeric dual-function probe derived from influenza C hemagglutinin-esterase. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(16):7782–6. pmid:PMC44486. doi: 10.1073/pnas.91.16.7782
[69]
Peng G, Sun D, Rajashankar KR, Qian Z, Holmes KV, Li F. Crystal structure of mouse coronavirus receptor-binding domain complexed with its murine receptor. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(26):10696–701. doi: 10.1073/pnas.1104306108 pmid:21670291; PubMed Central PMCID: PMC3127895.
[70]
Martin LT, Verhagen A, Varki A. Recombinant influenza C hemagglutinin-esterase as a probe for sialic acid 9-O-acetylation. Methods in enzymology. 2003;363:489–98. doi: 10.1016/S0076-6879(03)01074-7 pmid:14579598.
[71]
Chandrasekaran A, Srinivasan A, Raman R, Viswanathan K, Raguram S, Tumpey TM, et al. Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin. Nature biotechnology. 2008;26(1):107–13. doi: 10.1038/nbt1375 pmid:18176555.
[72]
Wang M, Zhang W, Qi J, Wang F, Zhou J, Bi Y, et al. Structural basis for preferential avian receptor binding by the human-infecting H10N8 avian influenza virus. Nature communications. 2015;6:5600. doi: 10.1038/ncomms6600 pmid:25574798.
[73]
Robert X, Gouet P. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014;42(Web Server issue):W320–4. doi: 10.1093/nar/gku316 pmid:24753421; PubMed Central PMCID: PMCPMC4086106.
[74]
Kearse M, Moir R, Wilson A, Stones-Havas S, Cheung M, Sturrock S, et al. Geneious Basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data. Bioinformatics. 2012;28(12):1647–9. doi: 10.1093/bioinformatics/bts199 pmid:22543367; PubMed Central PMCID: PMCPMC3371832.
