Emerging viruses Lecture 22 Biology W3310/4310 Virology Spring 2015

Nothing endures but change HERACLITUS Emerging viruses

• Emerging virus - causave agent of a new or previously unrecognized infecon • The term became popular in 1990s, but emerging viruses are not new • Since the rise of agriculture - 11,000 years ago - new infecous agents have invaded human populaons because they can be sustained by numbers that were unknown before agriculture and commerce Emerging viruses

• Expanded host range with an increase in disease not previously obvious • Transmission of a virus from a wild or domescated animal to humans - zoonosis • Cross-species infecon may establish a new virus in the populaon (SIV moving from chimps to humans) • Oen cross-species infecon cannot be sustained (e.g. Ebola and Marburg from bats to humans) Human - animal interface

6

16 32 Adapted pathogens (> Homo sapiens) Zoonoc pathogens Heirloom pathogens (< Homo spp.) Heirloom pathogens (> Homo spp.)

37

Viruses belonging to # of genera One Health, ASM Press

Convergent Forces of Disease Emergence

GLOBALIZATION RAPID AIR TRAVEL

ALTERED ECOSYSTEMS

EXPANDING POPULATIONS “MEGA- CITIES” POVERTY MICROBIAL EVOLUTION

DEFORESTATION ENVIRONMENTAL CHANGES Over-riding factors driving the emergence of infecous diseases of humans and animals:

Human populaon growth and incredible change occurring in all ecosystems brought about by human occupaon of almost every corner of the planet The Amazon North Region of Home to 183 Arthropod-borne and Other Vertebrate Viruses

Cacipacore, Trombetas, Mapuera, Serra do Navio, Oriximina, Turuna, Saraca, Juruaca Araguari, Amapari, Aura, EEE, Una, WEE, Bussuquara, Ilheus, Ieri, Cupixi Kairi, Maguari, Taiassui, Caraparu, Itaqui, Munguba, Jari, Jutai, Murutucu, Nepuyo, Melao, Acara, Benevides, Monte Dourado, Paru, Benfica, Bushbush, Capim, Guajara, 0º Tumucumaque, Almeirim Ananindeua, Bimiti, Catu, Mirim, , Timboteua, Utinga, Turlock, , Icoaraci, Itaporanga, Urucuri, Belem, Para, Acado-like, , Kwatta-like, Chaco, Timbo, Piry, Marco, Aruac, , Agua Preta, Cotia- like, Marajo, Mucambo, yellow fever, Tacaiuma, Tucunduba, Apeu, , Boa Vista Melgaco Oriboca, Caraparu-like, Guama, Anhanga, Mayaro dengue 1, dengue 4 dengue 2, dengue 3, Bocas, Triniti, Amapa Barcarena Roraima Macapa

Pixuna, SLE, Lukuni, Sororoca, Guaroa, Belem Oropouche, Candiru, Pacui, Caninde, Gurupi, , Ourem, Tembe, Cocal, Jurona

Balbina, Manaus Uatuma Para Arumateua, Caraipe,Tucurui,Guamboa-Like, Uriurana, , Aracai, Aratau, Aruana, Arawete, Bacuri, Canoal, Coari, Iopaka, Ipixaia, Iruana, Itaboca, Jandia, Jatuarana, Pacaja, Parakana, Murumbi Paranati, Pependana, Pindobai, Piratuba, Surumbi, Tekupeu, Timbozal, Tocantins, Tocaxa, Tuere, Xaraira, Xiwanga, , Trocara, Jatobal, Amazonas Jacunda.

Itupiranga

Palmas Porto Velho Iaco, Moriche, Acre Xingu, Ambe, Joa, Tapara, Purus, Sena Mojui dos Acatinga, Acurene, Altamira, Madureira, Campos, Santarem, Assurinis, Bacajai, Gorotire, Xiburema Rio Branco Belterra, Jamanxi Kararao, Uxituba, Cajazeira, Cuiaba, Tocantins Codajas, Galibi, Iriri, Uruara Rondonia Alenquer

