Family Bunyaviridae - Viruses And Human Disease

FAMILY BUNYAVIRIDAE

Other Orthomyxoviruses

Thogoto virus is present in regions of Africa, southern

The family Bunyaviridae contains more than 300 viruses

Europe, and Asia. It is a tick-borne virus that is primarily

grouped into five genera. A representative sampling of these

known from infection of livestock such as cattle, camels,

viruses is shown in Table 4.9. Members of four genera,

and sheep. There is significant amino acid sequence identity

Orthobunyavirus, Nairovirus, Phlebovirus, and Hantavirus,

between some of the Thogoto proteins and their counterparts

infect vertebrates and contain important human pathogens,

in influenza so these viruses are fairly closely related. It has

whereas viruses belonging to the genus Tospovirus infect

only six genomic segments, however. Human infection is

plants. The human pathogens in the family variously cause

known to occur in endemic areas.

hemorrhagic fever, hantavirus pulmonary syndrome which

Infectious salmon anemia virus infects salmonid fish.

can be fatal, encephalitis, or milder febrile illnesses, as

Atlantic salmon are particularly susceptible to the virus and

shown in the table. Some of these pathogens were listed in

the virus is a particular problem for fish farming. Farm pop-

Table 3.11, which contains a partial listing of arboviruses that

ulations can suffer 100% mortality in outbreaks. The virus

cause disease in humans. All members of the Bunyaviridae

has eight gene segments.

TABLE 4.9 Bunyaviridae

Virus name

Transmission/

Disease in

World

Genus/members

abbreviation

Usual host(s)

vector

humans

distribution

Orthobunyavirus (~48 viruses)

Bunyamwera

BUNV

Rodents, rabbits

Aedes mosquitoes

Febrile illness

Worldwide

La Crosse

LACV

Humans, rodents

Aedes triseriatis

Encephalitis

Midwest United States

Snowshoe hare

SSHV

Lagomorphs

Mosquitoes (Culiseta

Rarely infects

Northern United States

and Aedes)

humans

California encephalitis

CEV

Rodents, rabbits

Aedes melanimon,

Encephalitis (rare)

Western United States,

Ae. dorsalis

Canada

Jamestown Canyon

JCV

White-tailed deer

Aedes species,

Increasing

North America

C. inornata

Hantavirus (~22 viruses)

Hantaan

HTNV

Apodemus agrarius

Feces, urine, saliva

Hemorrhagic fever

Eastern Asia,

Eastern Europe

Seoul

SEOV

Rattus species

Feces, urine, saliva

Hemorrhagic fever

Worldwide

Prospect Hill

PHV

Microtus

None?

United States

pennsylvanicus

Sin Nombre

SNV

Peromyscus

Feces, urine, saliva

Pulmonary syndrome

Western United States

maniculatus

and Canada

Nairovirus (~7 viruses)

Dugbe

DUGV

Sheep, goats

Tick-borne

Africa

Crimean-Congo

C-CHFV

Humans, cattle,

Tick-borne

Hemorrhagic fever

Africa, Eurasia

hemorrhagic fever

sheep, goats

Phlebovirus (~9 viruses)

Rift Valley fever

RVFV

Sheep, humans,

Mosquitoes, also

Hemorrhagic fever

Africa

cattle, goats

contact, aerosols

Sandfly fever Sicilian

SFSV

Humans

Phlebotomous flies

Nonfatal febrile

Mediterranean

illness

Uukuniemi

UUKV

Birds

Tick-borne

Finland

Tospovirus (~8 viruses)

Tomato spotted wilt

TSWV

Plants

Thrips

None

Australia, Northern

hemisphere

Representative members of each genus are shown; the first virus listed is the type species.

except the hantaviruses are transmitted to their vertebrate

All bunyavirus genomes consist of three segments of RNA,

or plant hosts by arthropods, and transovarial transmission

referred to as S(mall), M(edium), and L(arge), that together

is important in the maintenance of many of the arboviruses

total from 11 to 19 kb, depending on the virus (Table 4.10).

