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Human Emerging and Re-emerging InfectionsViral and Parasitic InfectionsEdited by Sunit K. Singh

VOLUME 1

Human Emerging andRe-emerging Infections

Human Emerging andRe-emerging Infections

Viral and Parasitic Infections

Volume I

Edited by

Sunit Kumar SinghLaboratory of Human Molecular Virology and Immunology

Molecular Biology Unit, Faculty of Medicine, Institute of Medical SciencesBanaras Hindu University, Varanasi, India

Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Human emerging and re-emerging infections / edited by Sunit K. Singh.p. ; cm.

Includes index.ISBN 978-1-118-64471-3 (cloth)I. Singh, Sunit K., editor.[DNLM: 1. Communicable Diseases, Emerging. WA 110]RA643616.9–dc23

2015028631

Printed in Singapore

oBook ISBN: 9781118644843ePDF ISBN: 9781118644829ePub ISBN: 9781118644645

10 9 8 7 6 5 4 3 2 1

Dedicated to my parents

Contents

List of Contributors, ix

Preface, xvii

Acknowledgments, xix

About the Editor, xxi

1 Pathogenesis of the Old World Arenavirusesin Humans, 1Igor S. Lukashevich

2 Pathogenesis of New World Arenaviruses inHumans, 29Veronica Martın, Stefan Kunz, Esteban Domingo,and Noemı Sevilla

3 Pathogenesis of Emerging and NovelBunyaviruses in Humans, 43Cong Jin and Dexin Li

4 Pathogenesis of Rift Valley Fever inHumans, 73Inaia Phoenix and Tetsuro Ikegami

5 Pathogenesis of Hantavirus Infections, 95Tarja Sironen, Olli Vapalahti, and AlexanderPlyusnin

6 Molecular Pathogenesis of JapaneseEncephalitis Virus Infection, 113Sunit Kumar Singh

7 Dengue Virus Infection in Humans:Epidemiology, Biology, Pathogenesis, andClinical Aspects, 125Fatih Anfasa, Leonard Nainggolan, and ByronE. E. Martina

8 Pathogenesis of West Nile Virus inHumans, 145Rianna Vandergaast, Katherine L. Hussmann,and Brenda L. Fredericksen

9 Overview on Chikungunya VirusPathogenesis, 177Sunit Kumar Singh

10 Nipah Virus Infections in Humans, 189Kaw Bing Chua, Chong Tin Tan, and Kum ThongWong

11 Pathogenesis of Hendra Virus in Humans, 207Chad E. Mire, Benjamin A. Satterfield, andThomas W. Geisbert

12 Pathogenesis of Rotavirus in Humans, 227Carlos Fernando Narvaez, Martha C. Mesa,Alfonso Barreto, Luz-Stella Rodrıguez, and JuanaAngel

13 Pathogenesis of Papillomaviruses inHumans, 243John Doorbar

14 Kaposi’s Sarcoma–Associated HerpesvirusPathogenesis, 265Lia R. Walker, Anshul V. Subramanya, Zeal T.Akula, and Shaw M. Akula

15 Microsporidiosis in Humans, 281Henry Shikani, Elizabeth S. Didier, and Louis M.Weiss

16 Pathogenesis of Toxoplasma gondii inHumans, 303Hong-Juan Peng, Feng Tan, and David S. Lindsay

17 Pathogenesis of Human AfricanTrypanosomiasis, 319Jennifer Cnops and Stefan Magez

18 Pathogenesis of Leishmaniasis in Humans, 337Steve Oghumu, Gayathri Natarajan, and AbhayR. Satoskar

19 Pathogenesis of Chagas Disease inHumans, 349Marıa-Jesus Pinazo, Faustino Torrico, andJoaquim Gascon

20 Pathogenesis of Cryptosporidium inHumans, 371Gabriela Certad, Marwan Osman, and SadiaBenamrouz

21 Pathogenesis of Malarial Parasites inHumans, 393Caroline Lin Lin Chua, Ricardo Ataıde,Alexandra J. Umbers, and Phillipe Boeuf

viii Contents

22 Pathogenesis of Trichomonas vaginalis inHumans, 423Marlene Benchimol, Antonio Pereira-Neves, andWanderley de Souza

23 Loa loa Pathogenesis in Humans, 441Akue Jean Paul

24 Nematode Larva Migrans, 453Kumara Singaravelu, Christina M. Coyle, Yuri C.Martins, Louis M. Weiss, Fabiana S. Machado,Herbert B. Tanowitz, and Kevin R. Kazacos

25 Pathogenesis of Human Schistosomiasis, 481Thien-Linh Le, Susanne H. Sokolow, OlfatHammam, Chi-Ling Fu, and Michael Hsieh

26 Vector-Borne Parasitic Zoonotic Infectionsin Humans, 505Domenico Otranto and Filipe Dantas-Torres

Index, i1

List of Contributors

Shaw M. AkulaDepartment of Microbiology and Immunology, BrodySchool of Medicine at East Carolina University,Greenville, NC, USA

Zeal T. AkulaDepartment of Microbiology and Immunology, BrodySchool of Medicine at East Carolina University,Greenville, NC, USA

Fatih AnfasaDepartment of Viroscience, Erasmus Medical Center,Rotterdam, The NetherlandsDepartment of Internal Medicine, Faculty of Medicine,Universitas Indonesia, Jakarta, Indonesia

Juana AngelInstituto de Genetica Humana, Facultad de Medicina,Pontificia Universidad Javeriana, Bogota, Colombia

Olympia ApostolopoulouDepartment of Critical Care Medicine, Medical School,University of Athens, Chaidari-Athens, Greece

George ArabatzisMycology Research Laboratory, Department ofMicrobiology, Medical School, National andKapodistrian University, Athens, Greece

Alicia I. ArechavalaMycology Unit, Francisco J. Muniz Hospital, BuenosAires City, Argentine Republic

Ricardo AtaıdeBurnet Institute, Center for Biomedical Research,Melbourne, Victoria Australia

Lucilla BaldassarriDepartment of Infectious, Parasitic andImmune-Mediated Diseases, Istituto Superiore diSanita, Rome, Italy

Monique BarelUniversite Paris Descartes, Sorbonne Paris Cite,Batiment Leriche, Paris, FranceINSERM, U1151, Unite de Pathogenie des InfectionsSystemiques, Paris, France

Alfonso BarretoDepartamento de Microbiologıa, Facultad de Ciencias,Pontificia Universidad Javeriana, Bogota, Colombia

Daniela BassoDepartment of Medicine-DIMED, University of Padova,Padova, Italy

Sadia BenamrouzBiologie et Diversite des Pathogenes EucaryotesEmergents (BDEEP), Centre d’Infection et d’Immunitede Lille (CIIL), Institut Pasteur de Lille, INSERM U1019,CNRS UMR 8402, Universite de Lille, FranceEcologie et Biodiversite, Faculte Libre des Sciences etTechnologies de Lille, Universite Catholique de Lille,France

Marlene BenchimolUniversidade do Grande Rio, UNIGRANRIO, Rio deJaneiro, BrazilCentro Nacional de Biologia Estrutural e Bioimagem(CENABIO), Universidade Federal do Rio de Janeiro,Rio de Janeiro, BrazilInstituto Nacional de Metrologia, Qualidade eTecnologia – Inmetro, Duque de Caxias, Rio de Janeiro,Brazil

Mark Eric BenbowDepartment of Entomology and Department ofOsteopathic Medical Specialties, Michigan StateUniversity, MI, USA

Carlos Fernandez BenıtezUnidad de Gestion Clınica Centro de Salud de Laviana,Asturias, Spain

Alberto BerardiNeonatal Intensive Care Unit, Polyclinic UniversityHospital, Modena, Italy

Philippe BoeufBurnet Institute, Center for Biomedical Research,Melbourne, Victoria Australia

Jose Antonio BogaServicio de Microbiologıa, Hospital UniversitarioCentral de Asturias, Oviedo, Spain

Michael S. BronzeDepartment of Internal Medicine, University ofOklahoma Health Sciences Center, Oklahoma City, OK,USA

