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Structural Organization of a Filamentous Influenza a Virus

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Structural Organization of a Filamentous Influenza a Virus Structural organization of a filamentous influenza A virus Lesley J. Calder, Sebastian Wasilewski, John A. Berriman1, and Peter B. Rosenthal2 Division of Physical Biochemistry, MRC National Institute for Medical Research, London NW7 1AA, United Kingdom Edited* by Robert A. Lamb, Northwestern University, Evanston, IL, and approved April 27, 2010 (received for review February 26, 2010) Influenza is a lipid-enveloped, pleomorphic virus. We combine electron HA trimer in the neutral pH conformation (9), proteolytic frag- cryotomography and analysis of images of frozen-hydrated virions ments of the HA in the low pH conformation (10, 11), and the NA to determine the structural organization of filamentous influenza A tetramer (12, 13) have provided a molecular understanding of the virus. Influenza A/Udorn/72 virions are capsule-shaped or filamentous function of these proteins. particles of highly uniform diameter. We show that the matrix layer Further understanding of the virus life cycle requires 3D studies adjacent to the membrane is an ordered helix of the M1 protein and its of ultrastructure that can identify the specific molecular inter- close interaction with the surrounding envelope determines virion actions that govern virus self-assembly. In addition, ultrastructural morphology. The ribonucleoprotein particles (RNPs) that package the changes that are essential to membrane fusion and virion disas- genome segments form a tapered assembly at one end of the virus sembly during cell entry remain to be described. Electron cry- interior. The neuraminidase, which is present in smaller numbers than omicroscopy of influenza virions that are vitrified by rapid plunge- the hemagglutinin, clusters in patches and are typically present at the freezing (14–17) shows contrast from virion structures themselves end of the virion opposite to RNP attachment. Incubation of virus at and not from stain distributions, which can also distort or disrupt low pH causes a loss of filamentous morphology, during which we virus structure. However, an understanding of the structural or- observe a structural transition of the matrix layer from its helical, ganization of influenza virus has remained difficult because of its membrane-associated form to a multilayered coil structure inside the pleomorphic nature. Electron cryotomography can be used to virus particle. The polar organization of the virus provides a model for directly determine the structure of pleomorphic virions, although assembly of the virion during budding at the host membrane. Images at a resolution limited by the accumulated radiation damage and and tomograms of A/Aichi/68 X-31 virions show the generality of restricted angles of the tilt series. MICROBIOLOGY fi these conclusions to non- lamentous virions. In the present study, we investigate the structural basis for filamentous morphology in influenza virus. Filamentous mor- electron cryomicroscopy | matrix protein | ribonucleoprotein particles phology is typical of clinical isolates of influenza virus, whereas hemagglutinin | neuramindase a spherical morphology is observed in many laboratory-passaged influenza strains (18, 19). Taking advantage of the surprising nfluenza A virus is a lipid-enveloped orthomyxovirus and a cause structural regularity displayed by an influenza virus (A/Udorn/ Iof human disease by strains that arise through seasonal variation 72) of known, persistent filamentous phenotype (20), we com- and through pandemic infection resulting from viral reassortment bined electron cryotomography of frozen-hydrated virions with or adaptation that introduces new influenza viruses into the human analysis of higher resolution projection images to elucidate the population. The virus genome contains eight separate RNA seg- structural organization of influenza virus. We show that the M1 ments of negative polarity that encode eight structural proteins protein forms a helix associated with the uniform cylindrical and four additional proteins. The genome segments are packaged structure of filamentous Udorn virions. A polar organization of in the virus in complex with the nucleoprotein (NP) as ribonu- the virion is evident in both the packaging of the genome and in cleoprotein particles (RNPs) (1). The RNPs are also associated the structure of the surrounding envelope, and applies generally with the viral polymerase (composed of the PA, PB1, and PB2 to influenza virus based on comparison with images and tomo- subunits) (2), which is necessary for viral replication. The virus grams we obtained for the non-filamentous influenza A/Aichi/68 acquires a membrane envelope containing two types of spike gly- X-31. We also studied acid-treated Udorn virus by electron to- coprotein, the hemagglutinin (HA) and the neuraminidase (NA), mography to image virus ultrastructure at the low pH of the by budding