in nature. The hantaviruses, in contrast, are associated with

The S segment encodes the nucleocapsid protein, M the

rodents and are transmitted to humans by aerosolized excreta

two surface glycoproteins, and L the polymerase protein.

from infected rodents. Thus, their epidemiology resembles

In addition, viruses belonging to three of the genera encode

that of the arenaviruses considered later, rather than that of

two nonstructural proteins, NSs in segment S and NSm in

other bunyaviruses. In the following discussion, the term

seg-ment M.

bunyavirus refers to any member of the family unless indi-

Replication of bunyavirus genomes and the synthesis

cated otherwise.

of mRNAs take place in the cytoplasm. The L protein and

N protein are required components of the RNA synthesis

machinery. Like influenza viruses, these viruses engage in

Replication of the Bunyaviridae

cap-snatching in order to prime mRNA synthesis. In bun-

yaviruses, however, the caps are captured from cytoplasmic

Genome Organization

mRNAs rather than from nuclear pre-mRNAs. The promoter

The genomes of representative viruses belonging to the

for mRNA synthesis and for RNA replication involves nucle-

five genera of the Bunyaviridae are illustrated in Fig. 4.21.

otides located at both ends of the genomic template, which

Minus strand

S RNA

M RNA

L RNA

genome segments

(0.96-2.9 kb)

(3.2-4.8 kb)

(6.4-12.2kb)

(range of sizes in kb)

ORTHOBUNYA-

VIRUS

Co-translational cleavage

(BUNV)

NSs

Nested reading frames

NSm

NAIROVIRUS

Co-translational cleavage

(C-CHFV)

HANTAVIRUS

(HTNV)

Post-translational cleavage

NSs

PHLEBOVIRUS

(RVFV)

Co-translational cleavage

Ambisense transcription and translation NSm

NSm

NSs

TOSPOVIRUS

(TSWV)

Co-translational cleavage

Ambisense transcription and translation

FIGURE 4.21 Genome organization of five genera of Bunyaviridae. Protein products encoded in each of the three genome

segments and the various strategies used to produce these proteins are shown. Unless otherwise noted the mRNA (not shown)

would extend 5' to 3' from left to right, and the protein product is shown N terminal to C terminal in the same direction. The

products are illustrated roughly to scale. Structural proteins are N (the nucleocapsid protein) and the two glycoproteins,

named Gn and Gc according to their proximity to the N or C termini of the precursor polyprotein; white boxes are precursor

proteins. Arrows indicate the direction of synthesis and translation of ambisense mRNAs (magenta hatch). Note that not all

phleboviruses encode an NSm protein on the M segment. Virus abbreviations are as follows: BUNV, Bunyamwera; RVFV, Rift

Valley fever; TSWV, tomato spotted wilt; C-CHFV, Crimean-Congo hemorrhagic fever; HTNV, Hantaan.

Deduced Sizes (kD) of Proteins Encoded by Bunyaviruses

TABLE 4.10

Genus

RNA (nts)

Protein (kD)

Orthobunyavirus

Hantavirus

Nairovirus

Phlebovirus

Tospovirus

L Segment

68756980

65506562

12,255

64046423

87768897

L protein (RNA Polymerase)

259263

246247

459

238241

330332

M Segment

44584526

36163696

4888

32314215

48214972

Glycoprotein Gn

2941

6876

3045

5072

4658

Glycoprotein Gc

108120

5258

7284

5575

7278

Precursor preG

7885, 92115

Nonstructural NSm

1518

None

None or 78

3437

S Segment

961980

16962059

1712

16901869

29162992

Nucleoprotein N

1026

4854

2430

Nonstructural NSs

1013

None

2932

Sizes of precursor proteins are shown in blue, nonstructural proteins are shown in green, and those translated from ambisense transcripts are in red.

are complementary and form hairpin circles, but with some

otides so that the mRNA attached to the primer begins pre-

cisely at the 3¢ end of the template. This "prime and realign"

unpaired nucleotides that are thought to be important recog-

nition signals (Table 4.11). Thus, as with many other RNA

strategy (Fig. 4.22) works because of the repeat triplets at the

3¢ end of the RNA template (Table 4.11). Transcription con-

viruses, the viral RNA polymerase must interact with both

ends of the RNA template in order to initiate synthesis, and

tinues to near the end of the template, but the termination of

complementarity between nucleotides at the 5¢ and 3¢ ends

an mRNA does not appear to be precise and the exact mech-

is required for promoter recognition. The terminal comple-

anism used for termination of the mRNAs is not known. No

poly(A) is added to the 3¢ end of the mRNA upon its release

mentary sequences are highly conserved within each genus

of bunyaviruses but differ between genera (Table 4.11).

and, thus, the mRNAs are capped but not polyadenylated.