Andreas BurkovskiDepartment Biologie, Friedrich-Alexander-UniversitatErlangen-Nurnberg, Erlangen, Germany

x List of Contributors

Gabriela CertadBiologie et Diversite des Pathogenes EucaryotesEmergents (BDEEP), Centre d’Infection et d’Immunitede Lille (CIIL), Institut Pasteur de Lille, INSERM U1019,CNRS UMR 8402, Universite de Lille, France

Alain CharbitUniversite Paris Descartes, Sorbonne Paris Cite,Batiment Leriche, Paris, FranceINSERM, U1151, Unite de Pathogenie des InfectionsSystemiques, Paris, France

Kaw Bing ChuaTemasek Life Sciences Laboratory, National Universityof Singapore, Singapore

Jennifer CnopsLaboratory for Cellular and Molecular Immunology,Vrije Universiteit Brussel, Brussels, BelgiumDepartment of Structural Biology, VIB, Brussels,Belgium

Alexandra CorreiaInstituto de Biologia Molecular e Celular, Universidadedo Porto, Porto, PortugalInstituto de Ciencias Biomedicas de Abel Salazar,Universidade do Porto, Porto, Portugal

Christina M. CoyleDepartments of Medicine, Jacobi Medical Center andthe Montefiore Medical Center, Albert Einstein Collegeof Medicine, Bronx, NY, USA

Roberta CretiDepartment of Infectious, Parasitic andImmune-Mediated Diseases, Istituto Superiore diSanita, Rome, Italy

Filipe Dantas-TorresAggeu Magalhaes Research Centre, Oswaldo CruzFoundation, Recife, Pernambuco, Brazil

Frank R. DeLeoLaboratory of Human Bacterial Pathogenesis, RockyMountain Laboratories, National Institute of Allergyand Infectious Diseases, National Institutes of Health,Hamilton, MT, USA

Wanderley de SouzaCentro Nacional de Biologia Estrutural e Bioimagem(CENABIO), Universidade Federal do Rio de Janeiro,Rio de Janeiro, BrazilInstituto Nacional de Metrologia, Qualidade eTecnologia – Inmetro, Duque de Caxias, Rio de Janeiro,BrazilLaboratorio de Ultraestrutura Celular Hertha Meyer,Universidade Federal do Rio de Janeiro, Brazil

Elizabeth S. DidierDivision of Microbiology, Tulane National PrimateResearch Center, Covington, LA, USADepartment of Tropical Medicine, School of PublicHealth and Tropical Medicine, Tulane University, NewOrleans, LA, USA

George DimopoulosDepartment of Critical Care Medicine, Medical School,University of Athens, Chaidari-Athens, Greece

Esteban DomingoCentro de Biologıa Molecular “Severo Ochoa”(CSIC-UAM), Consejo Superior de InvestigacionesCientıficas (CSIC), Campus de Cantoblanco, Madrid,Spain

John DoorbarDepartment of Pathology, University of Cambridge,Cambridge, United Kingdom

Laurent DortetINSERM U914 “Emerging Resistance to Antibiotics”, LeKremlin-Bicetre, Paris, France

Douglas A. DrevetsDepartment of Internal Medicine, University ofOklahoma Health Sciences Center, Oklahoma City, OK,USADepartment of Veterans Affairs Medical Center,Oklahoma City, OK, USA

Taylor EddensRichard King Mellon Foundation Institute for PediatricResearch, Children’s Hospital of Pittsburgh of UPMC,Pittsburgh, PA, USA

Peter Q. EichackerCritical Care Medicine Department, Clinical Center,National Institutes of Health, Bethesda, MD, USA

Brenda L. FredericksenMaryland Pathogen Research Institute, University ofMaryland, College Park, MD, USADepartment of Cell Biology and Molecular Genetics,University of Maryland College Park, College Park,MD, USA

Chi-Ling FuDepartment of Urology, Stanford University School ofMedicine, Stanford, CA, USA

Joaquim GasconGlobal Health Institute (ISGlobal), HospitalClınic-Universitat de Barcelona, Barcelona, Spain

Thomas W. GeisbertDepartment of Microbiology and Immunology, TheUniversity of Texas Medical Branch, Galveston, TX, USA

Giovanni GherardiCentro Integrato di Ricerche, Laboratory ofMicrobiology, University Campus Biomedico, Rome,Italy

Namraj GoireMicrobiology Department, PathWest LaboratoryMedicine WA, Queen Elizabeth II Medical Centre,Nedlands, Western Australia, AustraliaQueensland Paediatric Infectious Diseases Laboratory,Queensland Children’s Medical Research Institute,Royal Children’s Hospital, Brisbane, Queensland,Australia

List of Contributors xi

Thaddeus G. GolosDepartment of Comparative Biosciences, WisconsinNational Primate Research Center, Madison, WI, USA

Christopher R. GourleySchool of Molecular Biosciences, College of VeterinaryMedicine, Washington State University, Pullman, WA,USA

Nathalie GrallLaboratoire de Bacteriologie, Hopital Bichat-ClaudeBernard, APHP, Paris, FranceEA 3964 - Universite Paris-Diderot, Paris, France

Luis Otero GuerraServicio de Microbiologıa, Hospital de Cabuenes, Gijon,Asturias, Spain

Belinda HallDepartment of Microbial and Cellular Sciences andSchool of Biosciences and Medicine, University ofSurrey, Guildford, UK

John J. HalperinDepartment of Neurosciences, Overlook MedicalCenter, Summit, NJ, USASidney Kimmel Medical College of Thomas JeffersonUniversity, Philadelphia, PA, USA

Olfat HammamDepartment of Urology, Stanford University School ofMedicine, Stanford, CA, USA

Alistair HarrisonThe Center for Microbial Pathogenesis, The ResearchInstitute at Nationwide Children’s Hospital, Columbus,OH, USA

Elizabeth L. HartlandDepartment of Microbiology and Immunology,University of Melbourne, Victoria, Australia

Caitlin HicksJohns Hopkins Hospital, Department of Surgery,Baltimore, MD, USA

Michael HsiehDivision of Urology, Children’s National Health System,Washington, DC, USADepartments of Urology and Pediatrics, The GeorgeWashington University, Washington, DC, USAThe Biomedical Research Institute, Rockville, MD, USA

Katherine L. HussmannDepartment of Cell Biology and Molecular Genetics,University of Maryland College Park, College Park,MD, USA

Tetsuro IkegamiDepartment of Pathology, The University of TexasMedical Branch at Galveston, Galveston, TX, USA

J. Igor IruretagoyenaDepartment of Obstetrics and Gynecology, Universityof Wisconsin-Madison, Madison, WI, USA

Cong JinNational Institute for Viral Disease Control andPrevention, Chinese Center for Disease Control andPrevention, Beijing, China

Heather Williamson JordanDepartment of Biological Sciences, Mississippi StateUniversity, MS, USA

Aniket KalotiRichard King Mellon Foundation Institute for PediatricResearch, Children’s Hospital of Pittsburgh of UPMC,Pittsburgh, PA, USA

Sophia KathariouDepartment of Food, Bioprocessing and NutritionSciences, North Carolina State University, Raleigh, NC,USA

Kevin R. KazacosDepartment of Comparative Pathobiology, PurdueUniversity College of Veterinary Medicine, WestLafayette, IN, USA

Jay K. KollsRichard King Mellon Foundation Institute for PediatricResearch, Children’s Hospital of Pittsburgh of UPMC,Pittsburgh, PA, USA

Michael E. KonkelSchool of Molecular Biosciences, College of VeterinaryMedicine, Washington State University, Pullman, WA,USA

Stefan KunzInstitute of Microbiology, University Hospital Centerand University of Lausanne, Lausanne, Switzerland

Monica M. LahraNeisseria Reference Laboratory and WHOCollaborating Centre for STD, MicrobiologyDepartment, South Eastern Area Laboratory Services,Prince of Wales Hospital, Sydney, New South Wales,Australia

Thien-Linh LeDepartment of Urology, Stanford University School ofMedicine, Stanford, CA, USA