Ariquemes

Atlantic Ocean , Pacora- like, , Flexal North Region South America

Serra Norte, Catete, , Serra Sites from which viruses were isolated at the Sul, Tapirope, Carajas, Maraba, Brazil Curianopolis, Evandro Chagas Instute Itacaiunas

Atlantic Ocean

0 500 1,000

Kilometers Virus Family Drivers of Emergence Urban population density, Dengue virus Flaviviridae mosquito breeding Human contact with natural Ebolavirus Filoviridae host; bushmeat Agriculture: human/rodent Hantaan virus Bunyaviridae contact Bats to horses to stable Hendra virus Paramyxoviridae workers HIV Retroviridae Bushmeat trade Influenza virus Orthomyxoviridae Pig/bird agriculture

Junin virus Arenaviridae Agriculture: human/rodent contact Nipah virus Paramyxoviridae Bats to pigs to humans

Machupo virus Arenaviridae Agriculture: human/rodent contact Rift Valley virus Bunyaviridae Dams, irrigation Weather, human/rodent Sin Nombre virus Bunyaviridae contact West Nile virus Flaviviridae Mosquito Principles of Virology, ASM Press Roles of Evoluon

• Leads to the biodiversity of pathogens exisng in nature (quasispecies) • Adaptaon to new hosts and environments (through variaon and selecon) The general interacons of hosts and viruses

• Stable: maintains virus in ecosystem • Evolving: passage of virus to naive populaon • Dead-end: one way to different species • Resistant host: infecon blocked Principles of Virology, ASM Press Stable host-virus interacons

• Both parcipants survive and mulply • Some are effecvely permanent - Humans are sole natural host for measles virus, herpes simplex virus, HCMV, smallpox • May include infecon of more than one species - Influenza A virus, flaviviruses, togaviruses

Principles of Virology, ASM Press Evolving host-virus relaonship

• Hallmarks are instability and unpredictability • Outcome of infecon may range from benign to death - Introducon of smallpox and measles to naves of Americas by Old World colonists and slave traders - Introducon of West Nile virus into Western Hemisphere, 1999 • Introducon of rabbits into Australia Principles of Virology, ASM Press Dead-end interacon

• Frequent outcome of cross-species infecon • Ebolavirus: humans, chimps, gorillas • New infected host may not transmit the infecon to others of the same species (H5N1) • Contribute lile to the spread of a natural infecon

Principles of Virology, ASM Press The complex life cycle of an arbovirus

Stable host- virus interacons

Principles of Virology, ASM Press Rodents and insect vectors move European ck-borne encephalis virus among many hosts

Dead-end hosts

Principles of Virology, ASM Press Other dead-end infecons

• Yellow fever (monkey) • Marburg, Ebola, Hendra, Nipah, SARS progenitor (bats) • Lassa, Junin, Sin Nombre (rodents) • Laboratory animal models Emerging infecons: Two steps

• Introducon • Establishment and disseminaon Encountering new hosts

• Rare chance encounters of viruses with new hosts may never be detected • Single-host infecons are not transmied among humans for many reasons Expanding viral niches

• Successful encounters require access to suscepble and permissive cells • Populaon density and health are important factors • Virus populaons will endure in nature only because of serial infecons (a chain of transmission) Human are constantly providing new ways to meet viruses

Dams and water impoundments Irrigaon Massive deforestaon Reroung of wildlife migraon paerns Wildlife parks Long distance transport of livestock and birds

Air travel Uncontrolled urbanizaon Day care centers Hot tubs Air condioning Used re trade

Blood transfusion Xenotransplantaon Sex and drug abuse

Principles of Virology, ASM Press Diseases of exploraon and colonizaon

• Explosive epidemic spread may occur when a virus enters a naive populaon • Smallpox reached Europe from the Far East in 710 AD, aained epidemic proporons • Smallpox changed the balance of human populaons in the New World - killed 3.5 million Aztecs in 2 years (1520 - spread from Hispaniola), allowing conquest by Cortez Yellow fever virus: Humans change the paern and pay the price

Yellow fever deaths, Philadelphia, 1793

“Yellow Fever will discourage the growth of great cies in our naon” THOMAS JEFFERSON, 1800

