023_W3310_13

Emerging virusesLecture 23

Biology W3310/4310Virology

Spring 2013

Nothing endures but change.HERACLITUS

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Emerging viruses

• Emerging virus -‐ causa1ve agent of a new or previously unrecognized infec1on

• The term became popular in 1990s, but emerging viruses are not new

• Since the rise of agriculture -‐ 11,000 years ago -‐ new infec1ous agents have invaded human popula1ons because they can be sustained by numbers that were unknown before agriculture and commerce

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Emerging viruses

• Expanded host range with an increase in disease not previously obvious

• Transmission of a virus from a wild or domesFcated animal to humans -‐ zoonosis

• Cross-‐species infecFon may establish a new virus in the populaFon (SIV moving from chimps to humans)

• OMen cross-‐species infecFon cannot be sustained (e.g. Ebola and Marburg from bats to humans)

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Six factors that drive viral emergence

Principles of Virology, ASM Press

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Over-‐riding factors driving the emergence of

infec8ous diseases of humans and animals:

Human popula9on growth and incredible change occurring in all ecosystems brought about by human occupa9on of almost every

corner of the planet

Na8onal Geographic SocietyWhite = city lights

Yellow = natural gas burnoffRed = fires

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Convergent Forces of Disease Emergence

DEFORESTATION

EXPANDING POPULATIONS“MEGA-‐ CITIES”

POVERTY

GLOBALIZATION RAPID AIR TRAVEL

ENVIRONMENTAL CHANGES

ALTERED ECOSYSTEMS

MICROBIALEVOLUTION

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Global avia8on network

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Roles of Evolu8on

• Leads to the biodiversity of pathogens exisFng in nature

• AdaptaFon to new hosts and environments (through variaFon and selecFon)

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The Amazon North Region of BrazilHome to 183 Arthropod-‐borne and Other Vertebrate Viruses

Acre

Rondonia

Amazonas

Para

Tocantins

AmapaRoraima

Porto Velho

Manaus

Belem

Macapa

Palmas

Rio Branco

0º

Boa Vista

Aura, EEE, Una, WEE, Bussuquara, Ilheus, Kairi, Maguari, Taiassui, Caraparu, Itaqui,

Murutucu, Nepuyo, Melao, Acara, Benevides, Benfica, Bushbush, Capim, Guajara,

Ananindeua, Bimiti, Catu, Mirim, Moju, Timboteua, Utinga, Turlock, Bujaru, Icoaraci, Itaporanga, Urucuri, Belem, Para, Acado-like, Mosqueiro, Kwatta-like, Chaco, Timbo, Piry, Marco, Aruac, Inhangapi, Agua Preta, Cotia-

like, Marajo, Mucambo, yellow fever, Tacaiuma, Tucunduba, Apeu, Marituba,

Oriboca, Caraparu-like, Guama, Anhanga, Mayaro

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

Jurona

Cacipacore, Trombetas, Mapuera, Oriximina, Turuna, Saraca, Juruaca

Arumateua, Caraipe,Tucurui,Guamboa-Like, Uriurana, Anapu, Aracai, Aratau, Aruana, Arawete,

Bacuri, Canoal, Coari, Iopaka, Ipixaia, Iruana, Itaboca, Jandia, Jatuarana, Pacaja, Parakana,

Paranati, Pependana, Pindobai, Piratuba, Surumbi, Tekupeu, Timbozal, Tocantins, Tocaxa, Tuere,

Xaraira, Xiwanga, Breu Branco, Trocara, Jatobal, Jacunda.

Xingu, Ambe, Joa, Tapara, Acatinga, Acurene, Altamira, Assurinis, Bacajai, Gorotire, Kararao, Uxituba, Cajazeira, Codajas, Galibi, Iriri, Uruara

Itaituba, Pacora-like,

Jacareacanga, Flexal

Santarem, Jamanxi

dengue 2, dengue 3, Bocas, Triniti,

Barcarena

Murumbi

Munguba, Jari, Jutai, Monte Dourado, Paru,

Tumucumaque, Almeirim

Serra Norte, Catete, Parauapebas, Serra

Sul, Tapirope, Carajas, Maraba,

Curianopolis, Itacaiunas

Itupiranga

Melgaco

Mojui dos Campos, Belterra, Cuiaba,

Alenquer

Serra do Navio, Araguari, Amapari,

Ieri, Cupixi

dengue 1, dengue 4

Iaco, Moriche, Purus, Sena Madureira, Xiburema

Ariquemes

Balbina, Uatuma

North Region

Atlant

ic Oce

an

Atlantic Ocean

0 500 1,000Kilometers

Brazil

South America

Sites from which viruses were isolated at the Evandro Chagas Ins1tute

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The general interac8ons of hosts and viruses