through the host plasma membrane. The matrix pro- endosome and observed a structural reorganization of the matrix tein (M1) is the most abundant protein in the virus and forms a layer associated with a change in virus morphology. layer associated with the inside of the envelope. An ion channel (M2) is also present in the virus envelope (3). Results During infection, the virus attaches to cell surface receptors Cryomicroscopy of Frozen-Hydrated Influenza Virions (H3N2) at pH 7. containing sialic acid, which are recognized by the HA protein Fig. 1 shows a gallery of images of both Udorn and X-31 virions (4), and the virus enters the cell by receptor-mediated endocy- aligned by in-plane rotation to emphasize common features. tosis. At the low pH of the endosome, a large structural rear- Udorn virions (Fig. 1 A–G), recorded in a tomogram of a rangement of the HA exposes a hydrophobic fusion peptide and single field of view (tomogram in Movie S1 and Fig. S1A), show mediates fusion of the virus membrane with the host endosomal an extended morphology with capsule-shaped particles (cylin- membrane (4), releasing the packaged contents of the virus (RNPs) into the host cytoplasm. In addition, acidification of the virus core through the M2 ion channel is necessary for mem- Author contributions: L.J.C. and P.B.R. designed research; L.J.C., S.W., and J.A.B. per- brane fusion and release of the RNPs (5, 6). The M1 protein also formed research; S.W. contributed new reagents/analytic tools; L.J.C., S.W., and P.B.R. has an RNP-binding function that regulates transport of RNPs to analyzed data; and L.J.C. and P.B.R. wrote the paper. the cell nucleus where replication and transcription of viral gene The authors declare no conflict of interest. products can occur and subsequently may also transport RNPs to *This Direct Submission article had a prearranged editor. the plasma membrane where virus assembly occurs (7). The NA 1Present address: 51 Oakhill Road, Putney SW15 2QJ, United Kingdom. glycoprotein is a receptor-destroying enzyme that removes sialic 2To whom correspondence should be addressed. E-mail: [email protected]. acid from potential receptors and may have roles in both virus This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. entry and exit (8). High resolution x-ray crystal structures of the 1073/pnas.1002123107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1002123107 PNAS Early Edition | 1of6 Downloaded by guest on September 29, 2021 Fig. 1. Tomogram sections of frozen-hydrated influenza A virions recorded in a single tomogram field. (A–G) A/Udorn/72 virions from single field shown in Fig. S1A and Movie S1. Virion in A is identical to that in B, but has been manually colored to indicate features corresponding to RNPs (red), multilayered-coil (blue), NA (purple), and HA (green). (K, L, and M) A/Aichi/68 X-31 virions from single field shown in Fig. S1b and Movie S2. Negative stain images of (H)HA rosette (green HA trimer model inset), (I) NA rosette (purple NA head domain tetramer model inset), and (J) RNP purified from X-31. Red lines are used for comparison of RNP length. Purple arcs in D and K indicate typical NA clusters at one end. drical with a hemispherical cap at each end), typically about 120 by negative stain microscopy (Fig. 1J). These may be tentatively nm in length, and longer filamentous particles, including some assigned to genomic segments 1 and 2, which have the longest over 1 μm in length (Fig. S2). The virions usually have their long sequence. The RNPs only appear to contact the matrix layer at axis in the plane of the thin ice film, but some of the smaller the tapered end of the assembly; they do not interact or make capsule-shaped virions have their axis tilted with respect to the regular contacts with the matrix layer along their length. Some of plane. The filamentous particles show a uniform diameter of the shorter virions are just long enough (120 nm) to package the about 55 nm (measured from the lipid bilayer), whereas the longest, straight RNP segments. average diameter of the shorter capsule-shaped particles is Although the Udorn particles give a clearer view of the extent somewhat wider at 59 nm. There is a tendency for end-to-end and asymmetry of the RNP assembly within the virion, the ar- association of the virions like a string of sausages (Fig. S3). rangement of RNPs within X-31 virions is highly similar (Fig. 1). X-31 virus (Fig. 1 K–M, Figs. S1B and S4, and Movie S2) However, the X-31 virions are shorter than Udorn so that the shows only occasional long filamentous particles, but, compared RNPs extend completely from one end to the other and follow to a previous study by cryomicroscopy (16), we observed that the ellipsoidal profile of the matrix layer and membrane but still a greater fraction are prolate ellipsoids with hemispherical ends. without making regular contacts. Thus, the X-31 RNP assembly Images show 87 out of 145 particles are elongated by a factor appears slightly wider than the Udorn assembly.
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