Arenaviruses

Arenaviruses are single-stranded ribonucleic acid (RNA) viruses that cause chronic asymptomatic infections in rodents and zoonotically acquired disease in humans through rodent excreta, especially urine. Rodents pass these infections to offspring, so they remain a continuous reservoir. The genus Arenavirus includes 22 viral species and 9 additional arenaviruses that have been recently discovered, for which taxonomic status remains pending. In 1934, the prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), was first isolated during serial monkey passage of human material that was obtained from a fatal infection in the first documented epidemic of St. Louis encephalitis, a totally unrelated virus. LCMV was the first recognized cause of aseptic meningitis in humans.

Other arenaviruses from South America and Africa are classic causes of viral hemorrhagic fever syndrome, whereas others have been identified but not found to cause disease or even infection in humans. Most of these viruses are under continuing study.

Arenaviruses have been divided into 2 groups based on whether the virus is found to infect Old World (ie, Eastern Hemisphere) rodents (family Muridae, subfamily Murinae) or New World (ie, Western Hemisphere) rodents (family Muridae, subfamily Sigmodontinae). The New World arenaviruses are further divided into 3 lineages designated clades: A, B, C. LCMV is the only arenavirus to exist in both areas but is classified as an Old World virus. The following are the major viruses and the other recognized Arenaviridae listed in relationship to their rodent reservoirs.

LCMV-Lassa virus ( Old World ) complex

Lymphocytic choriomeningitis virus

• Rodent -Mus musculus and Mus domesticus (ie, house mouse) and Mesocricetus auratus (ie, Syrian hamster)

• Location - Europe, Asia, and the Americas

• Habitat - Peridomestic, grasslands

• Season – September to October

• Human contact - Primarily within households

Lassa virus

• Rodent -Mastomys genus (ie, multimammate mouse)

• Location - West Africa

• Habitat - Savanna, forest clearing

• Season – January to April

• Human contact - Primarily within houses

Mopeia virus

• Rodent -M natalensis

• Location - Southern Africa

• Habitat – Savanna

• Season - Unknown

• Human contact – Unclear

Mobala virus

• Rodent -Praomys species (ie, soft-furred rat)

• Location - Central African Republic

• Habitat – Savanna

• Season - Unknown

• Human contact – Unclear

Ippy virus

• Rodent -Arvicanthus species (ie, Nile grass rat)

• Location - Central African Republic

• Habitat - Grassland, savanna

• Season - Unknown

• Human contact – Unclear

Lujo virus

• Rodent – Unknown

• Location – Zambia

• Habitat – Unknown, likely similar to Lassa virus

• Season – Unknown, likely similar to Lassa virus

• Human contact – Unclear, likely similar to Lassa virus

Other Old World arenaviruses

• Merino Walk virus (South Africa)

• Morogoro (Tanzania)

• Kodoko (Guinea)

• Dandenong (Australia)

Tacaribe virus  ( New World) c omplex

Clade A

• Allpahuayo virus (Peru)

• Flexal virus (Brazil)

• Parana virus (Paraguay)

• Pichinde virus (Colombia)

• Pirital virus (Venezuela)

Clade B

• Amapari virus

  • Rodent -Oryzomys goeldii (ie, rice rat), Neacomys guianae (ie, bristly mouse)

  • Location - Brazil

  • Habitat - Tropical forest

  • Human contact – Unclear

• Cupixi virus (Brazil)

• Guanarito virus (Venezuelan hemorrhagic fever)

  • Rodent -Zygodontomys brevicauda (ie, cane mouse)

  • Location – Central Venezuela

  • Habitat - Grasslands, brush, peridomestic

  • Season – November to January

  • Human contact - Within houses

• Junin virus (Argentine hemorrhagic fever)

  • Rodent -Calomys masculinus (ie, corn mouse), Akodon azarae (ie, grass field mouse), Bolomys obscurus (ie, dark field mouse)

  • Location - Argentina

  • Habitat - Grasslands, cultivated fields, and hedgerows

  • Season – February to May

  • Human contact - Occupational in fields

• Machupo virus (Bolivian hemorrhagic fever)

  • Rodent -Calomys callosus (ie, vesper mouse)

  • Location - Bolivia

  • Habitat - Peridomestic, grasslands

  • Season – April to July

  • Human contact - Primarily within houses

• Sabia virus (Brazilian hemorrhagic fever)

  • Rodent - Unknown

  • Location - