Viruses Associated with Birds - Viruses And Human Disease

ebolavirus is less virulent, and Ivory Coast ebolavirus is the

the United States, the army team quickly decided to eutha-

least virulent.

nize the monkeys and decontaminate the facility. Follow-up

The natural reservoir of Ebola virus in Africa has recently

studies showed that four animal handlers at the facility had

been shown to be bats. Three species of fruit bats collected

been infected by the virus but had suffered no illness. Thus

in Gabon and the Democratic Republic of Congo, close to

the strain of Ebola present in the Reston monkeys, called

areas where an epidemic of Ebola had devastated local gorilla

Reston ebolavirus, seems to be nonpathogenic for humans

and chimpanzee populations, showed evidence of infection.

although it remains pathogenic for monkeys. The story of

Significant numbers of Hypsignathus monstrosus (4 of 17

the Reston incident was recounted in a book called The Hot

tested), Epomops franqueti (8 of 117), and Myonycteris

Zone by Richard Preston. Since this first epidemic of Reston

torquata (4 of 58) were found to have antibodies to Ebola

ebolavirus, a new outbreak has occurred in Reston, two out-

virus, and viral nucleic acid was detected in liver or spleen of

breaks have occurred in an animal facility in Alice, Texas,

other bats of these three species (4 of 21, 5 of 117, and 4 of

and an outbreak took place in Sienna, Italy. All outbreaks

41, respectively). No viral RNA was found in any other ani-

occurred in monkeys imported from the Philippines and it

mal species tested, which included 222 birds and 129 small

seems probable that the virus is native to the Philippines.

vertebrates, among others. The infection of the bats appears

No serious illness in humans has occurred in any of these

to be asymptomatic, consistent with the hypothesis that the

outbreaks. Nucleotide sequencing has shown that Reston

fruit bat is the reservoir of Ebola virus. It is probable that

ebolavirus is closely related to the African ebolaviruses. The

bats are also the reservoir of Marburg virus.

reason it is attenuated in humans is still unexplained, and

It is clear that monkeys can be infected by the virus and

high containment is used for studies of Reston ebolavirus in

spread it to humans, but how the monkeys contract it is not

the laboratory.

known. Perhaps the monkeys eat fruit that has been partially

eaten by the bats. There have been serious die-offs of gorillas

Are Filoviruses a Major Threat?

and chimpanzees in the last decade or so that have severely

impacted the populations of these animals in some areas.

To date, the filoviruses have caused only a limited number

Some human epidemics get started when monkeys dying of

of human infections. However, if a filovirus were to adapt to

the disease are butchered for food, but in other epidemics

humans such that human-to-human transmission occurred

monkeys are not implicated and how the epidemic starts is

readily, it could become a major problem. The probability of

not known. Again, perhaps consumption of partially eaten

such an event is unknown.

fruit is to blame. The recent large die-offs of apes and chim-

panzees in some areas together with the increasing frequency

of human infection indicates that the virus is spreading more

VIRUSES ASSOCIATED WITH BIRDS

widely. Whether this is due to a new strain of virus that is

more easily spread to humans and nonhuman primates, or to

Many viruses are known for which birds are the verte-

the recent introduction of the virus from a source outside the

brate reservoir but which can also infect humans, causing

areas now experiencing epidemics, or to human alterations

outbreaks of serious illness. Because many species of birds

of the environment leading to more contact between humans

travel large distances during their annual migration, viruses

and nonhuman primates with the bats that carry the virus is

associated with such species are spread rapidly over a wide

not known.

geographic area. Here we consider the rapid spread of West

Nile virus in the Americas and the alarming appearance of

new strains of influenza virus that have the potential to cause

Reston Ebola Virus

very large epidemics of very serious influenza in human

A fourth strain of Ebola virus originating from the

populations.

Philippines (or, perhaps, another region of Asia) first

appeared as the causative agent of an epidemic of hemor-

West Nile Virus in the Americas

rhagic fever in monkeys imported from the Philippines. This

epidemic occurred in Reston, Virginia, near Washington,

Appearance and Spread of West Nile in the New World

D.C., in 1989. The deaths were at first attributed to simian

In the summer of 1999, West Nile virus, a mosquito-borne

hemorrhagic fever virus (SHFV), but investigation by the

flavivirus (Chapter 3), appeared in North America for the

U.S. Army Medical Research Institute for Infectious Diseases

first time. There were 62 human cases of West Nile disease

and the Centers for Disease Control and Prevention found

in the New York City area, of whom 7 died of encephalitis.

