Emerging viruses

Lecture 22
Biology 3310/4310
Virology
Spring 2017

Nothing endures but change

HERACLITUS
 Emerging viruses

• Emerging virus - causative agent of a new or previously unrecognized infection

• The term became popular in 1990s, but emerging viruses are not new
• Since the rise of agriculture - 11,000 years ago - new infectious agents have
invaded human populations because they can be sustained by numbers that
were unknown before agriculture and commerce
• Only recently have we become good at detecting emerging viruses

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Emerging viruses

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

• Transmission of a virus from a wild or domesticated animal to humans -
zoonosis
• Cross-species infection may establish a new virus in the population (SIV
moving from chimps to humans)
• Often cross-species infection cannot be sustained (e.g. Ebola and
Marburg from bats to humans)

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Human - animal interface

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

37

Viruses belonging to # of genera

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University One Health, ASM Press
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 Convergent forces of disease emergence

GLOBALIZATION 

RAPID AIR TRAVEL

ALTERED

ECOSYSTEMS

EXPANDING
POPULATIONS

“MEGA- CITIES”

POVERTY MICROBIAL

EVOLUTION

DEFORESTATION ENVIRONMENTAL CHANGES

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Over-riding factors driving the emergence of infectious diseases of
humans and animals:


Human population growth and incredible change occurring in all ecosystems brought about by human occupation of
almost every corner of the planet

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 The Amazon North Region of Brazil

Home to 183 Arthropod-borne and Other Vertebrate Viruses

Cacipacore, Trombetas, Mapuera, Oriximina,

Serra do Navio,
Turuna, Saraca, Juruaca Araguari, Amapari, Ieri, Aura, EEE, Una, WEE, Bussuquara, Ilheus, Kairi,
Cupixi Maguari, Taiassui, Caraparu, Itaqui, Murutucu,

0º
Munguba, Jari, Jutai, Monte Nepuyo, Melao, Acara, Benevides, Benfica,
Dourado, Paru, Tumucumaque,
Bushbush, Capim, Guajara, Ananindeua, Bimiti,
Almeirim 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,
Boa Vista Melgaco Tucunduba, Apeu, Marituba, Oriboca, Caraparu-like,
Guama, Anhanga, Mayaro
dengue 1, dengue 4

Amapa dengue 2, dengue 3,

Bocas, Triniti, Barcarena

Roraima Macapa

Belem Pixuna, SLE, Lukuni, Sororoca, Guaroa,

Oropouche, Candiru, Pacui, Caninde, Gurupi,
Irituia, Ourem, Tembe, Cocal, Jurona

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

Itupiranga

Palmas
Iaco, Moriche, Purus,
Acre Porto Velho
Xingu, Ambe, Joa, Tapara, Acatinga,
Mojui dos
Sena Madureira, Acurene, Altamira, Assurinis, Bacajai,
Campos, Santarem,
Xiburema
Rio Branco Jamanxi
Gorotire, Kararao, Uxituba, Cajazeira,

Tocantins
Belterra,
Codajas, Galibi, Iriri, Uruara
Cuiaba,
Rondonia Alenquer

Ariquemes

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

Sites from which viruses were isolated at the Serra Norte, Catete,
Parauapebas, Serra Sul,
Tapirope, Carajas, Brazil

Evandro Chagas Institute Maraba, Curianopolis,

Itacaiunas

an
e
Oc
ic
nt
la
At
0 500 1,000
Kilometers
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 Virus Family Drivers of Emergence

Urban population density,

Dengue virus Flaviviridae
mosquito breeding

Human contact with natural host;

Ebolavirus Filoviridae
bushmeat

Hantaan virus Bunyaviridae Agriculture: human/rodent contact

Hendra virus Paramyxoviridae Bats to horses to stable 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

Sin Nombre virus Bunyaviridae Weather, human/rodent contact

West Nile virus Flaviviridae Mosquito

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Roles of Evolution

• Leads to the biodiversity of pathogens existing in nature (quasispecies)

