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Nicole Tischler
Laboratorio de Virología Molecular, Fundación Ciencia & Vida, Av. Zañartu 1482

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Preprint content
Published: 18 May 2021
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The durability of circulating neutralizing antibody (nAb) responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their boosting by vaccination remains to be defined. We show that outpatient and hospitalized SARS-CoV-2 seropositive individuals mount a robust neutralizing antibody (nAb) response that peaks at days 23 and 27 post-symptom onset, respectively. Although nAb titers remained higher in hospitalized patients, both study groups showed long-lasting nAb responses that can persist for up to 12 months after natural infection. These nAb responses in previously seropositive individuals can be significantly boosted through immunization with two doses of the CoronaVac (Sinovac) or one dose of the BNT162b2 (BioNTech/Pfizer) vaccines, suggesting a substantial induction of B cell memory responses. Noteworthy, three obese previously seropositive individuals failed to mount a booster response upon vaccination, warranting further studies in this population. Immunization of naïve individuals with two doses of the CoronaVac vaccine or one dose of the BNT162b2 vaccine elicited similar levels of nAbs compared to seropositive individuals 4.2 to 13.3 months post-infection with SARS-CoV-2. Thus, this preliminary evidence suggests that both, seropositive and naïve individuals, require two doses of CoronaVac to ensure the induction of robust nAb titers.

ACS Style

Nicolás A. Muena; Tamara García-Salum; Catalina Pardo-Roa; Eileen F. Serrano; Jorge Levican; María José Avendaño; Leonardo I. Almonacid; Gonzalo Valenzuela; Estefany Poblete; Shirin Strohmeier; Erick Salinas; Denise Haslwanter; Maria Eugenia Dieterle; Rohit K. Jangra; Kartik Chandran; Claudia González; Arnoldo Riquelme; Florian Krammer; Nicole D. Tischler; Rafael A. Medina. Long-lasting neutralizing antibody responses in SARS-CoV-2 seropositive individuals are robustly boosted by immunization with the CoronaVac and BNT162b2 vaccines. 2021, 1 .

AMA Style

Nicolás A. Muena, Tamara García-Salum, Catalina Pardo-Roa, Eileen F. Serrano, Jorge Levican, María José Avendaño, Leonardo I. Almonacid, Gonzalo Valenzuela, Estefany Poblete, Shirin Strohmeier, Erick Salinas, Denise Haslwanter, Maria Eugenia Dieterle, Rohit K. Jangra, Kartik Chandran, Claudia González, Arnoldo Riquelme, Florian Krammer, Nicole D. Tischler, Rafael A. Medina. Long-lasting neutralizing antibody responses in SARS-CoV-2 seropositive individuals are robustly boosted by immunization with the CoronaVac and BNT162b2 vaccines. . 2021; ():1.

Chicago/Turabian Style

Nicolás A. Muena; Tamara García-Salum; Catalina Pardo-Roa; Eileen F. Serrano; Jorge Levican; María José Avendaño; Leonardo I. Almonacid; Gonzalo Valenzuela; Estefany Poblete; Shirin Strohmeier; Erick Salinas; Denise Haslwanter; Maria Eugenia Dieterle; Rohit K. Jangra; Kartik Chandran; Claudia González; Arnoldo Riquelme; Florian Krammer; Nicole D. Tischler; Rafael A. Medina. 2021. "Long-lasting neutralizing antibody responses in SARS-CoV-2 seropositive individuals are robustly boosted by immunization with the CoronaVac and BNT162b2 vaccines." , no. : 1.

Review
Published: 14 February 2021 in Viruses
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Phenuiviridae is a large family of arthropod-borne viruses with over 100 species worldwide. Several cause severe diseases in both humans and livestock. Global warming and the apparent geographical expansion of arthropod vectors are good reasons to seriously consider these viruses potential agents of emerging diseases. With an increasing frequency and number of epidemics, some phenuiviruses represent a global threat to public and veterinary health. This review focuses on the early stage of phenuivirus infection in mammalian host cells. We address current knowledge on each step of the cell entry process, from virus binding to penetration into the cytosol. Virus receptors, endocytosis, and fusion mechanisms are discussed in light of the most recent progress on the entry of banda-, phlebo-, and uukuviruses, which together constitute the three prominent genera in the Phenuiviridae family.

ACS Style

Jana Koch; Qilin Xin; Nicole Tischler; Pierre-Yves Lozach. Entry of Phenuiviruses into Mammalian Host Cells. Viruses 2021, 13, 299 .

AMA Style

Jana Koch, Qilin Xin, Nicole Tischler, Pierre-Yves Lozach. Entry of Phenuiviruses into Mammalian Host Cells. Viruses. 2021; 13 (2):299.

Chicago/Turabian Style

Jana Koch; Qilin Xin; Nicole Tischler; Pierre-Yves Lozach. 2021. "Entry of Phenuiviruses into Mammalian Host Cells." Viruses 13, no. 2: 299.

Journal article
Published: 28 January 2021 in Journal of Virology
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In this work, we investigate protein-protein interactions that drive the assembly of the hantavirus envelope. These emerging pathogens have the potential to cause deadly outbreaks in the human population.

ACS Style

R. A. Petazzi; A. A. Koikkarah; N. D. Tischler; S. Chiantia. Detection of Envelope Glycoprotein Assembly from Old World Hantaviruses in the Golgi Apparatus of Living Cells. Journal of Virology 2021, 95, 1 .

AMA Style

R. A. Petazzi, A. A. Koikkarah, N. D. Tischler, S. Chiantia. Detection of Envelope Glycoprotein Assembly from Old World Hantaviruses in the Golgi Apparatus of Living Cells. Journal of Virology. 2021; 95 (4):1.