Dexin LiNational Institute for Viral Disease Control andPrevention, Chinese Center for Disease Control andPrevention, Beijing, China

Caroline Lin Lin ChuaTaylor’s University Lakeside Campus, School ofBiosciences, Subang Jaya, Selangor, Malaysia

xii List of Contributors

David S. LindsayCenter for Molecular Medicine and Infectious Diseases,Department of Biological Sciences and Pathobiology,Virginia-Maryland Regional College of VeterinaryMedicine, Virginia Tech, Blacksburg, VA, USA

Camille LochtUniv. Lille, U1019 - UMR 8204 - CIIL - Centred’Infection et d’Immunite de Lille, F-59000 Lille, FranceCNRS, UMR 8204, F-59000 Lille, FranceInserm, U1019, F-59000 Lille, FranceCHU Lille, F-59000 Lille, FranceInstitut Pasteur de Lille, F-59000 Lille, France

Thea LuLaboratory of Human Bacterial Pathogenesis, RockyMountain Laboratories, National Institute of Allergyand Infectious Diseases, National Institutes of Health,Hamilton, MT, USA

Igor S. LukashevichDepartment of Pharmacology and Toxicology, School ofMedicine, Center for Predictive Medicine, NIH RegionalBio-containment Laboratory, University of Louisville,Louisville, USA

Fabiana S. MachadoDepartment of Biochemistry and Immunology,Institute of Biological Sciences, Faculty of Medicine,Federal University of Minas Gerais, Belo Horizonte,Brazil

Stefan MagezLaboratory for Cellular and Molecular Immunology,Vrije Universiteit Brussel, Brussels, BelgiumDepartment of Structural Biology, VIB, Brussels,Belgium

Helene MarquisDepartment of Microbiology and Immunology, CornellUniversity, Ithaca, NY, USA

Anandi MartinLaboratory of Microbiology, Department ofBiochemistry and Microbiology, Ghent University,Ghent, Belgium

Veronica MartınCentro de Investigacion en Sanidad Animal(CISA-INIA), Instituto Nacional de InvestigacionAgraria y Alimentaria, Valdeolmos, Madrid, Spain

Byron E. E. MartinaDepartment of Viroscience, Erasmus Medical Center,Rotterdam, The NetherlandsArtemis One Health Research Foundation, Utrecht,The Netherlands

Yuri C. MartinsDepartments of Pathology, Jacobi Medical Center andthe Montefiore Medical Center, Albert Einstein Collegeof Medicine, Bronx, NY, USA

Kevin M. MasonThe Center for Microbial Pathogenesis, The ResearchInstitute at Nationwide Children’s Hospital,Department of Pediatrics, Columbus, OH, USAThe Center for Microbial Interface Biology, The OhioState University, Columbus, OH, USA

Dimitrios K. MatthaiouDepartment of Critical Care Medicine, Medical School,University of Athens, Chaidari-Athens, Greece

Jean-Louis MegeUnite de Recherche sur les Maladies InfectieusesTropicales et Emergentes, Aix-Marseille Universite,Centre National de la Recherche Scientifique UniteMixte de Recherche 7278, Institut National de la Sante etde la Recherche Scientifique Unite 1095, Marseille,France

Martha C. MesaDepartamento de Microbiologıa, Facultad de Ciencias,Pontificia Universidad Javeriana, Bogota, Colombia

Nathalie MielcarekUniv. Lille, U1019 - UMR 8204 - CIIL - Centred’Infection et d’Immunite de Lille, F-59000 Lille, FranceCNRS, UMR 8204, F-59000 Lille, FranceInserm, U1019, F-59000 Lille, FranceCHU Lille, F-59000 Lille, FranceInstitut Pasteur de Lille, F-59000 Lille, France

Chad E. MireDepartment of Microbiology and Immunology, TheUniversity of Texas Medical Branch, Galveston, TX,USA

Lydia MosiUniversity of Ghana, Legon, GhanaWest African Center for Cell Biology of InfectiousPathogens, University of Ghana, Legon

Nikolaos MoussasDepartment of Critical Care Medicine, Medical School,University of Athens, Chaidari-Athens, Greece

Leonard NainggolanDepartment of Internal Medicine, Faculty of Medicine,Universitas Indonesia, Jakarta, Indonesia

Carlos Fernando NarvaezFacultad de Salud, Programa de Medicina, UniversidadSurcolombiana, Neiva, Colombia

Gayathri NatarajanDepartment of Microbiology, Ohio State University,Columbus, OH, USA

Ricardo NegroniMycology Unit, Francisco J. Muniz Hospital, BuenosAires City, Argentine Republic

List of Contributors xiii

Patrice NordmannINSERM U914 “Emerging Resistance to Antibiotics”, LeKremlin-Bicetre, Paris, FranceMedical and Molecular Microbiology Unit, Departmentof Medicine, Faculty of Science, University of Fribourg,Fribourg, Switzerland

Steve OghumuDepartment of Environmental Health Sciences, Collegeof Public Health, Ohio State University, Columbus, OH,USADepartment of Pathology, Ohio State UniversityMedical Center, Columbus, OH, USA

Marwan OsmanBiologie et Diversite des Pathogenes EucaryotesEmergents (BDEEP), Centre d’Infection et d’Immunitede Lille (CIIL), Institut Pasteur de Lille, INSERM U1019,CNRS UMR 8402, Universite de Lille, FranceCentre AZM pour la Recherche en Biotechnologie et sesApplications, Laboratoire Microbiologie, Sante etEnvironnement, Universite Libanaise, Tripoli, Lebanon

Domenico OtrantoDepartment of Veterinary Medicine, University of Bari,Valenzano (Bari), Italy

Celia PaisDepartment of Biology, Centre of Molecular andEnvironmental Biology (CBMA), University of Minho,Braga, Portugal

Juan Carlos PalominoLaboratory of Microbiology, Department ofBiochemistry and Microbiology, Ghent University,Ghent, Belgium

Akue Jean PaulInternational Center for Medical Research of Franceville(CIRMF), Franceville, Gabon

Sabine PellettDepartment of Bacteriology, University ofWisconsin-Madison, Madison, WI, USA

Michela PellosoDepartment of Medicine-DIMED, University of Padova,Padova, Italy

Hong-Juan PengDepartment of Pathogen Biology, School of PublicHealth and Tropical Medicine, Southern MedicalUniversity, Guangdong Province, P.R. China

Antonio Pereira-NevesFiocruz Pernambuco, Centro de Pesquisas AggeuMagalhaes, Departamento de Microbiologia,Laboratorio de Biologia Celular de Patogenos, Recife,BrazilCentro Nacional de Biologia Estrutural e Bioimagem(CENABIO), Universidade Federal do Rio de Janeiro,Rio de Janeiro, Brazil

Inaia PhoenixDepartment of Pathology, The University of TexasMedical Branch at Galveston, Galveston, TX, USA

Marıa-Jesus PinazoGlobal Health Institute (ISGlobal), HospitalClınic-Universitat de Barcelona, Barcelona, Spain

Mario PlebaniDepartment of Medicine-DIMED, University of Padova,Padova, Italy

Alexander PlyusninDepartment of Virology, Haartman Institute, Universityof Helsinki, Helsinki, Finland

Laurent PoirelINSERM U914 “Emerging Resistance to Antibiotics”, LeKremlin-Bicetre, Paris, FranceMedical and Molecular Microbiology Unit, Departmentof Medicine, Faculty of Science, University of Fribourg,Fribourg, Switzerland

Garyphalia PoulakouDepartment of Internal Medicine, Medical School,University of Athens, Chaidari-Athens, Greece

Kenneth E. RemyCritical Care Medicine Department, Clinical Center,National Institutes of Health, Bethesda, MD, USA

Sophie RobertsRoyal Liverpool Hospital, Liverpool, United Kingdom

Luz-Stella RodrıguezInstituto de Genetica Humana, Facultad de Medicina,Pontificia Universidad Javeriana, Bogota, Colombia

Tais Berelli SaitoDepartment of Pathology, University of Texas MedicalBranch, Galveston, TX, USA