that both SHFV and Ebola virus were present in the mon-

Numerous birds also died, including exotics in zoos as well

keys. Believing that the community was at risk for Ebola,

as native birds. With the end of the mosquito season the epi-

made even the more alarming because the epidemic was

demic died out, but the virus had become established. Over

occurring in the neighborhood of the central government of

the next 6 years the virus rapidly spread across the United

because humans are poorly able to pass on the virus as

States and north into Canada as well as south into Central

described in Chapter 3. A second possibility is that the virus

America, northern South America, and the Caribbean. The

arrived in a viremic bird being imported legally or illegally,

march of the virus across the United States is illustrated

although there is no evidence for such an event. It seems

in Figs. 8.4 and 8.5. The rapid spread of this virus into a

highly unlikely that a migratory bird that was off course

new ecological area requiring adaptation to new mosquito

introduced the virus because West Nile first appeared near

vectors as well as new vertebrate hosts is extraordinary. In

a major international airport. The favored hypothesis is that

the process, more than 20,000 Americans became ill from

the virus arrived in an infected mosquito that came along for

WN virus infection and more than 800 died of neurologi-

the ride in a jet aircraft. Introduction of the virus was almost

cal complications (Fig. 8.6). Figures 8.5 and 8.6 illustrate an

certainly a singular event.

interesting and not well understood phenomenon. After the

front passes through an area, there are many fewer human

Effects of West Nile on Wildlife

cases of disease in the following years. Yet only a minority

of humans in any area had been infected and are therefore

West Nile virus has had profound and well documented

immune to the virus, and the virus continues to be present.

effects on horses and wildlife as it moved across North

In some way the transmission cycle has been interrupted,

America. Many horses died of WN disease, and a vaccine

perhaps by the die-off of the birds that serve as the primary

has now been introduced in order to protect horses. The

amplifying hosts.

effect upon bird populations has been particularly dramatic.

WN virus strains from the United States are 99.7% identi-

Crows, jays, and raptors (hawks and owls) are particularly

cal to strains from Israel, and the U.S. strain certainly origi-

sensitive to the virus. Almost all crows die after infection,

nated in the Middle East. It presumably arrived in New York

for example, and in many parts of the country the crow

on a jet aircraft, and there are three possible vectors that

population crashed with the arrival of the virus, although

could have carried the virus. It is conceivable that a viremic

TMere are recent signs that the population is at least partially

human introduced the virus, although this seems unlikely

recovering. Many raptors prey upon small rodents and are

1999

2000

2001

Human Cases

FIGURE 8.4 The early spread of West Nile virus across the United States from 1999 to 2001. Data are from the

archives of the West Nile Virus Surveillance site from the Centers for Disease Control and Prevention at: http://www.cdc.

gov/ncidod/dvbid/westnile/surv&control.htm.

VT ME

2002

WV VA

MS AL

VT ME

2003

WV VA

MS AL

Cases/100,000 population

0 to 0.1

VT ME

2004

0.11 to 1.0

1.01 to 3.0

WV VA

3.01 to 15.0

>15.0

MS AL

VT ME

2005

IL IN

WV VA

MS AL

FIGURE 8.5 The spread of West Nile virus across the United States from 2002 to 2005. Data are from the archives of

the West Nile Virus Surveillance site from the Centers for Disease Control and Prevention at: http://www.cdc.gov/ncidod/

dvbid/westnile/surv&control.htm.

10,000

Total cases of West Nile

Cases of WNV Encephalitis/Meningitis

8000

6000

600

4000

400

2000

200

1999

2000

2001

2002

2003

2004

2005

Year

FIGURE 8.6 Total number of cases of West Nile fever, cases of encephalitis and meningitis due to WN virus, and deaths

from WN virus are shown for 1999 through 2005. Data are from the archives of the West Nile Virus Surveillance site from

the Centers for Disease Control and Prevention at: http://www.cdc.gov/ncidod/dvbid/westnile/surv&control.htm.

important in controlling their numbers, and a crash in their

spread of the virus. One encouraging finding relating to the

numbers results in an increase in rodent populations. As an

potential of the virus to cause future epidemics of disease

example of the sensitivity of some owls to WN virus, there

is the appearance of an attenuated variant of WN virus in

was an outbreak of WN disease in North American owls in

Texas in 2003. In a mouse model, this variant is attenuated

a rehabilitation facility in Ontario in 2002, associated with

in neurovirulence. The emergence of WN virus was associ-

the die-off of corvids in the area. Large owls with a north-

ated with the appearance in Europe and the Middle East of

ern breeding range were particularly susceptible. Snowy

a more virulent strain of virus, perhaps enabling it to spread

owls, northern hawk owls, great gray owls, and boreal owls

more easily. It seems possible that once the virus becomes

experienced 100% mortality, and northern saw-whet owls

endemic, attenuated strains may become dominant.

experienced 92% mortality.

Avian Influenza

The Future of West Nile in the Americas

Influenza A virus caused three pandemics of severe influ-

WN virus is now well established in the Americas and

enza in the twentieth century. The pandemic of 1918 was

will surely continue to cause sporadic cases of human illness,

especially severe, infecting perhaps 30% of the world's pop-

if not sporadic epidemics, and sporadic die-offs of birds. It

ulation and causing up to 100 million deaths. These pandem-

is possible that the interruption of its transmission cycle

ics were associated with the appearance of new subtypes of

described above is due to extensive die-off of susceptible

HA and NA, the surface glycoproteins of the virus, in human

species of birds that serve as its major amplifying vectors. If

adapted viruses. The reservoir of influenza A is birds and the

so, the resurgence of the crow population and the populations

bird viruses must ordinarily undergo adaptation in some way

of other amplifying species could lead to renewed outbreaks

to humans in order to infect and cause epidemic spread. In

similar to those that occurred with the first appearance and

part this adaptation involves reassortment of flu segments to

incorporate human adapted segments. It had been thought

including infection of the brain. In this same study, isolates

that virus circulating in birds will not infect humans and

from birds caused nonlethal infection with virus replication

cause disease without prior adaptation, and that only HA

restricted to the upper respiratory tract.