Chicago/Turabian Style

R. A. Petazzi; A. A. Koikkarah; N. D. Tischler; S. Chiantia. 2021. "Detection of Envelope Glycoprotein Assembly from Old World Hantaviruses in the Golgi Apparatus of Living Cells." Journal of Virology 95, no. 4: 1.

Journal article
Published: 15 September 2020 in Cell
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Summary Hantaviruses are rodent-borne viruses causing serious zoonotic outbreaks worldwide for which no treatment is available. Hantavirus particles are pleomorphic and display a characteristic square surface lattice. The envelope glycoproteins Gn and Gc form heterodimers that further assemble into tetrameric spikes, the lattice building blocks. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry via receptor-mediated endocytosis and endosomal membrane fusion. Here we describe the high-resolution X-ray structures of the heterodimer of Gc and the Gn head and of the homotetrameric Gn base. Docking them into an 11.4-Å-resolution cryoelectron tomography map of the hantavirus surface accounted for the complete extramembrane portion of the viral glycoprotein shell and allowed a detailed description of the surface organization of these pleomorphic virions. Our results, which further revealed a built-in mechanism controlling Gc membrane insertion for fusion, pave the way for immunogen design to protect against pathogenic hantaviruses.

ACS Style

Alexandra Serris; Robert Stass; Eduardo A. Bignon; Nicolás A. Muena; Jean-Claude Manuguerra; Rohit K. Jangra; Sai Li; Kartik Chandran; Nicole D. Tischler; Juha T. Huiskonen; Felix A. Rey; Pablo Guardado-Calvo. The Hantavirus Surface Glycoprotein Lattice and Its Fusion Control Mechanism. Cell 2020, 183, 442 -456.e16.

AMA Style

Alexandra Serris, Robert Stass, Eduardo A. Bignon, Nicolás A. Muena, Jean-Claude Manuguerra, Rohit K. Jangra, Sai Li, Kartik Chandran, Nicole D. Tischler, Juha T. Huiskonen, Felix A. Rey, Pablo Guardado-Calvo. The Hantavirus Surface Glycoprotein Lattice and Its Fusion Control Mechanism. Cell. 2020; 183 (2):442-456.e16.

Chicago/Turabian Style

Alexandra Serris; Robert Stass; Eduardo A. Bignon; Nicolás A. Muena; Jean-Claude Manuguerra; Rohit K. Jangra; Sai Li; Kartik Chandran; Nicole D. Tischler; Juha T. Huiskonen; Felix A. Rey; Pablo Guardado-Calvo. 2020. "The Hantavirus Surface Glycoprotein Lattice and Its Fusion Control Mechanism." Cell 183, no. 2: 442-456.e16.

Journal article
Published: 01 August 2020 in Emerging Infectious Diseases
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Andes virus (ANDV) is the only hantavirus transmitted between humans through close contact. We detected the genome and proteins of ANDV in breast milk cells from an infected mother in Chile who transmitted the virus to her child, suggesting gastrointestinal infection through breast milk as a route of ANDV person-to-person transmission.

ACS Style

Marcela Ferrés; Constanza Martínez-Valdebenito; Jenniffer Angulo; Carolina Henríquez; Jorge Vera-Otárola; María José Vergara; Javier Pérez; Jorge Fernández; Viviana Sotomayor; María Francisca Valdés; Diego González-Candia; Nicole Tischler; Cecilia Vial; Pablo Vial; Gregory Mertz; Nicole Le Corre. Mother-to-Child Transmission of Andes Virus through Breast Milk, Chile1. Emerging Infectious Diseases 2020, 26, 1885 -1888.

AMA Style

Marcela Ferrés, Constanza Martínez-Valdebenito, Jenniffer Angulo, Carolina Henríquez, Jorge Vera-Otárola, María José Vergara, Javier Pérez, Jorge Fernández, Viviana Sotomayor, María Francisca Valdés, Diego González-Candia, Nicole Tischler, Cecilia Vial, Pablo Vial, Gregory Mertz, Nicole Le Corre. Mother-to-Child Transmission of Andes Virus through Breast Milk, Chile1. Emerging Infectious Diseases. 2020; 26 (8):1885-1888.

Chicago/Turabian Style

Marcela Ferrés; Constanza Martínez-Valdebenito; Jenniffer Angulo; Carolina Henríquez; Jorge Vera-Otárola; María José Vergara; Javier Pérez; Jorge Fernández; Viviana Sotomayor; María Francisca Valdés; Diego González-Candia; Nicole Tischler; Cecilia Vial; Pablo Vial; Gregory Mertz; Nicole Le Corre. 2020. "Mother-to-Child Transmission of Andes Virus through Breast Milk, Chile1." Emerging Infectious Diseases 26, no. 8: 1885-1888.

Journal article
Published: 16 June 2020 in Journal of Virology
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Andes orthohantavirus (ANDV) is endemic in Argentina and Chile and is the primary etiological agent of hantavirus cardiopulmonary syndrome (HCPS) in South America. ANDV is distinguished from other hantaviruses by its unique ability to spread from person to person. In a previous report, we identified a novel ANDV protein, ANDV-NSs. Until now, ANDV-NSs had no known function. In this new study, we established that ANDV-NSs acts as an antagonist of cellular innate immunity, the first line of defense against invading pathogens, hindering the cellular antiviral response during infection. This study provides novel insights into the mechanisms used by ANDV to establish its infection.