Perhaps because of this, reassortment occurs only between

During replication of the genome, an exact complemen-

viruses belonging to the same genus.

tary copy, called cRNA or vcRNA, is produced. This RNA

During initiation of mRNA, as studied in hantaviruses,

serves as a template for producing genomic RNA and, in

the L protein cleaves the 5¢-terminal 718 nucleotides from

the case of ambisense segments, for producing the mRNA

a cellular mRNA. Cleavage is after a G residue, which pairs

for producing the ambisense-encoded protein. The switch to

with the C residue at position 3. The primer is elongated by

replication is assumed to use the same mechanisms as used

a few residues, and there is then a backward shift of 3 nucle-

by other (-)RNA viruses.

TABLE 4.11

Terminal Sequences of the Genome Segments

Expression of Proteins Encoded in S

of the Five Genera of Bunyaviridae

The S segment of bunyaviruses encodes one or two pro-

Nucleotide sequences of the L, M,

teins (Fig. 4.21). In the Hantavirus and Nairovirus genera,

Genus

and S segments

S encodes only N. In the other genera, S encodes both N and

NSs, using one of two different mechanisms. In the genus

5¢ U A G U A G U A ...

Hantavirus

Orthobunyavirus, the two proteins are translated from a

3′ A U C A U C A U C U G ...

single mRNA using two different start codons in different

5¢ U C A U C A C A U G A ...

Orthobunyavirus

reading frames. The coding region for NSs is completely

3′ A G U A G U G U G C U ...

contained within that for N. In the phleboviruses and tospo-

5¢ A G A G U U U C U ...

Nairovirus

viruses, however, an ambisense coding strategy is used for

3′ U C U C A A A G A ...

the two proteins (ambi = both). In this strategy, the two

5¢ U G U G U U U C ...

Phlebovirus

genes encoded in a genomic segment are linked tail to tail

3′ A C A C A A A G ...

so that they are in different polarities, as illustrated in Fig.

4.23. The gene for N is present at the 3¢ end of the genomic

5¢ U C U C G U U A ...

Tospovirus

3′ A G A G C A A U ...

S segment in the minus-sense orientation, and synthesis

of the mRNA for N occurs from the genome segment.

Expression of this gene occurs early because its mRNA is

Repeated sequences are underlined.

Step 1 - Priming

synthesized from the entering genome by the polymerase

activity present in viral nucleocapsids. The gene for NSs is

AUCAUCAUC...

3' terminus of minus-strand

plus sense within the genome, but the genomic RNA does

genome RNA

not serve as mRNA. Instead, an mRNA for NSs is synthe-

...G

CAP

Capped host-derived primer

sized from the antigenomic RNA. Thus, NSs is expressed

late because its mRNA can only be made after replication

of the incoming genomic RNA to produce the antigenomic

Step 2 - Initial Elongation

RNA. Termination of either mRNA occurs at a secondary

structure between the genes for N and NS, which appears

3' terminus of minus-strand

AUCAUCAUC...

to cause the polymerase to fall off and release the mRNA.

genome RNA

. . . GUAG

N has a number of functions in viral infection. It encap-

Nascent mRNA

CAP

sidates the viral RNA, interacts with L to synthesize viral

RNAs, and is believed to interact with one of the glyco-

proteins during virus assembly. In at least some viruses

Step 3 - Realigning

the protein also modifies cellular metabolism, presumably

AUCAUCAUC...

antagonizing antiviral defenses of the cell or otherwise sub-

verting cellular processes to support viral replication. The N

. . . G UAG

CAP

protein of hantaviruses, which is larger than those of other

bunyaviruses except for that of the nairoviruses, interacts

with a number of cellular proteins. The best studied of these

Step 3 - Final Elongation

are proteins in the small ubiquitin-like protein (SUMO)

pathways such as Ubc-9 (which conjugates SUMOs to pro-

3' terminus of minus-strand

AUCAUCAUC...

teins), SUMO-1 itself, and Daxx (to which SUMOs are con-

genome RNA

. . . G UAGUAGUAG...