Principles of Virology, ASM Press Changes in human populaons and environments

• Emergence of epidemic poliomyelis in the beginning of the 20th century: improved sanitaon delayed transmission • Known since 4,000 years ago, stable host-virus relaonship Poliomyelis: A disease of modern sanitaon

Principles of Virology, ASM Press Influenza

631 deaths | 253 deaths Bats: a source of zoonoc infecons

•Many new paramyxoviruses found in flying foxes since 1995, including Nipah and Hendra viruses

•Cause severe disease in domesc animals (horses and pigs) and are known to infect humans Nipah virus • First outbreak Malaysia 1998 - Outbreak of respiratory and neurological disease on pig farms - 105 human deaths, 1 million pigs culled • Fruit bats excrete virus in urine but are unaffected • Pig farmers plant mangoes near pigpens • Pigs spread infecon to humans • Subsequently humans infected by consuming date palm sap contaminated by bats (India, Bengladesh) • Human to human transmission; infecons connue Hendra virus

• Discovered in Hendra, Australia, September 1994 - Outbreak killed 14 racehorses and a trainer • Spread from flying foxes to horses, then to humans • Horses connue to acquire infecon hp://www.twiv.tv/2014/08/03/twiv-296/ Changing climate and animal populaons

• Hantavirus pulmonary syndrome - first noted in Four Corners area of New Mexico, 1993 • Disease is caused by Sin Nombre virus, endemic in the deer mouse (Peromyscus maniculatus, 30% virus posive) • Originally called Muerto Canyon virus, but residents objected Changing climate and animal populaons

• In 1992-93, abundant rainfall produced a large crop of piñon nuts, food for humans and the deer mouse. Mouse populaon rose, contact with humans increased. • Virus is excreted in mouse feces; contaminated blankets or dust from floors provided opportunies for human infecon • Humans not the natural host for Sin Nombre virus, human disease is rare • Not new - earliest known case 1959 Deer mouse, white-footed mouse, rice rat, coon rat

New World Hantaviruses New York Sin Nombre Peromyscus leucopus Peromyscus maniculatus Prospect Hill Muleshoe Microtus pennsylvanicus Sigmodon hispidus Bloodland Lake Microtus ochrogaster Isla Vista Bayou Microtus californicus Oryzomys palustris Black Creek Canal El Moro Canyon Sigmodon hispidus Reithrodontomys megalos Rio Segundo Calabazo Reithrodontomys mexicanus Zygodontomys brevicauda Juquiba Caño Delgadito Unknown Host Laguna Negra Choclo Sigmodon alstoni Calomys laucha Oligoryzomys fulvescens Rio Mamore Maciel Oligoryzomys micros Necromys benefactus Orán Hu39694 Oligoryzomys longicaudatus Unknown Host Bermejo Lechiguanas Oligoryzomys chacoensis Oligoryzomys flavescens Pergamino Andes Akodon azarae Oligoryzomys longicaudatus

(Virus Names in Orange are Associated with Human Disease) SARS

• Outbreak of severe atypical pneumonia, unknown eology, Guangdong Province, China, Nov 2002 - 305 cases, 5 deaths • Incubaon period 2-10 days • Illness begins with prodrome of fever - Chills, headache, malaise, myalgia • Next phase: dry cough, shortness of breath • 10-20% may require mechanical venlaon SARS (Severe acute respiratory syndrome)

• A Chinese doctor who treated first paents traveled to Hong Kong on 21 February 2003, stayed on ninth floor of Metropole Hotel • He died in hospital 22 February • Infecon spread to 10 people in hotel, who flew to Singapore, Vietnam, Canada, US before symptoms evident • Infecon spread to 8000 people in 29 countries, 10% mortality Spread from Hotel Metropole (21 February 2003) 249 cases traced to “A” as of March 28, 2003

Canada Guangdong F,G 18 HCW Province, China A F,G 11 close contacts

A Ireland K K A Hotel M 0 HCW Hong Kong Hong Kong SAR H,J I, L,M Hosp. 1: 99 HC H,J 8 hospitals total B C,D,E

Total: 156 close contacts of I,L,M HCW and paents B C,D,E United States Vietnam Singapore 1 HCW 37 HCW 34 HCW

