It

13' vcRNA I 5' Genome RNA

expressed late, after replication of the RNA begins. Its function is not known.

Natural History and Diseases

The natural history of the arenaviruses is very similar to that of the hantaviruses (Table 4.10). They establish a persistent infection in a single rodent host. Many cause hemor-rhagic fever in man following transmission by aerosolization of virus excreted in urine or feces. Like the hantaviruses, they appear to have coevolved with their hosts: An evolutionary tree of arenaviruses resembles the tree that describes their rodent hosts, as was true of the han-taviruses. The many similarities in genome organization and expression, the association with a single rodent species, and the nature of the disease caused in man all suggest that the arenaviruses are closely related to the hantaviruses. A reasonable hypothesis is that the arenaviruses arose from the hantaviruses by fusion of the S and M segments to form one segment, which allowed finer control of the virus life cycle.

The arenaviruses can be divided into Old World viruses and New World viruses (Table 4.10). Because of their association with a single rodent species, their geographic range is restricted to that of their host, and rodents have a restricted range. The exceptions are rodents that have been distributed widely by humans, such as the house mouse and the urban rat. Of interest in this regard is the Old World virus lymphocytic choriomeningitis virus (LCMV), which is associated with the house mouse Mus domesticus and Mus musculus. This virus is widespread in Europe, along with its host, and spread to the Americas with the (inadvertant) introduction of the house mouse by European travelers. LCMV has been intensively studied in the laboratory as a model for the arenaviruses, in part because it is widespread, often being present in colonies of laboratory mice as well as being found in wild mice, and in part because it is less virulent for man than most arenaviruses. LCMV infection of man usually results in mild illness, although serious illness can result with occasional mortality.

TABLE 4.10 Arenaviridae

Genus/members"

Virus name abbreviation

Natural Transmission host(s)4

Disease in humans

World distribution

Old World Arenaviruses Lymphocytic choriomeningitis Lassa Mopeia Mobala New World Arenaviruses Tacaribe complex lineage A Tamiami

Whitewater Arroyo

ParanĂ¡ Flexal Pichinde Pirital

Tacaribe complex lineage B Guanarito

Amapari

Machupo

Tacaribe

LCMV Mus musculus

LASV Mastomys sp.

MOPV Mastomys natalensis

MOBV Praomys sp.

TAMV Sigmodon hispidus

WWAV Neotoma albigula

PARV Oryzomys buccinatus

FLEV Oryzomys sp.

PICV Oryzomys albigularis

PIRV Sigmodon alstoni

GTOV Zygodontomys brevicauda

AMAV Oryzomys capito,

Neacomys guianae

JUNV Calomys musculinus

MACV Calomys callosus

SABV Unknown

TCRV Artibeus spp. bats

Urine, saliva

Urine, saliva

Urine, saliva Urine, saliva

Urine, saliva Urine, saliva Urine, saliva Urine, saliva

Urine, saliva Urine, saliva

Urine, saliva

? Has been isolated from mosquitoes

Aseptic meningitis

Hemorrhagic fever (HF) Nonpathogenic

Nonpathogenic?

Three fatal cases of ARDS in Californiac

Nonpathogenic?

Nonpathogenic?

Nonpathogenic?

Nonpathogenic?

Venezuelan HF

Unknown pathogenicity

Argentine HF

Bolivian HF

Isolated from a fatal case, and has caused two severe laboratory infections

Unknown pathogenicity

Worldwide West Africa

Mozambique, Zimbabwe Central African Republic

Florida (US) Western United States

Paraguay Brazil Colombia Venezuela

Venezuela

Brazil

Argentina

Bolivia

Brazil

Trinidad

Source: Adapted from Fields et al. (1996, Table 1, p. 1522) and Porterfield (1995, Table 11.1, p. 228). "LCMV is the type virus of the family.

AMost of these viruses cause chronic infections in their natural rodent hosts.

cARDS, acute respiratory distress syndrome. Until these cases in 1999-2000, WWAV was not known to cause human illness.

Many arenaviruses cause hemorrhagic fever in man with significant mortality rates (Table 4.10). Lassa virus causes an often fatal illness (mortality rate as high as 60% in some outbreaks) characterized by fever, myalgia, and severe prostration, often accompanied by hemorrhagic or neurological symptoms. Survivors may be deaf because of nerve damage. Lassa fever virus was first isolated in 1969 when a nurse in a rural mission hospital in Nigeria became infected. She was transported to Jos, Nigeria where several health care workers became infected. Serum samples were sent to the United States and a well-known virologist at the Yale Arbovirus Research Unit, Dr. Jordi Casals, became infected with the virus while working with it and became very seriously ill. He eventually recovered but later that same year a technician in another laboratory at Yale became infected with Lassa fever virus and died, whereupon Yale ceased to work with the virus. The containment facilities in 1969 were not of the quality of those in current use and virologists in those days literally took their lives in their hands when working with dangerous agents. The study of virology owes a great deal to the courage exhibited by these earlier workers.