Paula SampaioDepartment of Biology, Centre of Molecular andEnvironmental Biology (CBMA), University of Minho,Braga, Portugal

Abhay R. SatoskarDepartment of Pathology, Ohio State UniversityMedical Center, Columbus, OH, USADepartment of Microbiology, Ohio State University,Columbus, OH, USA

Benjamin A. SatterfieldDepartment of Microbiology and Immunology, TheUniversity of Texas Medical Branch, Galveston, TX, USA

Noemı SevillaCentro de Investigacion en Sanidad Animal(CISA-INIA), Instituto Nacional de InvestigacionAgraria y Alimentaria, Valdeolmos, Madrid, Spain

xiv List of Contributors

Henry ShikaniDivision of Parasitology and Tropical Medicine,Department of Pathology, Albert Einstein College ofMedicine, Bronx, NY, USA

Rachel SimmondsDepartment of Microbial and Cellular Sciences andSchool of Biosciences and Medicine, University ofSurrey, Guildford, UK

Kumara SingaraveluDepartments of Medicine, Jacobi Medical Center andthe Montefiore Medical Center, Albert Einstein Collegeof Medicine, Bronx, NY, USA

Sunit Kumar SinghLaboratory of Human Molecular Virology andImmunology, Molecular Biology Unit, Faculty ofMedicine, Institute of Medical Sciences, Banaras HinduUniversity, Varanasi, India

Tarja SironenDepartment of Virology, Haartman Institute, Universityof Helsinki, Helsinki, Finland

Susanne H. SokolowDepartment of Biology, Stanford University, Stanford,CA, USA

David J. SpeersMicrobiology Department, PathWest LaboratoryMedicine WA, Queen Elizabeth II Medical Centre,Nedlands, Western Australia, Australia

Jonathan Fernandez SuarezServicio de Microbiologıa, Hospital UniversitarioCentral de Asturias, Oviedo, Spain

Anshul V. SubramanyaDepartment of Microbiology and Immunology, BrodySchool of Medicine at East Carolina University,Greenville, NC, USA

Chong Tin TanDepartment of Medicine, University Malaya MedicalCentre, Kuala Lumpur, Malaysia

Feng TanDepartment of Parasitology, Wenzhou MedicalUniversity, Zhejiang province, P.R. China

Herbert B. TanowitzDepartment of Medicine and Pathology, Albert EinsteinCollege of Medicine, Bronx, NY, USA

Wiwit TantibhedhyabgkulUnite de Recherche sur les Maladies InfectieusesTropicales et Emergentes, Aix-Marseille Universite,Centre National de la Recherche Scientifique UniteMixte de Recherche 7278, Institut National de la Sante etde la Recherche Scientifique Unite 1095, Marseille,FranceDepartment of Immunology, Faculty of Medicine SirirajHospital, Mahidol University, Bangkok, Thailand

Alberto TessariDepartment of Medicine-DIMED, University of Padova,Padova, Italy

Faustino TorricoSchool of Medicine, San Simon University (UMSS),Cochabamba, Bolivia

Alexandra J. UmbersDepartment of Medicine, University of Melbourne,Parkville, Victoria, Australia

Fernando VazquezServicio de Microbiologıa, Hospital UniversitarioCentral de Asturias, Oviedo, SpainDepartamento Biologıa Funcional, Area deMicrobiologıa, Facultad de Medicina, Oviedo, Spain

Rianna VandergaastDepartment of Cell Biology and Molecular Genetics,University of Maryland College Park, College Park,MD, USA

Olli VapalahtiDepartment of Virology, Haartman Institute, Universityof Helsinki, Helsinki, Finland

Aristea VelegrakiMycology Research Laboratory, Department ofMicrobiology, Medical School, National andKapodistrian University, Athens, Greece

Manuel VilanovaInstituto de Biologia Molecular e Celular, Universidadedo Porto, Porto, PortugalInstituto de Ciencias Biomedicas de Abel Salazar,Universidade do Porto, Porto, Portugal

Adam J. VogrinDepartment of Microbiology and Immunology,University of Melbourne, Victoria, Australia

David H. WalkerDepartment of Pathology, University of Texas MedicalBranch, Galveston, TX, USA

Lia R. WalkerDepartment of Microbiology and Immunology, BrodySchool of Medicine at East Carolina University,Greenville, NC, USA

Louis M. WeissDivision of Infectious Diseases, Department ofMedicine, Albert Einstein College of Medicine, Bronx,NY, USA

David M. WhileyQueensland Paediatric Infectious Diseases Laboratory,Queensland Children’s Medical Research Institute,Royal Children’s Hospital, Brisbane, Queensland,Australia

List of Contributors xv

E.D. WilliamsonDefence Science and Technology Laboratory, PortonDown, Salisbury, United Kingdom

Kum Thong WongDepartment of Pathology, University MalayaMedical Centre, Kuala Lumpur,Malaysia

Pablo YagupskyClinical Microbiology Laboratory, Soroka UniversityMedical Center, Ben-Gurion University of the Negev,Beer-Sheva, Israel

Carlo-Federico ZambonDepartment of Medicine-DIMED, University of Padova,Padova, Italy

Preface

Infectious diseases are a global problem and representa continuous and increasing threat to human healthand welfare. Due to deforestation, migration of pop-ulations, travel and trade, and changes in agriculturalpractices, the infectious diseases outbreaks are takingplace frequently. Although the rate of morbidity andmortality due to infectious diseases have decreasedover the past decade, the worldwide impact of infec-tious diseases remains substantial.

Advances in the development of drugs and useof vaccines to prevent various infections have easedthe burden of infectious diseases. The evolution ofpathogens with resistance to antibacterial and antivi-ral agents continues to challenge us for the betterunderstanding of the mechanisms of drug resistanceand to devise new ways to circumvent the problem.

We have witnessed the re-emergence of malariaand tuberculosis, and the emergence of new viralinfections leading to the viral hemorrhagic feversand respiratory complications. The root causes ofthe emergence and re-emergence of infectious dis-eases include environmental changes due to urbaniza-tion and deforestation, rapid population growth, andmigration of populations. Estimation of the infectiousdisease outbreaks must include factors such as popu-lation susceptibility, infective dose, incubation period,modes of transmission, routes of transmission, mor-tality rate, effectiveness of treatment interventionsand population movement. Communicable infectiousdiseases have added another layer of complexity inthe form of transmission parameters such as period-icity of infections and secondary attack rates. There isneed of new disease-outbreak models to understandthe periodicity and patterns of outbreaks of infectiousdiseases. The capacity of all nations to recognize, pre-vent, and respond to the threat of emerging and re-emerging infectious diseases is the critical foundationfor an effective global response. Biomedical scientists

and clinicians should join their hands for collaborativeresearch in order to understand the molecular mech-anisms of pathogenesis and for developing new diag-nostic and therapeutic tools.

There is a need to enhance global investment inboth developed and developing countries to improvetheir research capacities, diagnosis, and response tothe emerging and re-emerging infections. Better coor-dination aligned to health system needs and transla-tional research capabilities are required to meet thechallenges posed by emerging and re-emerging infec-tions. Strong communication and surveillance strate-gies are required among national and internationalagencies for enhanced implementation of differentdisease control programs.

Significant progress has been made over the lastseveral years in dissecting out the molecular biol-ogy and pathogenesis of the many emerging and re-emerging pathogens. This book includes most com-mon emerging and re-emerging infections caused bybacteria, virus, fungi, and parasites. The book hasbeen published in two volumes. The volume oneincludes viral and parasitic infections, whereas vol-ume two includes bacterial and fungal infections.

This book is primarily aimed to virologists, clin-icians, biomedical researchers, health-care work-ers, microbiologists, immunologists, and students ofmedicine or biomedical sciences wishing to gain rapidoverview. This book will serve as a useful resource inthe field of infectious diseases.

A comprehensive book such as this is clearlybeyond the capacity of an individual’s efforts. Thelarge panel of internationally renowned infectiousdisease experts have contributed their chapters,whose detailed knowledge in diverse areas of infec-tious diseases have greatly enriched this book.