Nascent mRNA

CAP

jugated). Sumolation of proteins is an important regulatory

process in cellular metabolism.

FIGURE 4.22 Steps in the primealign mechanism of transcription

The NSs protein of Rift Valley fever virus, and presumably of

of mRNAs by hantaviruses. This mechanism is made possible by the

other viruses as well, inhibits host mRNA synthesis, including

nucleotide repeats in the 3′ and 5′ termini of bunyaviruses (see Table 4.11).

the mRNA for interferon-α and -β. Thus it suppresses the host

Adapted from Kukkonen et al. (2005).

immune response and is a major virulence factor.

NSs protein

Translation

CAP

NSsmRNA

mRNA

synthesis

vcRNA

Replication

Genome RNA

mRNA

synthesis

NmRNA

CAP

Translation

N protein

FIGURE 4.23

Ambisense coding strategy of the S RNA of a phlebovirus, family Bunyaviridae. The mRNA for the

N protein is synthesized from the S genome segment using primers derived by cap-snatching (similar to the mechanism

for influenza mRNA priming in Fig. 4.13) from cytoplasmic host mRNAs. The mRNA for the NSs protein is formed in

the same way, but with vcRNA as the template. Diagonally striped boxes are the self-complementary termini. The loops

in the middle of the viral genomic and antigenomic RNAs indicate a secondary structure in the RNAs which terminates

synthesis of the mRNAs. No poly(A) is added to the 3¢ terminus of the mRNAs.

came from a different bunyavirus. This reassortant virus,

Expression of Proteins Encoded in M

named Garissa virus, thus caused a disease different from

Two glycoproteins, at one time usually called G1 and G2

Bunyamwera virus, perhaps due to the different properties

but now called GN and GC, are translated from mRNA made

of the M segment.

from M (Fig. 4.21). They are produced as a polyprotein that

Viruses belonging to the California encephalitis group,

is cleaved by a cellular protease to separate the two glyco-

of which La Crosse virus is the best known, are also of

proteins, analogous to what happens in some of the (+)RNA

medical interest. La Crosse virus was named for the town

viruses that have envelopes (e.g., coronaviruses and flavi-

of La Crosse, Wisconsin, where it was first identified as the

viruses). GN is N terminal in the polyprotein and GC is C

causative agent of encephalitis, primarily in children. About

terminal. Where studied, the enzyme responsible for the

100 cases per year of encephalitis are caused by La Crosse

cleavage is a subtilase, SKI-1/S1P or a related enzyme. GN

virus, concentrated in the Midwest. Mortality is low (0.3%)

and GC form a heterodimer that is transported to the Golgi

but 10% of patients suffer neurological sequelae. No vac-

apparatus. Virus budding occurs at the Golgi membrane.

cine exists for the virus and control measures have involved

Heterodimerization recalls the processes that occur in the

control of the mosquito vector. The principal vector of La

assembly of alphaviruses and flaviviruses, and like E1 or

Crosse is Aedes triseriatus. This mosquito breeds in tree

E of these viruses, respectively, the GC protein is a class II

holes, but abandoned tires filled with rainwater constitute

fusion protein.

an important breeding area for it close to human habitation.