• Adaptation to new hosts and environments (through variation and selection)

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 The general interactions of hosts and viruses

Major pathways

• Stable: maintains virus in ecosystem

• Evolving: passage of virus to naive population (same or different host)
• Dead-end: one way passage to different species
• Resistant host: infection blocked
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Stable host-virus interactions

• Both participants survive and multiply

• Some are effectively permanent
- Humans are sole natural host for measles virus, herpes simplex virus, HCMV,
smallpox

• May include infection of more than one species

- Influenza A virus, flaviviruses, togaviruses
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Evolving host-virus relationship

• Hallmarks are instability and unpredictability

• Outcome of infection may range from benign to death
- Introduction of smallpox and measles to natives of Americas by Old World colonists and
slave traders

- Introduction of West Nile virus into Western Hemisphere, 1999

- Introduction of rabbits into Australia

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Dead-end interaction

• Frequent outcome of cross-species infection

• No sustained transmission from new infected host to others of the
same species
• Ebolavirus: humans, chimps, gorillas
• H5N1
• Contribute little to the spread of a natural infection
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 The complex life cycle of
an arbovirus

Stable host-virus interactions

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Rodents and insect vectors move European tick-borne
encephalitis virus among many hosts

Dead-end hosts

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Flaviviruses: Human pathogens

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Emerging infections: Two steps

• Introduction
• Establishment and dissemination

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Human are constantly providing new ways to meet viruses

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Encountering new hosts

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

detected
• Single-host infections are not transmitted among humans for many
reasons

horses, pigs, chickens

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Expanding viral niches

• Successful encounters require access to susceptible and permissive

cells
• Population density and health are important factors
• Virus populations will endure in nature only because of serial
infections (a chain of transmission)

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Diseases of exploration and colonization

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

population
• Smallpox reached Europe from the Far East in 710 AD, attained
epidemic proportions
• Smallpox changed the balance of human populations in the New
World - killed 3.5 million Aztecs in 2 years (1520 - spread from
Hispaniola), allowing conquest by Cortez

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Changes in human populations and environments

• Emergence of epidemic poliomyelitis in the beginning of the 20th

century: improved sanitation delayed transmission
• Known since 4,000 years ago, stable host-virus relationship
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 Poliomyelitis: A disease of modern sanitation

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Bats: A source of zoonotic infections

• Many new paramyxoviruses found in flying

foxes since 1995, including Nipah and Hendra
viruses
• Cause severe disease in domestic animals
(horses and pigs) and infect humans

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Nipah virus

• First outbreak Malaysia 1998

- Outbreak of respiratory and neurological disease on pig farms

- 105 human deaths, 1 million pigs culled

• Fruit bats are unaffected, excrete virus in urine

• Pig farmers plant mangoes near pigpens

• Pigs spread infection to humans

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

• Human to human transmission; infections continue

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 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 continue to acquire infection
• Vaccine for horses: One World health
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 Changing climate and animal populations

• 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 positive)

• Originally called Muerto Canyon virus, but residents objected

Bunyaviridae

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Changing climate and animal populations

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

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Principles of Virology, ASM Press
 HPS by State, January 2016
Range of P. maniculatus
n=690

https://www.cdc.gov/hantavirus/surveillance/reporting-state.html

Deer mouse, white-footed mouse, rice rat, cotton rat

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 Heartland virus disease

• 2012 - new phlebovirus identified in two farmers

in Missouri
• Six subsequent cases identified, tick vector?
• How long had it been infecting people?