21 close contacts 37 close contacts Probable cases of SARS by date of onset, Hong Kong: n = 1 753, as of 9 June 2003 120

100

80

60

Number of cases 40

Outbreak ends July 2003 20

0 0 1 Feb 13 Feb 25 Feb 9 Mar 21 Mar 2 Apr 14 Apr 26 Apr 8 May 20 May 1 Jun 9 Jun Probable SARS Cases Worldwide Reported to WHO as of Sept. 26, 2003

Europe: 10 countries (34) Canada (251) China (5327)

U.S. (29) Hong Kong (1755)

Taiwan (346) Vietnam (63)

Singapore (238 + 1)

Thailand (9) Australia (6)

Total: 8,098 cases; 774 deaths (9.6% case fatality) SARS-coronavirus

SARS virion ~120 nm SARS-CoV disease mechanisms

• Transmied by respiratory droplets • Virus enters respiratory tract and mulplies in epithelial cells • Mulplicaon in alveolar epithelial cells leads to lung injury • Immune suppression cause of severe disease?

Principles of Virology, ASM Press SARS and the economy: impact on global travel Airport screening and health informaon, Hong Kong, SARS, 2003 Origin of SARS-CoV • Human sera collected before SARS outbreak do not contain anbodies to SARS-CoV • Early Guangdong SARS cases were in handlers of animals for the exoc food market • Animal traders had significantly higher prevalence of an-SARS- CoV anbodies than control groups Origin of SARS-CoV

• SARS-like CoVs isolated from different species of horseshoe bats in regions of China >1000 km apart • Up to 84% of bats examined had an-SARS-CoV anbodies • Bat SARS-like-CoVs 88-92% sequence identy with human or civet strains • Greater genec diversity in bat viruses than those of humans or civets • Hypothesis: bats are reservoir of SARS-CoV, transmied to humans via market animals (e.g. civets) Will SARS Return?

CREDIT: MICHAEL REYNOLDS/EPA/NEWSCOM

• No further transmission of human SARS-CoV • December 2003 - January 2004: 4 SARS cases in Guangdong Province, new animal - human transmission • SARS-CoV precursor connues to circulate in animals; wild game banned in markets • Re-emergence will be more quickly recognized and contained MERS-CoV

• Index case September 2012: 60 yo male paent, died of pneumonia, renal failure • Virus recovered, genome sequenced, binds dipepdyl pepdase 4 receptor • Closely related to bat coronaviruses • Not SARS-CoV hp://www.who.int/csr/disease/coronavirus_infecons/archive_updates/en/ hp://www.who.int/csr/disease/coronavirus_infecons/archive_updates/en/ MERS-CoV

• As of 4/16/15: 1106 laboratory confirmed cases, 421 deaths • Case fatality rao: 421/1106 = 38% • Mortality rao unknown MERS-CoV in dromedary camels

Anbodies in serum PCR posive nasal swab MERS-CoV

• Are camels the reservoir? • Why did the virus recently cause human disease? • What is the role of bats if any? • How is the virus transmied to humans? • Why are so few humans infected? Will it spread? • Why doesn’t the virus transmit well among humans? • Should a camel vaccine be prepared? • Should we produce anvirals for infected paents? Coronavirus disease in humans

Virus Disease 1686 - 1800, bat CoV HCoV-229E •Respiratory diseases 1450 - 1191, bat CoV HCoV-NL63 • Febrile upper tract infecon 1890, bovine CoV HCoV-OC43 • Lower tract infecons HCoV-HKU1 • Asthma exacerbaon 2003, bat CoV SARS-CoV • Atypical pneumonia 2012, camel CoV MERS-CoV • Severe pneumonia Canine parvovirus: Cat-to-dog by two mutaons

• Canine parvovirus idenfied in 1978, cause of new enteric and myocardial infecon in dogs • Evolved from feline panleukopenia virus, another parvovirus - Infects cat, mink, racoon Canine parvovirus

two amino acid changes!

Internaonal travel allowed stable virus to be carried on contaminated footwear, not in infected dogs How common are host range jumps?

• Dead end: Very common • Those that produce sustaining transmission: Rare • Can we predict them? No • But we can know what is out there, and react (preparedness)