ACS Style

Jorge Vera-Otarola; Loretto Solis; Fernando Lowy; Valeria Olguín; Jenniffer Angulo; Karla Pino; Nicole Tischler; Carola Otth; Paula Padula; Marcelo López-Lastra. The Andes Orthohantavirus NSs Protein Antagonizes the Type I Interferon Response by Inhibiting MAVS Signaling. Journal of Virology 2020, 94, 1 .

AMA Style

Jorge Vera-Otarola, Loretto Solis, Fernando Lowy, Valeria Olguín, Jenniffer Angulo, Karla Pino, Nicole Tischler, Carola Otth, Paula Padula, Marcelo López-Lastra. The Andes Orthohantavirus NSs Protein Antagonizes the Type I Interferon Response by Inhibiting MAVS Signaling. Journal of Virology. 2020; 94 (13):1.

Chicago/Turabian Style

Jorge Vera-Otarola; Loretto Solis; Fernando Lowy; Valeria Olguín; Jenniffer Angulo; Karla Pino; Nicole Tischler; Carola Otth; Paula Padula; Marcelo López-Lastra. 2020. "The Andes Orthohantavirus NSs Protein Antagonizes the Type I Interferon Response by Inhibiting MAVS Signaling." Journal of Virology 94, no. 13: 1.

Preprint content
Published: 02 June 2020
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Hantaviruses are emerging pathogens that occasionally cause deadly outbreaks in the human population. While the structure of the viral envelope has been characterized with high precision, the protein-protein interactions leading to the formation of new virions in infected cells are not fully understood yet. In this work, we use quantitative fluorescence microscopy (i.e. Number&Brightness analysis and fluorescence fluctuation spectroscopy) to quantify the interactions that lead to oligomeric spike complex formation in the physiological context of living cells. To this aim, we have analyzed proteins from Puumala and Hantaan orthohantaviruses in several cellular models. For the first time, we quantified the oligomerization state of each protein in relation to its subcellular localization, concentration and the concentration of its interaction partner. Our results indicate that when expressed separately, both glycoproteins can form homo-multimers in a concentration-dependent manner. Fluorescence fluctuation analysis was applied to prove that Gc:Gc contacts observed on virions are also relevant for Gc-Gc interactions in living cells, in the absence of Gn. Furthermore, we proved that the membrane-distal lobes of Gn are not necessary for Gn homo-multimerization. In cells co-expressing both glycoproteins, we observe clear indication of Gn-Gc interactions and the formation of protein complexes with different sizes, while using various labelling schemes to minimize the influence of the fluorescent tags. Our data are compatible with an assembly model according to which hantavirus spikes are formed via the assembly of Gn-Gc hetero-dimers. Furthermore, our results indicate the interconnection of large Gn-Gc hetero-multimers in the Golgi apparatus. Such large glycoprotein multimers may be identified as multiple interacting viral spikes and provide a possible first evidence for the initial assembly steps of the viral envelope, within this organelle, directly in living cells.

ACS Style

Roberto Arturo Petazzi; A. A. Koikkarah; Nicole D. Tischler; Salvatore Chiantia. Detection of Envelope Glycoprotein Assembly from Old-World Hantaviruses in the Golgi Apparatus of Living Cells. 2020, 1 .

AMA Style

Roberto Arturo Petazzi, A. A. Koikkarah, Nicole D. Tischler, Salvatore Chiantia. Detection of Envelope Glycoprotein Assembly from Old-World Hantaviruses in the Golgi Apparatus of Living Cells. . 2020; ():1.

Chicago/Turabian Style

Roberto Arturo Petazzi; A. A. Koikkarah; Nicole D. Tischler; Salvatore Chiantia. 2020. "Detection of Envelope Glycoprotein Assembly from Old-World Hantaviruses in the Golgi Apparatus of Living Cells." , no. : 1.

Review article
Published: 15 February 2020 in Antiviral Research
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The 2019 11th International Conference on Hantaviruses (ICH 2019) was organized by the International Society for Hantaviruses (ISH), and held on September 1–4, 2019, at the Irish College, in Leuven, Belgium. These ICHs have been held every three years since 1989. ICH 2019 was attended by 158 participants from 33 countries. The current report summarizes research presented on all aspects of hantavirology: ecology; pathogenesis and immune responses; virus phylogeny, replication and morphogenesis; epidemiology; vaccines, therapeutics and prevention; and clinical aspects and diagnosis.

ACS Style

Jan Clement; Clas Ahlm; Tatjana Avšič-Županc; Jason Botten; Kartik Chandran; Colleen B. Jonsson; Hiroaki Kariwa; Jonas Klingström; Boris Klempa; Detlev H. Krüger; Herwig Leirs; Dexin Li; Mifang Liang; Alemka Markotić; Anna Papa; Connie S. Schmaljohn; Nicole Tischler; Rainer G. Ulrich; Antti Vaheri; Cecilia Vial; Richard Yanagihara; Piet Maes. Meeting report: Eleventh International Conference on Hantaviruses. Antiviral Research 2020, 176, 104733 .

AMA Style

Jan Clement, Clas Ahlm, Tatjana Avšič-Županc, Jason Botten, Kartik Chandran, Colleen B. Jonsson, Hiroaki Kariwa, Jonas Klingström, Boris Klempa, Detlev H. Krüger, Herwig Leirs, Dexin Li, Mifang Liang, Alemka Markotić, Anna Papa, Connie S. Schmaljohn, Nicole Tischler, Rainer G. Ulrich, Antti Vaheri, Cecilia Vial, Richard Yanagihara, Piet Maes. Meeting report: Eleventh International Conference on Hantaviruses. Antiviral Research. 2020; 176 ():104733.