Bunyaviridae

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Ebola hemorrhagic fever

• Simultaneous outbreaks in 1976 in DRC (318, 88%) and Sudan (284, 53%)
• Sudan index case: cotton factory workers
• Spread by use of contaminated needles, among family members
• Named after small river in northwestern DRC

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Outbreaks of Ebolavirus disease

Each outbreak represents a new zoonotic spillover

Guinea
Sierra Leone
Liberia
28,646
39.5%

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Pigott et al. eLife 2014;3:e04395. DOI: 10.7554/eLife.04395
 Biosafety level 4 (BSL-4)

• High mortality
• Person to person transmission
• No approved vaccine or antiviral

Threading the NEIDL https://youtu.be/tqAjkjGq8Ug

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 Ebolavirus

IFN IFN Tetherin RNA IFN

antagonist
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University antagonist antagonist synthesis antagonist
Principles of Virology, ASM Press
 How are humans infected?

• A classic zoonosis
• Index case: contact with animal carcass* (bushmeat)
• Transmitted to other humans by close contact with infected fluids
• Chains of human infections short
• R0 = 2

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University *not always identified
 Filovirus ecology

• Marburg virus has been isolated from cave-dwelling fruit bat

(Rousettus aegyptiacus)
• Zaire Ebolavirus RNA, antibodies found in three tree-roosting bats (but
not infectious virus)
• Humans, gorillas, chimpanzees are dead-end hosts
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University http://commons.wikimedia.org/wiki/File:Rousettus_aegyptiacus_Tel_Aviv_250504.jpg
 What is the origin of Ebolaviruses?
Bats

{
Chimp Gorilla Other
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University Pigott et al. eLife 2014;3:e04395. DOI: 10.7554/eLife.04395
 Ebolavirus outbreak examples

• Gabon, 1996 (Zaire ebolavirus, 37 cases) A chimpanzee found dead in the forest was
eaten by people hunting for food. Eighteen people who were involved in butchering
the animal became ill. Ten other cases occurred in their family members.

• Gabon, 1996-97 (Zaire ebolavirus, 60 cases) The index case was a hunter who lived
in a forest camp. A dead chimpanzee found in the forest at the time was infected
with Ebola virus.

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Ebolavirus emergence in
Guinea

N Engl J Med 2014; 371:1418-1425

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Human-human transmission

• Contact with infected blood or body fluids (urine, saliva, sweat, feces,
vomit, breast milk, semen) from someone who is sick or has died
• Contact with contaminated objects (needles, syringes)
• Not by insects, water, food, or aerosol

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Host entry

• Mucosal surfaces
• Breaks or abrasions in skin
• Parenteral (e.g. contaminated needles)
• Virus detected in skin, body fluids, nasal secretions, blood, semen

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Ebolavirus disease: Clinical features

• Incubation period 2-21 days (not contagious)

• Early symptoms: fever, headache, muscle pain, diarrhea, vomiting,
stomach pain
• Peak illness: rash, hemorrhage, convulsions, severe metabolic
disturbances, diffuse coagulopathy
• 30-90% case fatality ratio in Africa

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Clinical features: Multisystem involvement

• Systemic (prostration)
• Gastrointestinal (anorexia, nausea, vomiting, abdominal pain,
diarrhea)
• Respiratory (chest pain, shortness of breath, cough)
• Vascular (conjunctival injection, postural hypotension, edema)
• Neurological (headache, confusion, coma)
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 Pathogenesis

• Extensive necrosis in parenchymal cells of many organs (liver, spleen,

kidney, gonads)
• Broad cell tropism: Monocytes, macrophages, dendritic cells,
endothelial cells, fibroblasts, hepatocytes, adrenal cortical cells,
epithelial cells
• Elevation of liver enzymes, shock (adrenal)
• Massive lymphocyte death but not infected

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Immunopathogenesis

• Many inflammatory mediators produced, especially by infection/

activation of monocytes/macrophages
• Imbalanced cytokine production => disease
• Impairment of vascular and coagulation systems

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 An acute infection?
Persistence of Ebolavirus in ocular fluid during convalescence
9 weeks after clearance of viremia

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University http://www.nejm.org/doi/pdf/10.1056/NEJMoa1500306

 An acute infection?
Evidence of sexual transmission
Presence of viral genome in semen

46/93 men (49%)

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University http://www.nejm.org/doi/pdf/10.1056/NEJMoa1511410
 What have we learned?