Sunit Kumar Singh

Acknowledgments

I acknowledge the support provided by Virologists,Microbiologists, Immunologists and Infectious Dis-eases experts, whose willingness to share their workand expertise has made this extensive overview onHuman Emerging and Re-emerging Infections possible.My appreciations extend to my family and parents fortheir understanding and support during the prepara-

tion of this book. Above all I thank my wife Seema,daughter Eshita and son Shaurya, who supported andencouraged me despite all the time it took me awayfrom them. It was a long and difficult journey forthem. I am also thankful to Ms. Stephanie Dollan andMs. Mindy Okura-Marszycki of Wiley-Blackwell fortheir help and professional support.

About the Editor

Dr. Sunit Kumar Singh completed his bachelor’sdegree at GB Pant University of Agriculture and Tech-nology, Pantnagar, India, and his master’s degree atthe CIFE, Mumbai, India. After receiving his mas-ter’s degree, Dr. Singh joined the Department ofPediatric Rheumatology, Immunology, and Infec-tious Diseases, Children’s Hospital, University ofWurzburg, Wurzburg, Germany, as a biologist. Hecompleted his PhD degree at the University ofWurzburg in the area of molecular infection biology.

Dr. Singh has completed his postdoctoral trainingsat the Department of Internal Medicine, Yale Uni-versity, School of Medicine, New Haven, CT, USA,and the Department of Neurology, University ofCalifornia Davis Medical Center, Sacramento, CA,USA, in the areas of vector-borne infectious diseasesand neuroinflammation, respectively. He has alsoworked as visiting scientist at the Department ofPathology, Albert Einstein College of Medicine,NY, USA; Department of Microbiology, College ofVeterinary Medicine, Chonbuk National University,Republic of Korea; Department of Arbovirology,Institute of Parasitology, Ceske Budejovice, CzechRepublic; and Department of Genetics and Lab-oratory Medicine, University of Geneva, Geneva,

Switzerland. He has extensive experience in the areaof virology and immunology. Dr. Singh served as ascientist and led a research group in the area of molec-ular neurovirology and inflammation biology at theprestigious CSIR–Centre for Cellular and MolecularBiology (CCMB), Hyderabad, India. Presently, he isworking as Associate Professor (Molecular Immunol-ogy) and leading a research group in the area ofhuman molecular virology and immunology, in theMolecular Biology Unit, Faculty of Medicine, Instituteof Medical Sciences (IMS), Banaras Hindu University(BHU), Varanasi, India. His main areas of researchinterest are host–pathogen interaction in hemorrhagicfever viral infections, molecular neurovirology andimmunology. There are several awards to his credit,including the Skinner Memorial Award, Travel GrantAward, NIH-Fogarty Fellowship, and Young ScientistAward. Dr. Singh has published many research papersin the areas of neurovirology and inflammation biol-ogy in various peer-reviewed journals. He has editedseveral books such as Neuroviral Infections, ViralHemorrhagic Fevers, Human Respiratory Viral Infectionsand Viral Infections and Global Change, etc. Dr. Singhis associated with several international journals ofrepute as associate editor and editorial board member.

Chapter 1

Pathogenesis of the Old WorldArenaviruses in Humans

Igor S. Lukashevich

Department of Pharmacology and Toxicology, School of Medicine, Center for Predictive Medicine, NIH Regional Bio-containment Laboratory,

University of Louisville, Louisville, USA

1.1 The Old World arenaviruses:taxonomic and zoonotic introduction

Arenaviruses represent a fast-growing group ofrodent-borne viruses (see Notes in the Proofs) whichare an example of how environmental changes dis-rupt the natural animal virus–host balance and resultin unexpected diseases. In the wild, arenaviruses existas chronic infections in specific rodent hosts. Thisprovides ideal conditions for competition within viralquasispecies for improved adaptation to the host.Analysis of arenavirus phylogeny and rodentcytochrome-b sequences provides examples of coevo-lution of arenaviruses with their rodent hosts. Basedon their antigenic properties and geographic dis-tribution approximately two dozen arenavirusesdiscovered so far are placed into two groups: theOld World (OW) or Lassa–LCMV complex and theNew World (NW) or Tacaribe complex (Salvato et al.,2012). In general, the OW viruses are hosted byrodents of the family Muridae, subfamily Murinae.The NW arenaviruses are associated with rodents ofthe subfamily Sigmodontinae which are divided intothe North and South American lineages. Phylogenet-ically the NW arenaviruses are further divided intoclades A, B, C, and a recombinant A/B clade.

Lymphocytic choriomeningitis virus (LCMV), theprototypic arenavirus that belongs to the OW group,is hosted by the house mouse (Mus musculus). Thevirus is distributed worldwide and can cause asep-tic meningitis or meningoencephalitis in immuno-competent children and adults. Recent studies indi-cate that LCMV is also an under-recognized causeof congenital infection and neurological disease inthe fetus and newborns (Bonthius, 2012; Laposova

et al., 2013). In addition, LCMV and/or LCMV-like viruses have been also associated with clustersof fatal illness among tissue transplant recipients(Waggoner et al., 2013). All other human pathogensfrom the Arenaviridae cause viral hemorrhagic fevers(VHFs).

The VHFs encompass a diverse group of viralinfectious diseases of animals and humans causedby distinct RNA viruses from four major fami-lies. In humans these viruses can induce severelife-threatening diseases, with fever, malaise, hemor-rhage, and hypovolemic shock resembling bacterialLPS (lipopolysaccharide)-induced sepsis-like shockat terminal stage of the diseases. The VHFs mayoccur as isolated case(s), such as imported case(s)from endemic areas, or may cause devastating lethaloutbreaks (Goeijenbier et al., 2013; Ippolito et al.,2012; Moraz and Kunz, 2011; Vela, 2010).

The Arenaviridae family contains the largest num-ber of virus species causing VHFs. Lassa virus (LASV)is the most prominent human pathogen of the Are-naviridae responsible for several hundred thousandinfections and death of thousands of patients withLassa fever (LF) annually in West Africa (Fichet-Calvet and Rogers, 2009; Richmond and Baglole,2003). Recently isolated in South Africa, LuJo virus(LUJV) will be a novel OW species (Briese et al.,2009). All pathogenic NW arenaviruses causing SouthAmerican VHFs belong to clade B and include Juninvirus (JUNV), Machupo virus (MACV), Guanaritovirus (GTOV), Sabia virus (SABV), and the recentlydiscovered Chapare virus (CHAPV) (Salvato et al.,2012).

In addition to arenaviruses, causative agents ofVHFs were found among Bunyaviridae (e.g., Crimean

Human Emerging and Re-emerging Infections: Viral & Parasitic Infections, Volume I, First Edition. Edited by Sunit K. Singh.© 2016 John Wiley & Sons, Inc. Published 2016 by John Wiley & Sons, Inc.

2 Human Emerging and Re-emerging Infections

Congo HF, CCHF; hemorrhagic fever with renal syn-drome, HFRS; Rift Valley fever, RVF), Filoviridae(Ebola and Marburg HFs), and Flaviviridae (e.g.,dengue HF; yellow fever, YF). With recent discoveryof Bas-Congo virus isolated from human HF outbreakin Congo (Grard et al., 2012), Rhabdoviridae family,comprising the most diverse and widely distributedviruses in nature (Dietzgen et al., 2012), can be addedto this list.

VHFs are predominantly zoonotic infections exist-ing in certain geographic areas. According to the mostrecently published estimates (Falzarano and Feld-mann, 2013), more than a third of the world’s popu-lation live in areas that are at risk for VHFs. As shownin Figure 1-1, the most prevalent VHFs are dengueHF, LF, and YF. Climate changes and urbanizationaffect behavior of viral vectors (e.g., rodents, ticks,mosquitoes). These factors, together with substantialimprovements in diagnosis and virus detection, sug-gest that novel viruses, including human pathogens,will continue to emerge in the coming years.