• Stable: maintains virus in ecosystem

• Evolving: passage of virus to naive populaFon

• Dead-‐end: one way to different species

• Resistant host: infecFon blockedPrinciples of Virology, ASM Press

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Stable host-‐virus interac8ons

• Both parFcipants survive and mulFply

• Some are effecFvely permanent

-‐ Humans are sole natural host for measles virus, herpes simplex virus, HCMV, smallpox

• May include infecFon of more than one species

-‐ Influenza A virus, flaviviruses, togavirusesPrinciples of Virology, ASM Press

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Evolving host-‐virus rela8onship

• Hallmarks are instability and unpredictability

• Outcome of infecFon may range from benign to death

-‐ IntroducFon of smallpox and measles to naFves of Americas by Old World colonists and slave traders

-‐ IntroducFon of West Nile virus into Western Hemisphere, 1999

• Virus may acquire new property that increases virulence or spread, or if host changes (e.g. famine or populaFon change during wars)


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Dead-‐end interac8on

• Frequent outcome of cross-‐species infecFon, but not of intraspecies infecFons

• OMen host is killed so quickly that there is li[le or no transmission to others

• AlternaFvely, the new infected host cannot transmit the infecFon to others of the same species

• Contribute li[le to the spread of a natural infecFonPrinciples of Virology, ASM Press

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The complex life cycle of an arbovirus

Stable host-‐virus interac1ons


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Rodents and Insect Vectors Move EuropeanTick-‐borne Encephali8s Among Many Hosts

Dead-‐end hosts


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Other dead-‐end infec8ons

• Yellow fever (monkey)

• Marburg, Ebola, Hendra, Nipah, SARS progenitor (bats)

• Lassa, Junin, Sin Nombre (rodents)

• Laboratory animal models

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Emerging infec8ons: Two steps

• IntroducFon

• Establishment and disseminaFon

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Encountering new hosts

• Rare chance encounters of viruses with new hosts may never be detected

• Single-‐host infecFons are not transmi[ed among humans for many reasons

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Expanding viral niches

• Successful encounters require access to suscepFble and permissive cells

• PopulaFon density and health are important factors

• Virus populaFons will survive in nature only because of serial infec9ons (a chain of transmission)

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Human are constantly providing new ways to meet viruses


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Bats: a source of zoono8c infec8ons

•Four previously unknown paramyxoviruses isolated from flying foxes since 1995, including Nipah and Hendra viruses

•Three cause severe disease in domes1c animals (horses and pigs) and are known to infect humans

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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 infecFon to humans

• Subsequently humans infected by consuming date palm sap contaminated by bats (India, Bengladesh)

• Human to human transmission; infecFons conFnue25

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 conFnue to acquire infecFon

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Diseases of explora8on and coloniza8on

• Explosive epidemic spread may occur when a virus enters a naive populaFon

• Smallpox reached Europe from the Far East in 710 AD, a[ained epidemic proporFons

• Smallpox changed the balance of human populaFons in the New World -‐ killed 3.5 million Aztecs in 2 years (1520 -‐ spread from Hispaniola), allowing conquest by Cortez

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Yellow fever virus: Humans change the paUern and pay the price

Yellow fever deaths, Philadelphia, 1793


“Yellow Fever will discourage the growth of great ci9es in our na9on”THOMAS JEFFERSON, 1800

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Changes in human popula8ons and environments

• Emergence of epidemic poliomyeliFs in the beginning of the 20th century: improved sanitaFon delayed transmission

• Known since 4,000 years ago, stable host-‐virus relaFonship

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Poliomyeli8s: A disease of modern sanita8on


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Changing climate and animal popula8ons

• Hantavirus pulmonary syndrome -‐ first noted in the Four Corners area of New Mexico, 1993

• Disease is caused by Sin Nombre virus, endemic in the deer mouse (Peromyscus maniculatus, 30% virus posi1ve)

• Originally called Muerto Canyon virus, but residents objected to the name

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Changing climate and animal popula8ons

• In 1992-‐93, abundant rainfall produced a large crop of piñon nuts, food for humans and the deer mouse. Mouse popula1on rose, contact with humans increased.