Chicago/Turabian Style

Jan Clement; Clas Ahlm; Tatjana Avšič-Županc; Jason Botten; Kartik Chandran; Colleen B. Jonsson; Hiroaki Kariwa; Jonas Klingström; Boris Klempa; Detlev H. Krüger; Herwig Leirs; Dexin Li; Mifang Liang; Alemka Markotić; Anna Papa; Connie S. Schmaljohn; Nicole Tischler; Rainer G. Ulrich; Antti Vaheri; Cecilia Vial; Richard Yanagihara; Piet Maes. 2020. "Meeting report: Eleventh International Conference on Hantaviruses." Antiviral Research 176, no. : 104733.

Journal article
Published: 30 November 2019 in Biomolecules
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Segmentation is one of the most important stages in the 3D reconstruction of macromolecule structures in cryo-electron microscopy. Due to the variability of macromolecules and the low signal-to-noise ratio of the structures present, there is no generally satisfactory solution to this process. This work proposes a new unsupervised particle picking and segmentation algorithm based on the composition of two well-known image filters: Anisotropic (Perona–Malik) diffusion and non-negative matrix factorization. This study focused on keyhole limpet hemocyanin (KLH) macromolecules which offer both a top view and a side view. Our proposal was able to detect both types of views and separate them automatically. In our experiments, we used 30 images from the KLH dataset of 680 positive classified regions. The true positive rate was 95.1% for top views and 77.8% for side views. The false negative rate was 14.3%. Although the false positive rate was high at 21.8%, it can be lowered with a supervised classification technique.

ACS Style

Miguel Carrasco; Patricio Toledo; Nicole D. Tischler. Macromolecule Particle Picking and Segmentation of a KLH Database by Unsupervised Cryo-EM Image Processing. Biomolecules 2019, 9, 809 .

AMA Style

Miguel Carrasco, Patricio Toledo, Nicole D. Tischler. Macromolecule Particle Picking and Segmentation of a KLH Database by Unsupervised Cryo-EM Image Processing. Biomolecules. 2019; 9 (12):809.

Chicago/Turabian Style

Miguel Carrasco; Patricio Toledo; Nicole D. Tischler. 2019. "Macromolecule Particle Picking and Segmentation of a KLH Database by Unsupervised Cryo-EM Image Processing." Biomolecules 9, no. 12: 809.

Journal article
Published: 10 June 2019 in eLife
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The hantavirus envelope glycoproteins Gn and Gc mediate virion assembly and cell entry, with Gc driving fusion of viral and endosomal membranes. Although the X-ray structures and overall arrangement of Gn and Gc on the hantavirus spikes are known, their detailed interactions are not. Here we show that the lateral contacts between spikes are mediated by the same 2-fold contacts observed in Gc crystals at neutral pH, allowing the engineering of disulfide bonds to cross-link spikes. Disrupting the observed dimer interface affects particle assembly and overall spike stability. We further show that the spikes display a temperature-dependent dynamic behavior at neutral pH, alternating between ‘open’ and ‘closed’ forms. We show that the open form exposes the Gc fusion loops but is off-pathway for productive Gc-induced membrane fusion and cell entry. These data also provide crucial new insights for the design of optimized Gn/Gc immunogens to elicit protective immune responses.

ACS Style

Eduardo A Bignon; Amelina Albornoz; Pablo Guardado-Calvo; Félix A Rey; Nicole D Tischler. Molecular organization and dynamics of the fusion protein Gc at the hantavirus surface. eLife 2019, 8, 1 .

AMA Style

Eduardo A Bignon, Amelina Albornoz, Pablo Guardado-Calvo, Félix A Rey, Nicole D Tischler. Molecular organization and dynamics of the fusion protein Gc at the hantavirus surface. eLife. 2019; 8 ():1.

Chicago/Turabian Style

Eduardo A Bignon; Amelina Albornoz; Pablo Guardado-Calvo; Félix A Rey; Nicole D Tischler. 2019. "Molecular organization and dynamics of the fusion protein Gc at the hantavirus surface." eLife 8, no. : 1.

Review
Published: 01 June 2019 in Virologie
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ACS Style

Zina M. Uckeley; Jana Koch; Nicole Tischler; Psylvia Léger; Pierre-Yves Lozach. Cell biology of phlebovirus entry. Virologie 2019, 23, 176 -187.

AMA Style

Zina M. Uckeley, Jana Koch, Nicole Tischler, Psylvia Léger, Pierre-Yves Lozach. Cell biology of phlebovirus entry. Virologie. 2019; 23 (3):176-187.

Chicago/Turabian Style

Zina M. Uckeley; Jana Koch; Nicole Tischler; Psylvia Léger; Pierre-Yves Lozach. 2019. "Cell biology of phlebovirus entry." Virologie 23, no. 3: 176-187.

Journal article
Published: 19 February 2019 in Nature Communications
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Lipid membrane fusion is an essential function in many biological processes. Detailed mechanisms of membrane fusion and the protein structures involved have been mainly studied in eukaryotic systems, whereas very little is known about membrane fusion in prokaryotes. Haloarchaeal pleomorphic viruses (HRPVs) have a membrane envelope decorated with spikes that are presumed to be responsible for host attachment and membrane fusion. Here we determine atomic structures of the ectodomains of the 57-kDa spike protein VP5 from two related HRPVs revealing a previously unreported V-shaped fold. By Volta phase plate cryo-electron tomography we show that VP5 is monomeric on the viral surface, and we establish the orientation of the molecules with respect to the viral membrane. We also show that the viral membrane fuses with the host cytoplasmic membrane in a process mediated by VP5. This sheds light on protein structures involved in prokaryotic membrane fusion. Lipid membrane fusion is an essential function in many biological processes but little is known about membrane fusion in prokaryotes. The authors here study how haloarchaeal pleomorphic viruses (HRPVs) infect archaeal hosts. The structure-function analysis of the spike proteins shed light on prokaryotic membrane fusion.