Currently, only six OW arenavirus species havebeen recognized by the International Committee forTaxonomy of Viruses (ICTV) (Salvato et al., 2012).Among them, two viruses, LCMV and LASV, arehuman pathogens, and others, Mopeia (MOPV),Morogoro (MORV), Mobala (MOBV), and Ippy(IPPYV), are non-pathogenic virus species. To bedefined as a novel arenavirus species the putativevirus must meet the following criteria: (i) associa-tion with a host species; (ii) circulation in a definedgeographic area; (iii) human disease association; (iv)lack of cross-neutralization activity with geneticallyrelated arenaviruses; and (v) significant (>12%)amino acid difference from other arenavirus species(Salvato et al., 2012). During the last decade, severalarenaviruses have been isolated, mostly in Africa.Some of them have been identified as putative newspecies of the OW group of arenaviruses.

In 2008, LUJV caused a HF outbreak with unprece-dentedly high case-fatality rate in Lusaka (Zambia)

and Johannesburg (South Africa) (Briese et al., 2009;Paweska et al., 2009). Phylogenetic analysis showedthat LUJV is a novel OW species and branches offthe ancestral node of the OW arenaviruses. Screen-ing of Mastomys natalensis trapped in Zambia, wherethe first patient infected with LUJV was identi-fied, resulted in the isolation of Luna virus (LUNV)genetically related to non-pathogenic MOBV (Ishiiet al., 2011).

LCMV-like Dandenong virus (DANV) was iso-lated from one of the three transplant recipients whoreceived visceral organs (liver and kidneys) from thesame donor from the former Yugoslavia. All threerecipients died from febrile illness (Palacios et al.,2008). Phylogenetic analysis revealed that DANV ismost closely related to LCMV. One more virus, namedKodoko virus (KODV), related to but distinct fromLCMV, was isolated in Guinea from Mus (Nanno-mys) minutoides (Albarino et al., 2010; Lecompte et al.,2007).

In 1985, Merino Walk virus (MWV), a proposednovel tentative species, was isolated from a novelrodent host Myotomys unisulcatus collected at MerinoWalk at Eastern Cape (South Africa) (Palacios et al.,2010). Full-length genomic sequence revealed thatMWV is distantly related to sublineage MOBV-MOPV-IPPYV with the lowest amino acid sequencedivergence, 31.4%, to MOPV.

In several field studies, screening of small mam-mals in Africa with advanced molecular virologytools resulted in detection of potentially novel OWspecies based only on RNA sequence analysis, with-out isolation of replication-competent virus. In Tan-zania, search for rodent hosts for Morogoro virus(MORV) using RT-PCR targeting the arenavirus large(L) gene (see sub-section 1.2.1), revealed a novel are-navirus sequence from blood samples of Lemniscomysrosalia (de Bellocq et al., 2010). A portion of the L genesequence (320 bp) encoded the amino acid sequencewhich was clustered with IPPYV but had 17.3% diver-gence (e.g., amino acid divergence between LASV

Fig. 1-1 Estimated global burden ofviral hemorrhagic fevers(approximately 500,000 cases peryear): DF, Dengue HF and Dengueshock syndrome; LF, Lassa Fever;YF, Yellow fever; HFRS, HF feverwith renal syndrome; NWA, HFcaused by OW and NWarenaviruses; RVF, Rift Valley fever;CCHF, Congo-Crimean HF; KFD,Kyasanur forest disease; OHF,Omsk HF; E/MHF, Ebola andMarburg HF; SFTS, severe feverwith thrombocytopenia syndrome.From Falzarano and Feldmann,2013. With permission from Elsevier.

Pathogenesis of the Old World Arenaviruses in Humans 3

and MOBV is 14.5%), indicating that the L sequencefound in L. rosalia appears to be associated with a newspecies of OW arenavirus.

Extensive screening for novel arenaviruses inCote d’Ivoire using pan-OW arenavirus RT-PCRprimers targeting small (S) and L RNA genomesegments identified unique sequences of putativenovel Menekre virus (MENV) and Gbagroube virus(GBAV), the sequences of which were detected inHylomyscus sp. and Mus (Nannomys) setulosus, respec-tively (Coulibaly-N’Golo et al., 2011). Notably, theGBAV sequence was closely related to LASV, whilethe MENV sequence clustered with IPPYV-MOBV-MOPV. Detection of LASV-like sequences in Mussetulosus suggests that co-evolution of African are-naviruses and their hosts can potentially include host-switching events, predicting isolation of novel are-navirus species in the future.

Recently, a group of highly diverse novel virusesdistantly related to arenaviruses but also to filoviruseswas isolated from snakes with fatal boid inclusionbody disease (BIBD) (Bodewes et al., 2013; Hetzelet al., 2013; Koellhoffer et al., 2014; Stenglein et al.,2012). These viruses can be potentially placed ina novel taxonomic entity within the Arenaviridaewith putative name BIBD-associated arenaviruses.Preliminary phylogenetic analysis based on con-servative RNA polymerase motifs showed thatsnake-borne arenaviruses shared ancestry withNW and OW arenaviruses. While taxonomic sta-tus of these viruses is not defined, it is obviousthat phylogenic tree of the Arenaviridae will besignificantly changed in the nearest future (seeNotes in the Proofs). Importantly, isolation of BIBDarenaviruses from non-mammal hosts indicatesthat these viruses can infect very broad range ofspecies with unpredictable pathogenic potential forhumans.

This chapter focuses on the OW arenavirus humanpathogens, LCMV, LASV, and LUJV. LASV has thehighest human impact of any VHF (with the excep-tion of Dengue HF), and the aim of this chap-ter is to summarize our current knowledge onpathogenesis of LASV infection in experimentallyinfected non-human primates and on natural LF inhumans. Although pathogenic and non-pathogenicarenaviruses shared many similarities in terms ofmolecular structure and mechanism of replication,recent studies revealed clear differences at the earlystage of the host responses even between closelyrelated arenaviruses with different pathogenic poten-tial (Djavani et al., 2007; Malhotra et al., 2013; Zapataet al., 2013b). It indicates that key events determiningthe infection outcome significantly precede viremia,before release of newly synthesized virions in cir-culating blood. Detection of “molecular signatures”discriminating pathogenic versus non-pathogenicarenavirus infections will improve diagnosis andtreatment of patients.

1.2 Genome structure

1.2.1 Arenavirus genome structure

Purified and negatively stained LASV virions havetypical arenavirus morphology and appear as roundor oval particles with a mean diameter of approx-imately 110–130 nm (Figure 1-2). Internal granuleswithin virions are morphologically similar to hostribosomes, and RNA isolated from purified LASVcontains variable amount of host cell 28S and 18Sribosomal RNAs in addition to genome RNA seg-ments, the large (L, ∼7.2 kb) and small (S, ∼3.4kb) RNA (Lukashevich and Salvato, 2006; Luka-shevich et al., 1984). Incorporation of host ribo-somes into arenaviral particles seems to be a ran-dom event depending on host and viral factors andis not required for the replication of infectious viruses(Leung and Rawls, 1977; Lukashevich and Salvato,2006).

Viral RNA species are not presented in equimolaramounts, suggesting that each virion contains morethan one copy of virus-specific sequences (Lukashe-vich, 1987; Romanowski and Bishop, 1983). Geneticexperiments with ts mutants of LCMV confirmed thatthe genome of this virus was diploid with respectto the S RNA (Romanowski and Bishop, 1983). Gen-eration of recombinant LCMV with tri-segmentedgenomes stably expressing two additional genes ofinterest (Emonet et al., 2009b) provides additional evi-dence of arenaviral genome plasticity and ability toaccommodate additional RNA species. Importantly,r3LCMVs were strongly attenuated in vivo. It providesa new avenue for the development of multivalent are-naviral vaccines (Emonet et al., 2011b; Ortiz-Rianoet al., 2013).

Self-annealing experiments with RNA isolatedfrom purified viruses demonstrated the existence offull-length complementary RNA molecules (Lukashe-vich, 1986a; Vezza et al., 1978), suggesting that are-navirus RNA contains complementary strands similarto paramyxoviruses (Kolakofsky et al., 1974). The roleof these complementary RNA species in arenavirusgenomes is not understood. If these RNA species formdouble-stranded RNAs (dsRNAs) they will probablybe capable to induce IFN.