• The virus is excreted in mouse droppings, and contaminated blankets or dust from floors provided opportuni1es for human infec1on

• Humans are not the natural host for Sin Nombre virus, the human disease is rare

• Not new -‐ earliest known case 1959

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Distribu8on of Peromyscus maniculatus and Loca8on of HPS Cases as of August 27, 2003

Total Cases (N=349 in 31 States)

Peromyscusmaniculatus

SNVOther virus

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Sin NombrePeromyscus maniculatus

Rio SegundoReithrodontomys mexicanus

El Moro CanyonReithrodontomys megalo9s

AndesOligoryzomys longicaudatus

BayouOryzomys palustris

Black Creek CanalSigmodon hispidus

Rio MamoreOligoryzomys micro9s

Laguna NegraCalomys laucha

MuleshoeSigmodon hispidus

New YorkPeromyscus leucopus

Juqui8baUnknown Host

MacielNecromys benefactus

Hu39694Unknown Host

LechiguanasOligoryzomys flavescens

PergaminoAkodon azarae

OránOligoryzomys longicaudatus

Caño DelgaditoSigmodon alstoni

Isla VistaMicrotus californicus

Bloodland LakeMicrotus ochrogaster

Prospect HillMicrotus pennsylvanicus

BermejoOligoryzomys chacoensis

CalabazoZygodontomys brevicauda

ChocloOligoryzomys fulvescens

(Virus Names in Orange are Associated with Human Disease)

New World Hantaviruses

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Hantavirus zoono8c infec8on is a warning that poten8al human diseases lurk in the wild if we

inadvertently intrude upon another host-‐parasite rela8onship

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SARS -‐ Rise and fall of a zoono8c infec8onPNEUMONIA -‐ CHINA (GUANGDONG): RFI ********************************** A ProMED-‐mail post<hfp://www.promedmail.org>ProMED-‐mail is a program of the Interna1onal Society for Infec1ous Diseases <hfp://www.isid.org> [1] Date: 10 Feb 2003 From: Stephen O. Cunnion, MD, PhD, MPH <[email protected]> This morning I received this e-‐mail and then searched your archives and found nothing that pertained to it. Does anyone know anything about this problem?"Have you heard of an epidemic in Guangzhou? An acquaintance of mine from a teacher's chat room lives there and reports that the hospitals there have been closed and people are dying.“ -‐-‐Stephen O. Cunnion, MD, PhD, MPHInterna1onal Consultants in Health, IncMember ASTM&H, ISTM<[email protected]>

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SARS

• Outbreak of severe atypical pneumonia, unknown eFology, Guangdong Province, China, Nov 2002

-‐ 305 cases, 5 deaths

• IncubaFon 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 venFlaFon

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SARS (Severe acute respiratory syndrome)

• A Chinese doctor who treated first paFents traveled to Hong Kong on 21 February 2003, stayed on ninth floor of Metropole Hotel

• He died in hospital 22 February

• InfecFon spread to 10 people in hotel, who flew to Singapore, Vietnam, Canada, US before symptoms evident

• InfecFon spread to 8000 people in 29 countries, 10% mortality

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Hotel MHong Kong

Guangdong Province, China

A

A

H,JA

H,J

Hong Kong SAR

Hosp. 1: 99 HC

8 hospitals total

Total: 156 close contacts of HCW and pa8ents

United States

1 HCW

I, L,M

I,L,M

K Ireland

0 HCWK

Singapore

34 HCW

37 close contacts

C,D,E

C,D,E

B

B

Vietnam

37 HCW

21 close contacts

F,G

Canada

18 HCWF,G

11 close contacts

Spread from Hotel Metropole(21 February 2003)

249 cases traced to “A” as of March 28, 2003

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SARS virion

~120 nm

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SARS-‐CoV disease mechanisms

• Transmifed by respiratory droplets

• Virus enters respiratory tract and mul1plies in epithelial cells

• Mul1plica1on in alveolar epithelial cells leads to lung injury

• Immune suppression cause of severe disease?


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Probable cases of SARS by date of onset,Hong Kong: n = 1 753, as of 9 June 2003

Num

ber o

f cases

01 Feb 13 Feb 25 Feb 9 Mar 21 Mar 2 Apr 14 Apr 26 Apr 8 May 20 May 1 Jun 9 Jun

0

20

40

60

80

100

120

Outbreak ends July 2003

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Probable SARS Cases Worldwide Reported to WHO as of Sept. 26, 2003

China (5327)

Singapore (238 + 1)

Hong Kong (1755)

Vietnam (63)

Canada (251)

U.S. (29)

Europe:10 countries (34)

Thailand (9)

Taiwan (346)

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

Australia (6)

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SARS and the economy:impact on global travel

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Airport screening and health informa8on, Hong Kong, SARS, 2003

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Public Health Responses to SARS