ACS Style

Kamel El Omari; Sai Li; Abhay Kotecha; Thomas S. Walter; Eduardo Bignon; Karl Harlos; Pentti Somerharju; Felix De Haas; Daniel K. Clare; Mika Molin; Felipe Hurtado; Mengqiu Li; Jonathan M. Grimes; Dennis H. Bamford; Nicole D. Tischler; Juha Huiskonen; David I. Stuart; Elina Roine. The structure of a prokaryotic viral envelope protein expands the landscape of membrane fusion proteins. Nature Communications 2019, 10, 1 -11.

AMA Style

Kamel El Omari, Sai Li, Abhay Kotecha, Thomas S. Walter, Eduardo Bignon, Karl Harlos, Pentti Somerharju, Felix De Haas, Daniel K. Clare, Mika Molin, Felipe Hurtado, Mengqiu Li, Jonathan M. Grimes, Dennis H. Bamford, Nicole D. Tischler, Juha Huiskonen, David I. Stuart, Elina Roine. The structure of a prokaryotic viral envelope protein expands the landscape of membrane fusion proteins. Nature Communications. 2019; 10 (1):1-11.

Chicago/Turabian Style

Kamel El Omari; Sai Li; Abhay Kotecha; Thomas S. Walter; Eduardo Bignon; Karl Harlos; Pentti Somerharju; Felix De Haas; Daniel K. Clare; Mika Molin; Felipe Hurtado; Mengqiu Li; Jonathan M. Grimes; Dennis H. Bamford; Nicole D. Tischler; Juha Huiskonen; David I. Stuart; Elina Roine. 2019. "The structure of a prokaryotic viral envelope protein expands the landscape of membrane fusion proteins." Nature Communications 10, no. 1: 1-11.

Letter
Published: 21 November 2018 in Nature
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The zoonotic transmission of hantaviruses from their rodent hosts to humans in North and South America is associated with a severe and frequently fatal respiratory disease, hantavirus pulmonary syndrome (HPS)1,2. No specific antiviral treatments for HPS are available, and no molecular determinants of in vivo susceptibility to hantavirus infection and HPS are known. Here we identify the human asthma-associated gene protocadherin-1 (PCDH1)3,4,5,6 as an essential determinant of entry and infection in pulmonary endothelial cells by two hantaviruses that cause HPS, Andes virus (ANDV) and Sin Nombre virus (SNV). In vitro, we show that the surface glycoproteins of ANDV and SNV directly recognize the outermost extracellular repeat domain of PCDH1—a member of the cadherin superfamily7,8—to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.

ACS Style

Rohit K Jangra; Andrew S. Herbert; Rong Li; Lucas Jae; Lara M. Kleinfelter; Megan Slough; Sarah L. Barker; Pablo Guardado-Calvo; Gleyder Román-Sosa; M. Eugenia Dieterle; Ana I. Kuehne; Nicolás A. Muena; Ariel S. Wirchnianski; Elisabeth K. Nyakatura; J. Maximilian Fels; Melinda Ng; Eva Mittler; James Pan; Sushma Bharrhan; Anna Z. Wec; Jonathan R. Lai; Sachdev S. Sidhu; Nicole Tischler; Felix Rey; Jason Moffat; Thijn R. Brummelkamp; Zhongde Wang; John M. Dye; Kartik Chandran. Protocadherin-1 is essential for cell entry by New World hantaviruses. Nature 2018, 563, 559 -563.

AMA Style

Rohit K Jangra, Andrew S. Herbert, Rong Li, Lucas Jae, Lara M. Kleinfelter, Megan Slough, Sarah L. Barker, Pablo Guardado-Calvo, Gleyder Román-Sosa, M. Eugenia Dieterle, Ana I. Kuehne, Nicolás A. Muena, Ariel S. Wirchnianski, Elisabeth K. Nyakatura, J. Maximilian Fels, Melinda Ng, Eva Mittler, James Pan, Sushma Bharrhan, Anna Z. Wec, Jonathan R. Lai, Sachdev S. Sidhu, Nicole Tischler, Felix Rey, Jason Moffat, Thijn R. Brummelkamp, Zhongde Wang, John M. Dye, Kartik Chandran. Protocadherin-1 is essential for cell entry by New World hantaviruses. Nature. 2018; 563 (7732):559-563.

Chicago/Turabian Style

Rohit K Jangra; Andrew S. Herbert; Rong Li; Lucas Jae; Lara M. Kleinfelter; Megan Slough; Sarah L. Barker; Pablo Guardado-Calvo; Gleyder Román-Sosa; M. Eugenia Dieterle; Ana I. Kuehne; Nicolás A. Muena; Ariel S. Wirchnianski; Elisabeth K. Nyakatura; J. Maximilian Fels; Melinda Ng; Eva Mittler; James Pan; Sushma Bharrhan; Anna Z. Wec; Jonathan R. Lai; Sachdev S. Sidhu; Nicole Tischler; Felix Rey; Jason Moffat; Thijn R. Brummelkamp; Zhongde Wang; John M. Dye; Kartik Chandran. 2018. "Protocadherin-1 is essential for cell entry by New World hantaviruses." Nature 563, no. 7732: 559-563.