The L RNA encodes a large protein (L, or RdRp,∼ 220 kDa) and a small zinc-binding (Z, ∼11 kDa)protein that functionally resembles the matrix proteinfound in many negative-stranded RNAviruses (Luka-shevich and Salvato, 2006; Strecker et al., 2003). TheL protein is responsible for transcription and repli-cation and contains conservative domains involvedin different functional activities (Brunotte et al., 2011;Lukashevich et al., 1997; Salvato et al., 1989; Viethet al., 2004). Crystal structure of N-terminal domainof the LCMV L protein revealed a type II endonu-clease structure similar to the N-terminal end ofthe influenza virus PA protein (Morin et al., 2010).This endonuclease activity seems to be involved in

4 Human Emerging and Re-emerging Infections

(a) (b)

(d)

100 nm 100 nm

L mRNA

z mRNA

L vRNA

S vRNA

NP mRNA

GPC mRNA

Replication

Replication

5′

5′

5′

5′

5′

5′

5′

5′

Transcription

Transcription

Transcription

100 nm

(c)

Fig. 1-2 Electron microscopy of Lassa virus. (a) LASV purified in isopycnic sucrose gradient, negative staining (×200,000). (b, c)Ultrathin sections of infected Vero cells. A particle which appears to be budding from plasma membrane (B, ×170,000) and thediscrete area of membrane thickening associated with viral buds (c, ×30,000). Arrows indicate LASV glycoprotein on the virussurface (a, b) or in the cell budding site; (d) arenavirus ambisense replication strategy. Genes and antigenomic RNAs are shown asopen boxes separated by intergenic areas; subgenomic mRNAs are in black.

cleavage of methylated 5′-terminal sequences (caps)from cellular RNAs to prime viral RNA transcription.

LASV polymerase domain (RdRp) contains at leastsix strictly conserved motifs described for RdRp ofsegmented negative-stranded viruses (Lukashevichet al., 1997). Mutational analysis of this domainrevealed two residues which are important for tran-scription but not replication of the viral genome (Hasset al., 2008). An oligomerization, formation of the L–L complexes cotranslationally, seems to be a strongrequirement for the polymerase activity (Sanchez andde la Torre, 2005) and co-immunoprecipitation studiesrevealed physical interaction between N-terminal andC-terminal parts of LASV L protein (Brunotte et al.,2011).

Electron microscopy of a negatively stained func-tional MACV L protein revealed a ring-like struc-ture conserved within viral L proteins of negative-stranded RNA viruses (Morin et al., 2013). The MACVL protein contains a core ring (∼79–88 Å) with a cen-tral channel (∼21–25 Å) and “arm-like” appendagesinvolved in mRNA cap formation (Kranzusch et al.,2010). This structure is probably fully applicable forOW arenaviruses.

While the pathogenesis of severe arenaviral infec-tions seems to be multigenic, several lines of evi-dence indicate that the viral replicative capacity asso-ciated with L protein is the primary determinant of

the OW arenavirus pathogenicity. A fatal LF-like dis-ease in guinea pigs and in monkeys and the func-tional disturbance of hepatocellular homeostasis havebeen mapped to the L segment of LCMV-WE, butnot to LCMV-ARM (Djavani et al., 2005; Lukashevichet al., 2002a; Lukashevich et al., 2004; Riviere et al.,1985). Comparison of nucleotide sequences for bothLCMV strains revealed 84% L RNA homology. At theamino acid level, similarity between these two strainsis 87% and 88% in the Z and L proteins, respectively(Djavani et al., 1997). Interestingly, the most diver-gent region has been found in the N-terminal domainof the L protein involved in “can-snatching” activity.LCMV replication capacity is also the primary deter-minant of persistence and immunosuppression. A sin-gle mutation in L protein of the LCMV-ARM Clone 13,a widely used model of chronic viral infection, wasnecessary and partially sufficient for viral persistenceand immunosuppression (Bergthaler et al., 2010).

In a surrogate model of LF-like disease in guineapigs infected with pathogenic strain P18 of PICV, threeL mutations, N1906, N1889, and L1839, were criti-cal for high replication capacity of P18, liver pathol-ogy, and death of experimental animals (McLay et al.,2013b). These mutations may potentially be involvedin L–L interaction or contribute to another unknownfunction(s) of C-terminal domain of arenavirus L pro-tein (Morin et al., 2013).

Pathogenesis of the Old World Arenaviruses in Humans 5

In good correlation with clinical observations inhumans (McCormick et al., 1986), LF pathogenesis innon human primates (NHPs) and guinea pigs wasalso directly associated with replication capacity andmaps to the L RNA (Lukashevich et al., 2005a). TheMOP/LAS reassortant (clone ML29) carrying the LRNA of non-pathogenic MOPV and the S RNA ofLASV was fully attenuated in experimental animalsand protected them against fatal LF. Currently, ML29is the most promising LASV vaccine candidate (Luka-shevich, 2012).

The S RNA encodes the major structural proteins,nucleoprotein (NP, ∼64 kDa) and glycoprotein pre-cursor (GPC, ∼76 kDa), cleaved into GP1 (attach-ment protein), GP2 (fusion protein), and the stable sig-nal peptide (SSP; 58 aa) (Auperin et al., 1986; Clegget al., 1991; Eichler et al., 2003; Lenz et al., 2000; Lenzet al., 2001). Trimers of GP1 and GP2 form club-likespikes on the surface of the mature virions (Figure1-2) and SSP remains stably associated with the GPcomplex.

The GP1 is located on the top of viral surface andis responsible for interaction with the major cellularreceptor of the OW arenaviruses, α-dystroglycan (α-DG), a ubiquitous receptor for extracellular matrix(ECM) proteins (Cao et al., 1998). Interaction of LASVGP1 with α-DG perturbs cross-talk between DG andβ1 integrins contributing to cellular dysfunctions thatare associated with LF clinical manifestations (Rojeket al., 2012). Two C-type lectin family members,DC-SIGN and LSECtin, and two TAM family mem-bers, Axl and Tyro3, have been recently identifiedas additional LASV and LCMV receptors (Shimo-jima and Kawaoka, 2012; Shimojima et al., 2012). Inhuman dendritic cells (DCs) DC-SIGN serves primar-ily as LASV attachment factor, while the role of thisreceptor in LASV entry is not so certain (Goncalveset al., 2013).

The GP2 is a typical transmembrane class I fusionglycoprotein that mediates pH-dependent endocyto-sis (Glushakova et al., 1992; Klewitz et al., 2007). Thehighly conserved N-terminal (aa 260–266) domain ofLASV and LCMV contains the canonical fusion tri-peptide Gly–X–Phe. Our in vitro studies showed thatLASV GP2 peptide containing an internal hydropho-bic sequence (aa 276–298) also has fusogenic activ-ity at pH 4.5–5.5 (Glushakova et al., 1992). Laterstudies using highly sensitive cell–cell fusion assayand point mutations showed that both N-terminalhydrophobic stretches of LASV GP2 are requiredfor fusion (Klewitz et al., 2007). Correct processingof the GPC and interaction of SSP with the GP2are required for fusion and infectivity. Crystal struc-ture of LCMV GP2 revealed the presence of charac-teristic trimeric coiled coil present in class I fusionproteins. The structure also showed a number ofintrachain salt bridges stabilizing the GP2 postfusionhairpin (Igonet et al., 2011). Interestingly, the closeststructural homolog of LCMV GP2 was the influenzaHA2 protein.