The M segments of hantaviruses and nairoviruses encode

Such abandoned tires serve as a beautiful incubator for the

only the two glycoproteins, but in the other three genera M

development of mosquito larvae, and efforts to eliminate

encodes a third protein called NSm (Fig. 4.21 and Table 4.10).

this source of mosquitoes, as well as the institution of other

In phleboviruses and members of the genus Bunyavirus,

mosquito control measures, has resulted in a reduction in the

NSm forms part of the polyprotein translated from the single

number of cases of disease.

mRNA produced from M. NSm is formed during posttrans-

Abandoned tires are important in the transmission

lational processing of the polyprotein. In tospoviruses, an

of other arboviruses as well. Old tires are abundant in

ambisense strategy is used to encode NSm and the translation

Puerto Rico, for example, and contribute to the endemic

strategy is the same as that shown in Fig. 4.23. The function

transmission of dengue virus, all four serotypes of which

of NSm is not known.

are present on the island. Old tires have also been respon-

There is no matrix protein in bunyaviruses. Budding at

sible for the introduction into the United States of Aedes

the Golgi membrane is assumed to involve a direct interac-

albopictus, the so-called Asian tiger mosquito that is the

tion between the glycoproteins and the nucleocapsid pro-

vector of dengue virus in Asia. Loads of old tires that

tein. The virion is spherical, 80120 nm in diameter. The

were brought from Asia to Houston for recycling con-

three nucleocapsids are circular when isolated from the

tained eggs or larvae of the mosquito. After its introduc-

virion.

tion into the Houston area, this mosquito spread over

large areas of the United States and there is fear that it

might become an efficient vector of arboviral disease in

Genus Orthobunyavirus

this country.

There are about 50 currently recognized species in the

genus Orthobunyavirus, of which the majority have several

Genus Phlebovirus

distinct strains that are often given separate names. Together,

these viruses have a worldwide distribution. Most of these

The ICTV currently recognizes 9 species of phlebovi-

viruses are mosquito-borne, although some are tick-borne

ruses but there are an additional 16 tentative species. Many

and some may be transmitted by culicoid flies or phleboto-

of the species have a number of strains that are given their

mines. They are true arboviruses, replicating in the arthro-

own names. All are arboviruses transmitted by mosquitoes,

pod vector as well as in vertebrates.

phlebotomine flies, or ticks. The most important of these is

Bunyamwera virus, the prototype member of the genus,

Rift Valley fever virus, an African virus that was first iso-

was first isolated in Uganda in 1943. It causes a febrile ill-

lated in 1930 in the Rift Valley of East Africa. The virus

ness accompanied by headache, arthralgia, rash, and occa-

is transmitted by mosquitoes and causes hemorrhagic fever

sional nervous system involvement. There are 24 named

in humans. It also causes disease in domestic animals, and

subtypes in the bunyamwera serogroup. Of interest is a

many widespread epidemics in cattle, sheep, and humans

reassortant virus isolated during an epidemic of hemor-

have occurred over the years in Africa. In 19771978, for

rhagic fever in Kenya and Somalia in 1998. Rift Valley

example, an epizootic in Egypt infected 2550% of cattle

fever virus was responsible for some of the cases, but many

and sheep in some areas, and 200,000 human cases resulted

were caused by a bunyavirus whose L and S segments were

in at least 600 deaths. A more recent large epidemic in

derived from a Bunyamwera virus but whose M segment

East Africa in 19971998 was associated with the heavi-

est rainfall in 35 years, 60100 times normal in some areas.

species have a number of named strains. Many hantaviruses

As described before, the epidemic was caused by Rift Valley

cause serious human disease, including hemorrhagic fevers

fever virus and by Garissa virus. Losses of 70% of sheep and

and hantavirus pulmonary syndrome. Unlike other members

goats and 2030% of cattle and camels were reported, and

of the Bunyaviridae, they are not arboviruses. The hantavi-

there were hundreds of cases of human hemorrhagic fever.

ruses are associated with rodents, which form their natural

Contact with livestock was statistically associated with

reservoir, and are transmitted to humans through contact

acute infection with Rift Valley fever virus, indicating that

with aerosolized urine or feces from infected rodents. Each

during epidemics contact transmission becomes important

hantavirus establishes persistent infections in one particular

as a means of spread to humans. Laboratory-acquired cases

species of rodent and is maintained in nature in this way.

contracted through aerosols are also known.

Humans are not an important host for the virus and do

Sand fly fever virus is transmitted by phlebotomine flies

not contribute to its maintenance in nature. Related to this

and causes an acute, nonfatal influenza-like disease in man.

is the fact that the viruses do not cause serious disease in

It is found in the Mediterranean area, North Africa, and

their rodent hosts, but many cause quite serious illness in

Southwest Asia. Related viruses are found in South America.

humans.