Research article
Published: 26 October 2016 in PLoS Pathogens
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Hantaviruses are important emerging human pathogens and are the causative agents of serious diseases in humans with high mortality rates. Like other members in the Bunyaviridae family their M segment encodes two glycoproteins, GN and GC, which are responsible for the early events of infection. Hantaviruses deliver their tripartite genome into the cytoplasm by fusion of the viral and endosomal membranes in response to the reduced pH of the endosome. Unlike phleboviruses (e.g. Rift valley fever virus), that have an icosahedral glycoprotein envelope, hantaviruses display a pleomorphic virion morphology as GN and GC assemble into spikes with apparent four-fold symmetry organized in a grid-like pattern on the viral membrane. Here we present the crystal structure of glycoprotein C (GC) from Puumala virus (PUUV), a representative member of the Hantavirus genus. The crystal structure shows GC as the membrane fusion effector of PUUV and it presents a class II membrane fusion protein fold. Furthermore, GC was crystallized in its post-fusion trimeric conformation that until now had been observed only in Flavi- and Togaviridae family members. The PUUV GC structure together with our functional data provides intriguing evolutionary and mechanistic insights into class II membrane fusion proteins and reveals new targets for membrane fusion inhibitors against these important pathogens.

ACS Style

Shmuel Willensky; Hagit Bar-Rogovsky; Eduardo Bignon; Nicole Tischler; Yorgo Evgenios Modis; Moshe Dessau. Crystal Structure of Glycoprotein C from a Hantavirus in the Post-fusion Conformation. PLoS Pathogens 2016, 12, e1005948 .

AMA Style

Shmuel Willensky, Hagit Bar-Rogovsky, Eduardo Bignon, Nicole Tischler, Yorgo Evgenios Modis, Moshe Dessau. Crystal Structure of Glycoprotein C from a Hantavirus in the Post-fusion Conformation. PLoS Pathogens. 2016; 12 (10):e1005948.

Chicago/Turabian Style

Shmuel Willensky; Hagit Bar-Rogovsky; Eduardo Bignon; Nicole Tischler; Yorgo Evgenios Modis; Moshe Dessau. 2016. "Crystal Structure of Glycoprotein C from a Hantavirus in the Post-fusion Conformation." PLoS Pathogens 12, no. 10: e1005948.

Research article
Published: 26 October 2016 in PLOS Pathogens
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Hantaviruses are zoonotic viruses transmitted to humans by persistently infected rodents, giving rise to serious outbreaks of hemorrhagic fever with renal syndrome (HFRS) or of hantavirus pulmonary syndrome (HPS), depending on the virus, which are associated with high case fatality rates. There is only limited knowledge about the organization of the viral particles and in particular, about the hantavirus membrane fusion glycoprotein Gc, the function of which is essential for virus entry. We describe here the X-ray structures of Gc from Hantaan virus, the type species hantavirus and responsible for HFRS, both in its neutral pH, monomeric pre-fusion conformation, and in its acidic pH, trimeric post-fusion form. The structures confirm the prediction that Gc is a class II fusion protein, containing the characteristic β-sheet rich domains termed I, II and III as initially identified in the fusion proteins of arboviruses such as alpha- and flaviviruses. The structures also show a number of features of Gc that are distinct from arbovirus class II proteins. In particular, hantavirus Gc inserts residues from three different loops into the target membrane to drive fusion, as confirmed functionally by structure-guided mutagenesis on the HPS-inducing Andes virus, instead of having a single “fusion loop”. We further show that the membrane interacting region of Gc becomes structured only at acidic pH via a set of polar and electrostatic interactions. Furthermore, the structure reveals that hantavirus Gc has an additional N-terminal “tail” that is crucial in stabilizing the post-fusion trimer, accompanying the swapping of domain III in the quaternary arrangement of the trimer as compared to the standard class II fusion proteins. The mechanistic understandings derived from these data are likely to provide a unique handle for devising treatments against these human pathogens. Hantaviruses belong to the Bunyaviridae family of enveloped viruses. This family englobes in total five established genera: Tospovirus (infecting plants), and Phlebovirus, Orthobunyavirus, Nairovirus and Hantavirus infecting animals, some of which cause serious disease in humans. An important characteristic of the hantaviruses is that they are not transmitted to humans by arthropod vectors, as those from the other genera, but by direct exposure to excretions from infected small mammals. As all enveloped viruses, they require the activity of a membrane fusogenic protein, Gc, for entry into their target cells. Our structural analysis of the hantavirus fusion protein Gc led to the identification of a conserved pattern of cysteines involved in disulfide bonds stabilizing the Gc fold. This motif is matched exclusively by all of the available bunyavirus Gc sequences in the database, with the notable exception of phlebovirus Gc, which appears closer in structure to the fusion proteins of other families of arthropod-borne viruses, such as the flaviviruses and alphaviruses. This analysis further suggests mechanistic similarities with hantaviruses in the fusion mechanism of viruses in the remaining three most closely related bunyavirus genera, which we propose belong to a new separate sub-class of fusion proteins with a multipartite membrane targeting region.

ACS Style

Pablo Guardado-Calvo; Eduardo A. Bignon; Eva Stettner; Scott Allen Jeffers; Jimena Perez-Vargas; Gérard Pehau-Arnaudet; M. Alejandra Tortorici; Jean-Luc Jestin; Patrick England; Nicole D. Tischler; Félix A. Rey. Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc. PLOS Pathogens 2016, 12, e1005813 .

AMA Style

Pablo Guardado-Calvo, Eduardo A. Bignon, Eva Stettner, Scott Allen Jeffers, Jimena Perez-Vargas, Gérard Pehau-Arnaudet, M. Alejandra Tortorici, Jean-Luc Jestin, Patrick England, Nicole D. Tischler, Félix A. Rey. Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc. PLOS Pathogens. 2016; 12 (10):e1005813.