The NP is tightly associated with the genomicRNA segments to form an NP–RNA complex. Thiscomplex together with L protein (RdRp) forms theviral ribonucleoprotein (RNP) directing the synthe-sis of virus RNA (transcription/replication). Crys-tal structures of the RNA-binding domain of LASVNP in complex with RNA revealed that LASV RNAbinds in a deep, basic crevice located entirely withinthe N-terminal domain (Hastie et al., 2011b). Struc-tural and functional studies suggest a unique gat-ing mechanism by which NP opens to accept RNA.The C-terminal portion of NP of LASV and LCMVhas the DEDDh motif associated with exonucleaseactivity specific for double-stranded RNA substrates(Hastie et al., 2012a; Hastie et al., 2011a; Hastie et al.,2012b; Hastie et al., 2011b; Jiang et al., 2013; Qiet al., 2010). This activity is essential for the abil-ity of arenavirus NP to suppress the translocation ofIFN regulatory factor 3 and to block the activationof innate immune responses (Martinez-Sobrido et al.,2009; Martinez-Sobrido et al., 2007; Martinez-Sobridoet al., 2006).

Electron microscopy has revealed encapsidatedarenavirus genomes as closed circulated filamentsand this circular structure seems to be maintainedby complementary inverted sequences at 3′ and 5′

ends of the viral RNA segments. Indeed, the terminal19 nucleotides of each RNA segment are highly con-servative among arenaviruses and represent the pro-moter directing the virus gene expression and genomereplication (Auperin et al., 1982; Hass et al., 2006;Perez and de la Torre, 2003).

The terminal sequences are mostly complementaryto each other, since perfect complementarity withinthe terminal non-coding regions (NCRs) is requiredfor efficient RNA replication (Barr and Wertz, 2004).Mutational analysis of LASV promoter showed thatthis promoter coordinates transcription and repli-cation. It contains two regions, a sequence-specificregion (residues in positions 1–12) and a variablecomplementarity region (positions 13–19) (Hass et al.,2006). Within the first 18 nt of the arenavirus con-sensus terminal sequence, only nucleotides 6 and 8can be substituted by any of other three bases, indi-cating that these positions are not critical for repli-cation of a model minigenome (MG) (Hass et al.,2006). Interestingly, the length of NCRs betweensequences involved in the formation of putative pan-panhandled structures and the first methionine codonvaried between different LASV and LCMV strains.As it has been shown recently, while these NCRswere not absolutely required for LASV replicationin vitro, the NCR deletions did impact virus growthefficiency in tissue culture and, more importantly, inbrain tissues of mice (Albarino et al., 2011). Role ofthese LASV NCRs in virus virulence remains to beelucidated.

The requirement of panhandle structure in the are-navirus polymerase complex has been challenged inthe study with purified catalytically active MACV L

6 Human Emerging and Re-emerging Infections

protein (Kranzusch et al., 2010). It was shown that thisprotein formed sequence-specific complex with highaffinity with 3′ RNA, while interacted with the 5′ ter-minal sequences with lower affinity. Notably, double-stranded character of the promoter complex was notrequired for L recruitment, and short double-strandedRNA even inhibited the MACV L RNA binding to the3′ terminus (see also Section 3.3).

One non-templated G residue is often present atthe 5′ end of genomic or antigenomic RNA of LASVand other arenaviruses (Auperin et al., 1986; Garcinand Kolakofsky, 1990; Meyer and Southern, 1994;Polyak et al., 1995; Raju et al., 1990), suggestingthat these sequences arise by a cap-stealing mecha-nism as has been described for the prime-and-realignmodel proposed for TACV (Garcin and Kolakofsky,1990). Recent studies have shown that the unpaired5′ pppG found in arenavirus dsRNA panhandles arenot recognized by RIG-I, a cytoplasmic sensor of RNAviruses (Marq et al., 2010). In addition, short dsR-NAs with an overhanging 5′ ppp-nucleotide in are-navirus genomes acted as RIG-I decoy to avoid acti-vating the IFN system (Marq et al., 2011). Interest-ingly, in an LASV mini-replicon system the removalof the unpaired G residue increased the activity of theLASV promoter (Hass et al., 2004). A possible non-templated 5′ pppG was also found in LUJV (Bergeronet al., 2012). Notably, in contrast to other arenaviruses,an additional 3′C residue was found at the terminiof both segments of LUJV. In addition, LUJV genomecontains an adenine and an uracil in positions 6 and8, respectively, while all other arenaviruses contain U6and A8 (Bergeron et al., 2012).

Two genes in ambisense orientation within eachRNA segment of arenavirus RNA are separated byan intergenic region (IGR) with the potential to formstem-loop structures. Translation termination codonshave been described on the proximal sides of the IGRstem loops on the S RNA and L RNA. It seems thatin conjunction with the encoded stop codons, the IGRloops help to efficiently stop translation. So far, thepredicted structures did not show distinct groupingor correlation between the IGR secondary structuresand biological features of OW or NW arenaviruses.For example, a single IGR loop was predicted forLASV, LCMV, and PICV, while two potential stem-loop structures were found in MOPV, JUNV, TACV,and MACV (rev. by Lukashevich and Salvato, 2006).The size of IGR was also variable from 67 nt in S RNAof LASV to 182 nt in TAMV and did not correlate withthe predicted loop structures (Archer and Rico-Hesse,2002; Emonet et al., 2006).

Recently, reverse genetics allowed recovering addi-tional sequences in L-IGR of LUJV and restore theauthentic 140-bp L-IGR (Bergeron et al., 2012). Theseadditional nucleotides were predicted to form at leastthree hairpin structures. Notably, incorporation of thelong and more stable IGR into recombinant LUJV wasassociated with more efficient virus replication in vitroin comparison with a less stable 104-nt L RNA IGR. It

suggests that a stable secondary structure within theL-IGR is critical for LUJV replication.

1.2.2 Genetic diversity of LASV and LCMV

Genetic diversity among LASV strains is the highestamong the Arenaviridae and causes a great challengefor vaccine development. Phylogenetic analysis of thepartial NP sequences of 54 strains of LASV showedthat LASV isolates comprise four lineages, three ofwhich are found in Nigeria, with the fourth one foundin Guinea, Liberia, and Sierra Leone. This diversityeven raised concern about the status of LASV as asingle species (Bowen et al., 2000; Bowen et al., 1997;Lozano et al., 1997). The prototype LP strain isolatedby Buckley and Casals in 1969 from Eastern Nige-ria occupied the most basal lineage I. Strains isolatedfrom Southern Central and Northern Central Nige-ria were placed in lineages II and III, respectively.It seems that Nigerian strains from lineages I and IIdiverged prior to strains from northern part of centralNigeria and Guinea, Liberia, and Sierra Leone. A fifthlineage, which falls between III and IV, has been pro-posed for the AV strain isolated from a patient thatwas infected (presumably) in Ghana or Ivory Coast(Gunther et al., 2000).

Overall strain variation among the 54 LASV strainsis as high as 27% and 15% at the nucleotide and aminoacid levels, respectively. The genetic distance betweendifferent strains correlates with geographic distance,rather than with time of strain isolation (Bowen et al.,2000). Full-sequence analysis did not find evidence ofrecombination among LASV strains and showed thatNigerian LASV strains seem to be ancestral to strainsfrom Guinea, Liberia, and Sierra Leone. Surprisingly,this analysis also demonstrated that structural genesin the S RNA segment had a lower variability incomparison with the polymerase gene, RdRp (Bowenet al., 2000; Emonet et al., 2006; Vieth et al., 2004).Analysis of evolutionary history of LASV suggeststhat the virus appeared 750–900 years in Nigeria andhas been relatively recently moved into the westernendemic areas (Bowen et al., 2000; Clegg, 2002; Laliset al., 2012).

Analysis of LCMV strains collected from a vari-ety of geographic and temporal sources showed thatthese viruses are highly diverse genetically and bio-logically (Albarino et al., 2010; Dutko and Oldstone,1983). Genomic analysis placed 29 strains of LCMV(including LCMV-like DANV and KODV) into threeand four lineages based on the sequence of the L andthe S RNAs, respectively. Notably, two KODV iso-lates formed a distinct phylogenetic lineage separatedfrom the LCMV lineages (Albarino et al., 2010). Highlevels of diversity, 6–18%, were found between andwithin LCMV lineages at nucleotide and protein lev-els. This diversity between LCMV strains was compa-rable only with LASV strain variations.

Lineage I (S RNA) comprises the most extensivecollection of LCMV strains in the USA and includes