An evolutionary tree of hantaviruses is shown in Fig.

4.24. The rodent hosts for the viruses are also indicated.

Genus Nairovirus

The viruses assort by host rather than by geographical

The nairoviruses have a much larger genome than mem-

proximity. All of the viruses whose hosts belong to the

bers of the other genera, primarily because the L segment is

order Murinae group together, as do those that use rodents

twice the size of those of the other genera of animal viruses

in the order Arvicolinae and those that use rodents in the

(Table 4.10). They are named for Nairobi sheep disease

order Sigmodontinae. As one example, consider Prospect

virus, now considered a strain of Dugbe virus. There are

Hill virus and New York virus, both found in the north-

seven species recognized, all of which consist of multi-

eastern United States. Prospect Hill virus is associated

ple strains with distinct names. The viruses are tick-borne

with rodents of the genus Microtus, order Arvicolinae, and

although a few can also be transmitted by culicoid flies or

is more closely related to Puumala virus of Europe, which

mosquitoes. Nairobi sheep disease virus causes acute gas-

uses Clethrionomys glareolus, order Arvicolinae, than it

troenteritis with hemorrhagic symptoms in sheep and goats,

is to New York virus. New York virus is associated with

with mortality rates over 90% in some populations. It was

rodents in the genus Peromyscus, order Sigmodontinae and

first identified as the causative agent of the disease in 1917

is closely related to Sin Nombre virus of the southwestern

and is transmitted by the tick Rhipicephalus appendicula-

United States, which is associated with Peromyscus man-

tus. Humans can be infected by the virus but suffer only

iculatus. The fact that the evolutionary tree of the hantavi-

mild illness. There is a close relative of the virus called

ruses resembles that of their rodent hosts rather than being

Ganjam virus present in India which also causes disease in

based on geographical proximity is evidence that they

sheep and goats; it is transmitted by the tick Haemaphysalis

have coevolved with their rodent hosts over a very long

intermedia.

period of time.

Crimean-Congo hemorrhagic fever virus (CCHF) is the

The first of the hantaviruses to be identified was the caus-

most important nairovirus in terms of human disease. It was

ative agent of more than 3000 cases of hemorrhagic fever

first identified in the 1940s in the Crimean region of the

with renal syndrome, now called Korean hemorrhagic fever,

former USSR and in the Democratic Republic of Congo. The

that occurred in U.S. troops during the Korean war. The

virus is now known from at least 30 countries. It is found from

virus was called Hantaan virus after a river in the area where

southern Africa through Eastern Europe and the Middle East

it was isolated. In Korea, Hantaan virus is associated with

to western China. The principal vector is Hyalomma ticks,

the field mouse Apodemus agrarius. The virus also occurs

but Dermacentor and Rhipicephalus ticks can also transmit

in Eastern Europe and China, where it is associated with

the virus. Sheep, goats, cattle, ostriches, wild herbivores, and

Apodemus flavicollis and causes a disease similar to Korean

hares become infected by CCHF but most infections result in

hemorrhagic fever (Fig. 4.25).

subclinical disease. In contrast, infection of humans results in

Viruses related to Hantaan virus have now been isolated

severe hemorrhagic fever with a 30% mortality rate. Humans

from all over the world, including the Americas. Many Old

are infected by the bite of a tick or by contact with blood

World viruses cause hemorrhagic fever in humans, and more

or tissues of infected livestock. Transmission to hospital

than 100,000 cases occur worldwide with a case fatality rate

personnel treating infected patients has occurred.

between 0.1 and 10%, depending on the virus. Puumula virus

occurs in Western Europe (Fig. 4.25) and causes a disease

characterized by acute fever with renal involvement. Seoul

Genus Hantavirus

virus, first identified in Seoul, Korea, is associated with wild

There are 22 species of hantaviruses currently recognized,

urban rats (Rattus norvegicus) and has been found all over

and, as with other genera of the bunyaviruses, many of the

the world because wild urban rats have been inadvertently

Rodent-borne Hantaviruses

Rodent hosts

76-118

cumc-b11

Hantaan

hojo

isolates

lee

hv114

Murinae

(Old world rats and mice,

Seoul

sr-11

found in Europe and Asia)

isolates

80-39

Thailand

Dobrava

vindeln

vranica

Puumala

cg1820

isolates

Arvicolinae

sotkamo

(Voles; found in Europe,

90-13

Asia, and the Americas)