Chicago/Turabian Style

Pablo Guardado-Calvo; Eduardo A. Bignon; Eva Stettner; Scott Allen Jeffers; Jimena Perez-Vargas; Gérard Pehau-Arnaudet; M. Alejandra Tortorici; Jean-Luc Jestin; Patrick England; Nicole D. Tischler; Félix A. Rey. 2016. "Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc." PLOS Pathogens 12, no. 10: e1005813.

Research article
Published: 14 July 2016 in PLOS Neglected Tropical Diseases
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Hantaviruses can cause hantavirus pulmonary syndrome or hemorrhagic fever with renal syndrome in humans. To enter cells, hantaviruses fuse their envelope membrane with host cell membranes. Previously, we have shown that the Gc envelope glycoprotein is the viral fusion protein sharing characteristics with class II fusion proteins. The ectodomain of class II fusion proteins is composed of three domains connected by a stem region to a transmembrane anchor in the viral envelope. These fusion proteins can be inhibited through exogenous fusion protein fragments spanning domain III (DIII) and the stem region. Such fragments are thought to interact with the core of the fusion protein trimer during the transition from its pre-fusion to its post-fusion conformation. Based on our previous homology model structure for Gc from Andes hantavirus (ANDV), here we predicted and generated recombinant DIII and stem peptides to test whether these fragments inhibit hantavirus membrane fusion and cell entry. Recombinant ANDV DIII was soluble, presented disulfide bridges and beta-sheet secondary structure, supporting the in silico model. Using DIII and the C-terminal part of the stem region, the infection of cells by ANDV was blocked up to 60% when fusion of ANDV occurred within the endosomal route, and up to 95% when fusion occurred with the plasma membrane. Furthermore, the fragments impaired ANDV glycoprotein-mediated cell-cell fusion, and cross-inhibited the fusion mediated by the glycoproteins from Puumala virus (PUUV). The Gc fragments interfered in ANDV cell entry by preventing membrane hemifusion and pore formation, retaining Gc in a non-resistant homotrimer stage, as described for DIII and stem peptide inhibitors of class II fusion proteins. Collectively, our results demonstrate that hantavirus Gc shares not only structural, but also mechanistic similarity with class II viral fusion proteins, and will hopefully help in developing novel therapeutic strategies against hantaviruses.

ACS Style

Gonzalo P. Barriga; Fernando Villalón-Letelier; Chantal L. Márquez; Eduardo A. Bignon; Rodrigo Acuna; Breyan Ross; Octavio Monasterio; Gonzalo A. Mardones; Simon E. Vidal; Nicole D. Tischler. Inhibition of the Hantavirus Fusion Process by Predicted Domain III and Stem Peptides from Glycoprotein Gc. PLOS Neglected Tropical Diseases 2016, 10, e0004799 .

AMA Style

Gonzalo P. Barriga, Fernando Villalón-Letelier, Chantal L. Márquez, Eduardo A. Bignon, Rodrigo Acuna, Breyan Ross, Octavio Monasterio, Gonzalo A. Mardones, Simon E. Vidal, Nicole D. Tischler. Inhibition of the Hantavirus Fusion Process by Predicted Domain III and Stem Peptides from Glycoprotein Gc. PLOS Neglected Tropical Diseases. 2016; 10 (7):e0004799.

Chicago/Turabian Style

Gonzalo P. Barriga; Fernando Villalón-Letelier; Chantal L. Márquez; Eduardo A. Bignon; Rodrigo Acuna; Breyan Ross; Octavio Monasterio; Gonzalo A. Mardones; Simon E. Vidal; Nicole D. Tischler. 2016. "Inhibition of the Hantavirus Fusion Process by Predicted Domain III and Stem Peptides from Glycoprotein Gc." PLOS Neglected Tropical Diseases 10, no. 7: e0004799.

Review
Published: 24 May 2016 in Viruses
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The Bunyaviridae is the largest family of RNA viruses, with over 350 members worldwide. Several of these viruses cause severe diseases in livestock and humans. With an increasing number and frequency of outbreaks, bunyaviruses represent a growing threat to public health and agricultural productivity globally. Yet, the receptors, cellular factors and endocytic pathways used by these emerging pathogens to infect cells remain largely uncharacterized. The focus of this review is on the early steps of bunyavirus infection, from virus binding to penetration from endosomes. We address current knowledge and advances for members from each genus in the Bunyaviridae family regarding virus receptors, uptake, intracellular trafficking and fusion.

ACS Style

Amelina Albornoz; Anja B. Hoffmann; Pierre-Yves Lozach; Nicole D. Tischler. Early Bunyavirus-Host Cell Interactions. Viruses 2016, 8, 143 .

AMA Style

Amelina Albornoz, Anja B. Hoffmann, Pierre-Yves Lozach, Nicole D. Tischler. Early Bunyavirus-Host Cell Interactions. Viruses. 2016; 8 (5):143.

Chicago/Turabian Style

Amelina Albornoz; Anja B. Hoffmann; Pierre-Yves Lozach; Nicole D. Tischler. 2016. "Early Bunyavirus-Host Cell Interactions." Viruses 8, no. 5: 143.