• Epi Surveillance and early warning

• Case inves1ga1on, contact tracing

• Interven1ons

-‐ Immuniza1on: NOT AVAILABLE

-‐ An1viral agents: NOT AVAILABLE

-‐ Travel restric1ons, quaran1ne: WIDELY USED

-‐ Public educa1on

• Infec1on control for healthcare providers and in healthcare setngs

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Origin of SARS-‐CoV• Human sera collected

before SARS outbreak do not contain anFbodies to SARS-‐CoV

• Early Guangdong SARS cases were in handlers of animals for the exoFc food market

• Animal traders had significantly higher prevalence of anF-‐SARS-‐CoV anFbodies than control groups

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An8body to coronavirus in humans, Guandong Province

Occupa8on # An8body (%)

Wild animal trader 20 8 (40)

Animal slaughterer 15 3 (20)

Vegetable handler 20 1 (5)

Control(hosp., non-‐resp.) 60 0 (0)

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Origin of SARS-‐CoV

• Virus isolated from Himalayan palm civets in live-‐animal market in Guangdong (May 2003)

• Evidence that some SARS infec1ons in China were transmifed from civets to humans

• Civet culling and quaran1ne imposed

• Probably not animal reservoir of the virus:

‣ Civet viruses >99.6% iden1ty

‣ Virus not owen isolated from farm or wild civets

Paguma larvata (Palm civet)Link to humans?

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Origin of SARS-‐CoV

• SARS-‐like CoVs isolated from different species of horseshoe bats in different regions of China

• Isolated from provinces >1000 km apart

• Up to 84% of bats examined had anF-‐SARS-‐CoV anFbodies

• Bat SARS-‐like-‐CoVs 88-‐92% sequence idenFty with human or civet strains

• Greater geneFc diversity in bat viruses than those of humans or civets

• Hypothesis: bats are reservoir of SARS-‐CoV, transmi[ed to humans via market animals (e.g. civets)

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How did SARS-‐CoV adapt to humans?

• Hundreds of SARS viral RNA genomes were sequenced from humans and animals during and aMer the epidemic

• CoV spike glycoprotein is a major determinant of species specificity of infecFon

• Human and civet strains differ by only four amino acids in the receptor-‐binding domain, but cause >1000-‐fold difference in binding affinity to cell receptor, human angiotensin-‐converFng enzyme 2 (ACE2)

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SARS-‐Cov -‐ ACE2 interac8on

large binding interface

addi1on of charge

dele1on of methyl

pro reduces binding surface

large glycan

lacks hydrophobic

pocket

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Will SARS Return?

• No known transmission of human SARS-‐CoV. Most recent human cases of SARS-‐CoV infecFon were laboratory-‐acquired (China, April 2004)

• December 2003 -‐ January 2004: 4 SARS cases in Guangdong Province, new animal -‐ human transmission

• SARS-‐CoV precursor conFnues to circulate in animals; wild game banned in markets

• Re-‐emergence will be more quickly recognized and contained

CREDIT: MICHAEL REYNOLDS/EPA/NEWSCOM

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CoV-‐EMC

• 17 cases, 11 fataliFes, March 2013

• Closely related to bat coronaviruses

• Not SARS-‐CoV

• Virus circulaFng in Arabian peninsula

• Binds dipepFdyl pepFdase 4 receptor

Science 5 April 2013: Vol. 340 no. 6128 pp. 17-‐18

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Virus Disease

HCoV-‐229EHCoV-‐NL63HCoV-‐OC43HCoV-‐HKU1SARS-‐CoV

•Respiratory diseases• Febrile upper tract infec1on• Lower tract infec1ons• Asthma exacerba1on• Atypical pneumonia

Coronavirus disease in humans

1890, bovine CoV

1686 -‐ 1800, bat CoV

1450 -‐ 1191, bat CoV

CoV-‐EMC • Severe pneumonia2003, bat CoV

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Canine parvovirus: Cat-‐to-‐dog by two muta8ons

• Canine parvovirus idenFfied in 1978, cause of new enteric and myocardial infecFon in dogs

• Evolved from feline panleukopenia virus, another parvovirus

-‐ Infects cat, mink, racoon

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Canine parvovirus

two amino acid changes!

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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)

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Emerging infec8ons can be detected and controlled only by socie8es willing to pay

• Research and development in academia and industry

• Early detecFon and idenFficaFon technology

• Databases of all viral genomes in the ecosystem

• First responder acFons combined with rapid communicaFon

• Public health acFon including vaccines, drug stockpiles, quaranFnes

• Inter-‐agency communicaFon and cooperaFon among local, state, and federal government

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