Tula

Prospect Hill

Bayou

Black Creek Canal

Laguna Negra

Sigmodontinae

Sin Nombre

(New World rats and mice,

found only in the Americas)

New York

El Moro Canyon

FIGURE 4.24 Phylogenetic tree of rodent-borne hantaviruses derived from the nucleotide sequence of the M RNA

segment. This tree illustrates that hantaviruses have coevolved with their rodent hosts for millions of years. However, note

(*) that in contrast to other members of this group, Seoul virus, which infects Rattus norvegicus, is found worldwide, due

to the widespread distribution of these rats. Adapted from Peters (1998a), Figure 2.

Hantaan virus

Seoul virus

Variant Hantaan

Puumala virus

Variant Hantaan

and Puumala

FIGURE 4.25 Map of Eurasia showing the disjunct distribution of different hantaviruses. Adapted from Porterfield

(1995) p. 276 and data from Lee (1996).

introduced almost everywhere. It causes a mild form of

is associated with the deer mouse Peromyscus maniculatus.

Korean hemorrhagic fever in Seoul but does not cause

Sin Nombre virus or related viruses have now been identi-

apparent illness in most other areas where it has been found.

fied in virtually all states within the United States and into

The discovery of Seoul virus led to an intensive study of rats

Latin America, and fatalities due to infection by the virus

in central Baltimore, where it was found that a high percent-

have occurred in many states. One of the cases in California

age of them were infected with Seoul virus and, furthermore,

is of interest because the person died more than a year before

that a substantial fraction of the people living in the slums

the Four Corners epidemic; retrospective studies of serum

of downtown Baltimore showed evidence of infection by

collected from the patient at the time of his hospitalization

hantavirus. No disease is known to be associated with this

showed that he was infected with a hantavirus. The number

virus, but statistical studies suggest that infection may lead

of cases of HPS in the Americas from 1993 to 1998, totaled

to high blood pressure and, possibly, renal failure.

by country, and the names of the viruses responsible in vari-

The New World hantaviruses that cause disease in humans

ous areas are shown in Fig. 4.26. Of interest is Andes virus,

cause a syndrome called hantavirus pulmonary syndrome or

which has the potential for human-to-human transmission.

HPS, which has a fatality rate of 2040%. The first such

The mortality rate following infection with Sin Nombre

virus to be identified was Sin Nombre virus, which caused

virus or its close relatives is close to 50%. The mortality in

an epidemic of HPS in the Four Corners area of the United

the earliest cases was even higher because the pulmonary

States in 1993 that resulted in about 25 deaths. The virus

syndrome results from the rapid extravasation of fluids into

Canada

Sin Nombre

New York

Monongahela

United States

Bayou

Black Creek Canal

Choclo

Panama

Juquitiba

Brazil

Bolivia

Paraguay

Laguna Negra

Number of HPS cases

Oran

Argentina

1993-2004

Uruguay

No report

Lechiguanas

11-50

Andes

51-150

151-350

Chile

>351

FIGURE 4.26 Cases of hantavirus pulmonary syndrome (HPS) in the Americas, with locations and names of the viruses

responsible. Case numbers are cumulative totals from the time that HPS was recognized in 1993 in the Four Corners region

of Arizona and New Mexico through 2004. Although several other hantaviruses have been isolated in this region, only

those which have been identified as human pathogens are shown. To the current time, cases of HPS have been diagnosed

in the United States in 30 states, predominantly in the Western United States, with a few cases as far East as Rhode Island.

The total number of cases represented on this map is 1910. Adapted from Peters (1998a) Figure 1 and Table 3, and updated

with data from Yates et al. (2002), and the Pan American Health Organization at http://www.paho.org/.

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