Lassa virus is endemic to West Africa. The full extent of Lassa disease is not known because most Africans infected by the virus do not seek help and there is little monitoring of the disease. However, estimates range from 100,000 to 300,000 cases per year. The virus has been imported to the United States on at least one occasion, when a resident of Chicago attended the funerals of relatives in Nigeria who had died of Lassa fever. He became infected there. On return to Chicago he began suffering symptoms of Lassa fever but the local hospitals were unable to diagnose the cause of his disease, being unfamiliar with it. He eventually died of Lassa fever, but fortunately there were no secondary cases.

New World arenaviruses include several South American viruses that are very important disease agents because they cause large outbreaks of hemorrhagic fever with high mortality rates. The names of a number of these viruses and the places where they are found are shown in Fig. 4.25. They include Junin virus (causative agent of Argentine hemor-rhagic fever), Machupo virus (Bolivian hemorrhagic fever), Guanarito virus (Venezuelan hemorrhagic fever), Sabia virus (cause of an unnamed disease in Brazil), and Oliveros virus (cause of an unnamed disease in Argentina). The diseases caused by these viruses are often referred to as emerging diseases because the number of human cases has increased with development and expanding populations. The increasing number of cases results from development of the pampas or other areas for farming, bringing humans in closer association with the rodent reservoirs. Furthermore, the storage of grain near human habitation results in an increase in the local rodent population, and plowing of the fields leads to the production of aerosols which may transmit the disease to man. An attenuated virus vaccine against Junin virus has been developed and is widely used in populations at risk. The vaccine is effective and has reduced dramatically the number of cases of Argentine hemorrhagic fever. No vaccines are in use for the other viruses, however.

Two arenaviruses have been isolated in the United States. They are Whitewater Arroyo virus, present in the Southwest, and Tamiami virus, present in Florida. Neither of these viruses had been known to cause illness in humans until very recently. In 1999-2000, three Californians died following infection by Whitewater Arroyo virus. The disease these three suffered was ARDS, although two also had hemorrhagic manifestations. Thus, like the han-taviruses, the U.S. arenaviruses may cause isolated cases of serious illness.

Agents Causing Hemorrhagic Fevers in Humans

Many viruses, belonging to several different families, have been described that cause hemorrhagic fever in

Tamiami (1964)

(Sigmodon hispidus)

Whitewater Arroyo (<1995)

(Neotoma albigula)

Guanarito (1990)

(Zygodontomys brevicauda)

Tacaribe (1956)

(Artibeus Bats)

Pichinde (1965)

(Oryzomys albigularis)

Tamiami (1964)

(Sigmodon hispidus)

Guanarito (1990)

(Zygodontomys brevicauda)

Pichinde (1965)

(Oryzomys albigularis)

Virus Isolates

Tacaribe (1956)

(Artibeus Bats)

Pirital (1995)

(Sigmodon alstoni)

Amapari (1964)

(Oryzomys capito)

Sabia (1990)

host unknown

Oliveros (1990)

(Bolomys obscurus)

(Calomys callosus)

Latino (1965)

(Calomys callosus)

FIGURE 4.25 Arenavirus isolates in the New World. Also shown are the year of first isolation and the rodent host of each virus where known. [Adapted from Peters (1998a, Fig. 1).]

(Calomys callosus)

Latino (1965)

(Calomys callosus)

Parana (1965)

(Oryzomys buccinatus)

Pirital (1995)

(Sigmodon alstoni)

Amapari (1964)

(Oryzomys capito)

Sabia (1990)

host unknown

Virus Isolates

Oliveros (1990)

(Bolomys obscurus)

Junin (1958)

(Calomys musculinus1)

FIGURE 4.25 Arenavirus isolates in the New World. Also shown are the year of first isolation and the rodent host of each virus where known. [Adapted from Peters (1998a, Fig. 1).]

Family Arenaviridae TABLE 4.11 Viruses That Cause Hemorrhagic Fevers in Humans

Virus

Disease"

Geographic range

Vector transmission

Case mortality %

Treatment (prevention)

Arenaviridae Junin

Machupo Guanarito Sabia

Lassa

Bunyaviridae Rift Valley fever Crimean-Congo HF

Hantaan, Seoul, Puumala, and others Sin Nombre and others

Filoviridae Marburg, Ebola

Flaviviridae Yellow fever

Dengue

Kyasanur Forest disease Omsk hemorrhagic fever

Argentine HF Argentine pampas

Bolivian HF Venezuelan HF HF

Lassa fever

Rift Valley fever Crimean-Congo HF

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