• Every infectious disease is a global problem

- 4 cases in US: 2 imported (Dallas, NYC), 2 locally acquired
• Ebolavirus vaccines have been ready for clinical trials for some time
• What other viruses should we be preparing for?

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University https://en.wikipedia.org/wiki/Ebola_virus_cases_in_the_United_States#/media/File:USA-Ebola-outbreak-2014.svg

 Zika virus

• 1947, Zika Forest, Uganda

• Isolated from A. africanus
• Virus isolated from humans, Nigeria, 1954
• Serological detection throughout Africa, Asia but no outbreaks
• Vector for human infections: A. aegypti
• <20 cases over next 50 years
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 • 2007 outbreak on Yap Island (5,005/6,892 residents) first outside Africa,
Asia
• 2013 outbreak French Polynesia (30,000, 11% of population)
• 2014 New Caledonia (1,400, 0.8%), Cook Islands (905), Easter Island (50)
• 2015 Vanuatu, Solomon Islands, Samoa, Fiji

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Zika virus

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Type II fusion protein

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Zika virus

• Disease: rash, fever, joint pain, conjunctivitis, headache (similar to

dengue, chikungunya)
• Incubation period 2-10 days
• 1 in 5 develop symptoms; 5 day course
• Fatalities rare

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Zika virus shedding

• Semen
• Urine (PCR) - up to 30 days after symptom onset
• Saliva (more frequently than in blood)
• Blood
• Breast milk
• Except for blood, unknown how virus reaches these sites

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Zika sexual transmission

• CDC surveillance report shows 23 out of 2,382 (1%) reported cases resulted
from sexual contact with a traveller to an affected area
• CDC advises against pregnant women traveling to endemic areas, or having
unprotected sex with potentially infected partners
• RNA persists in semen 188 days, but is it infectious virus?
• Likely can’t sustain transmission via sex alone: sexually transmissible, not
sexually transmitted

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Zika virus in the US

• 5011 travel-associated cases in states

• 223 locally vector-acquired cases (217 FL, 6 TX)
• US territories: 36,526 locally acquired cases (PR, US VI, American Samoa)
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 http://currents.plos.org/outbreaks/article/on-the-seasonal-occurrence-and-abundance-of-the-zika-virus-vector-mosquito-aedes-aegypti-in-the-contiguous-united-states/

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Zika in the US

• Minimal local US spread of dengue virus and chikungunya virus,

vectored by Aedes (FL, TX)
• 1793 yellow fever epidemic, Philadelphia
• Screens, A/C, population density
• West Nile spread across US in 1999 - different mosquito (Culex sp),
bird reservoir

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Central nervous system complications associated with
Zika virus infection
Adults Infants

• Guillain-Barré Syndrome • Microcephaly

(post-infection autoimmune
neuropathy; weakness, • Lissencephaly
paralysis, death)
• Macular atrophy
• Acute myelitis
• Encephalopathy
• Meningoencephalitis
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 Zika virus - Asian and African lineages

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University

 Emergence of Zika epidemics: Evolution or introduction into a
new population?

http://mbio.asm.org/content/8/1/e02063-16

• Adaptive evolution: Genetic changes in virus during spread to Pacific allowed higher
replication in vectors, altered human tropism to include congenital infection

• Stochastic introduction: ZIKV was simply transported stochastically to locations with

large-enough naive human populations, accompanied by large urban mosquito vector
populations, for an explosive outbreak. Formerly rare conditions were suddenly
recognized when large enough numbers of infections occurred.

• Peter Hotez, NYT Op-Ed 8 April 2016: “There are many theories for Zika’s rapid rise, but
the most plausible is that the virus mutated from an African to a pandemic strain a
decade or more ago and then spread east across the Pacific from Micronesia and
French Polynesia, until it struck Brazil.”
Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University
 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)

Virology Lectures 2017 • Prof. Vincent Racaniello • Columbia University