subtypes H1, H2, and H3 were compatible with spread in

There have been three or four pandemics of influenza

humans. Recently, however, there have been numerous

every century for as long as can be ascertained from his-

cases of direct human infection by several strains of avian

torical studies and there is every reason to believe that pan-

influenza resulting in serious, even fatal, illness involving

demics will come again in the twenty-first century. If H5N1

new subtypes of HA. Three such viruses, H5N1, H7N7, and

virus should acquire the ability to spread readily from per-

H9N2 will be considered here.

son to person, and if its high lethality for humans should

continue unabated, it could cause a devastating pandemic.

Efforts are being made to prepare defenses against this

H5N1 Influenza

virus, including vaccines and antiviral drugs, supported by

H5N1 virus was first detected in China in 1996 where

the U.S. government and other governments. Promising vac-

it caused the death of a number of geese. After undergoing

cines are being developed and tested in clinical trials, and

reassortment to obtain new genes, it surfaced in Hong Kong

plans are to stockpile such a vaccine for possible use if an

in 1997 where it became widespread in live poultry markets.

epidemic of this virus arises. This effort is complicated by

Eighteen people were infected by the virus and six died.

the fact that H5N1 influenza, like all influenzas, continues

The virus was eradicated by culling all domestic chickens

to evolve, and stockpiled vaccine might not be completely

in Hong Kong. Different reassortants of H5N1 continued to

effective against the strain that ultimately might emerge as

arise and in 2002 an epidemic of influenza killed most birds,

a pandemic strain. Nevertheless, there is hope that at least

domestic and wild, in Hong Kong nature parks. Two people

partial immunity might be effected by such a vaccine that

were infected and one died. The virus then spread widely

could ameliorate the symptoms of the disease and protect

over eastern Asia. The virus killed wild as well as domestic

against the extreme virulence of the virus. As described in

waterfowl and chickens, and together with repeated efforts

Chapter 4, new approaches to flu vaccine development are

to stop the spread of the virus by culling of birds, the death

being tried, including development of a universal flu vac-

of more than 140 million birds occurred. The virus has a

cine that would work against any influenza A strain, but

high mortality rate in humans, about 50%, and as of early

such an approach will clearly require many more years of

2007 more than 150 people have died as a result of H5N1

research before a licensed vaccine for general use could be

infection. There is no evidence for human-to-human trans-

produced. Efforts are also being directed toward producing

mission at the current time. All human infections appear to

and stockpiling antiviral compounds directed against influ-

have originated from close contact with infected birds.

enza. Unfortunately, most H5N1 isolates tested are resistant

The virus has continued to spread westward. It has now

to amantadine and related compounds, antiflu agents that

reached many countries in Europe and established a beach-

have been in use for years and that are readily available. It is

head in Africa. It is thought that the virus will soon reach

thought that this is the result of the wide use of amantadine

North America, brought by migratory birds. The mechanism

by Chinese farmers to protect their chicken flocks from influ-

of its rapid spread is not completely clear. It is thought that

enza, thereby selecting for amantadine-resistant variants of

transport of domestic birds may be responsible in part for

the viruses. This effect may be moderating, however, as some

the spread, but there is reason to believe that wild waterfowl,

recent isolates are sensitive to amantadine. Inhibitors of the

ducks, geese, and swans, are also spreading the virus. These

influenza neuraminidase such as oseltamivir (Tamiflu) and

birds undergo seasonal migrations over large distances, and

zanamivir appear to be reasonably effective against H5N1

episodes of dead and dying migratory birds have been associ-

virus, but these drugs must be used early in infection if they

ated with the appearance of the virus in new areas. The virus

are to be effective. Production of these compounds is limit-

is continuing to evolve. Unlike most avian influenza viruses,

ing at present, but production is being accelerated in order

it is highly pathogenic in chickens and many strains are also

to stockpile them for possible use if or when a pandemic

pathogenic in ducks, both domestic and wild. Virulence in

erupts.

wild ducks seems to be moderating, as some recent isolates

do not kill wild ducks, but virulence in chickens continues.

H7N7 Influenza

All isolates contain the multibasic cleavage site in HA that

is recognized by furin, which is correlated with increased

An epidemic of H7N7 influenza A erupted in The

virulence.

Netherlands in 2003. A total of 89 human infections was

Studies of H5N1 virus in mice and ferrets have shown

recorded, of whom 86 were directly involved in handling

that many virus isolates are highly virulent for these mam-

poultry. Human-to-human transmission occurred and three

mals. In one study with ferrets, isolates from humans caused

family members were also affected. The primary disease

a fatal infection characterized by broad tissue tropism,

syndrome was conjunctivitis but there were two cases

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