Journal article
Published: 01 November 2015 in Journal of General Virology
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The hantavirus membrane fusion process is mediated by the Gc envelope glycoprotein from within endosomes. Yet, little is known about the specific mechanism that triggers Gc fusion activation and its pre- and post-fusion conformations. We established cell-free in vitro systems to characterize hantavirus fusion activation. Low pH was sufficient to trigger the interaction of virus-like particles (VLPs) with liposomes. This interaction was dependent on a pre-fusion glycoprotein arrangement. Further, low pH induced Gc multimerization changes leading to non-reversible Gc homotrimers. These trimers were resistant to detergent, heat and protease digestion, suggesting characteristics of a stable post-fusion structure. No acid-dependent oligomerization rearrangement was detected for the trypsin-sensitive Gn envelope glycoprotein. Finally, acidification induced fusion of glycoprotein-expressing effector cells with non-susceptible CHO cells. Together, the data provide novel information on the Gc fusion trigger and its non-reversible activation involving lipid interaction, multimerization changes and membrane fusion which ultimately allow hantavirus entry into cells.

ACS Style

Rodrigo Acuña; Eduardo A. Bignon; Roberta Mancini; Pierre-Yves Lozach; Nicole D. Tischler. Acidification triggers Andes hantavirus membrane fusion and rearrangement of Gc into a stable post-fusion homotrimer. Journal of General Virology 2015, 96, 3192 -3197.

AMA Style

Rodrigo Acuña, Eduardo A. Bignon, Roberta Mancini, Pierre-Yves Lozach, Nicole D. Tischler. Acidification triggers Andes hantavirus membrane fusion and rearrangement of Gc into a stable post-fusion homotrimer. Journal of General Virology. 2015; 96 (11):3192-3197.

Chicago/Turabian Style

Rodrigo Acuña; Eduardo A. Bignon; Roberta Mancini; Pierre-Yves Lozach; Nicole D. Tischler. 2015. "Acidification triggers Andes hantavirus membrane fusion and rearrangement of Gc into a stable post-fusion homotrimer." Journal of General Virology 96, no. 11: 3192-3197.

Review
Published: 21 April 2014 in Viruses
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In recent years, ultrastructural studies of viral surface spikes from three different genera within the Bunyaviridae family have revealed a remarkable diversity in their spike organization. Despite this structural heterogeneity, in every case the spikes seem to be composed of heterodimers formed by Gn and Gc envelope glycoproteins. In this review, current knowledge of the Gn and Gc structures and their functions in virus cell entry and exit is summarized. During virus cell entry, the role of Gn and Gc in receptor binding has not yet been determined. Nevertheless, biochemical studies suggest that the subsequent virus-membrane fusion activity is accomplished by Gc. Further, a class II fusion protein conformation has been predicted for Gc of hantaviruses, and novel crystallographic data confirmed such a fold for the Rift Valley fever virus (RVFV) Gc protein. During virus cell exit, the assembly of different viral components seems to be established by interaction of Gn and Gc cytoplasmic tails (CT) with internal viral ribonucleocapsids. Moreover, recent findings show that hantavirus glycoproteins accomplish important roles during virus budding since they self-assemble into virus-like particles. Collectively, these novel insights provide essential information for gaining a more detailed understanding of Gn and Gc functions in the early and late steps of the hantavirus infection cycle.

ACS Style

Nicolás Cifuentes-Muñoz; Natalia Salazar-Quiroz; Nicole D. Tischler. Hantavirus Gn and Gc Envelope Glycoproteins: Key Structural Units for Virus Cell Entry and Virus Assembly. Viruses 2014, 6, 1801 -1822.

AMA Style

Nicolás Cifuentes-Muñoz, Natalia Salazar-Quiroz, Nicole D. Tischler. Hantavirus Gn and Gc Envelope Glycoproteins: Key Structural Units for Virus Cell Entry and Virus Assembly. Viruses. 2014; 6 (4):1801-1822.

Chicago/Turabian Style

Nicolás Cifuentes-Muñoz; Natalia Salazar-Quiroz; Nicole D. Tischler. 2014. "Hantavirus Gn and Gc Envelope Glycoproteins: Key Structural Units for Virus Cell Entry and Virus Assembly." Viruses 6, no. 4: 1801-1822.

Brief report
Published: 11 December 2013 in Journal of Virology
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How hantaviruses assemble and exit infected cells remains largely unknown. Here, we show that the expression of Andes (ANDV) and Puumala (PUUV) hantavirus Gn and Gc envelope glycoproteins lead to their self-assembly into virus-like particles (VLPs) which were released to cell supernatants. The viral nucleoprotein was not required for particle formation. Further, a Gc endodomain deletion mutant did not abrogate VLP formation. The VLPs were pleomorphic, exposed protrusions and reacted with patient sera.

ACS Style

Rodrigo Acuña; Nicolás Cifuentes-Muñoz; Chantal L. Márquez; Manuela Bulling; Jonas Klingstrom; Roberta Mancini; Pierre-Yves Lozach; Nicole D. Tischler. Hantavirus Gn and Gc Glycoproteins Self-Assemble into Virus-Like Particles. Journal of Virology 2013, 88, 2344 -2348.

AMA Style

Rodrigo Acuña, Nicolás Cifuentes-Muñoz, Chantal L. Márquez, Manuela Bulling, Jonas Klingstrom, Roberta Mancini, Pierre-Yves Lozach, Nicole D. Tischler. Hantavirus Gn and Gc Glycoproteins Self-Assemble into Virus-Like Particles. Journal of Virology. 2013; 88 (4):2344-2348.

Chicago/Turabian Style

Rodrigo Acuña; Nicolás Cifuentes-Muñoz; Chantal L. Márquez; Manuela Bulling; Jonas Klingstrom; Roberta Mancini; Pierre-Yves Lozach; Nicole D. Tischler. 2013. "Hantavirus Gn and Gc Glycoproteins Self-Assemble into Virus-Like Particles." Journal of Virology 88, no. 4: 2344-2348.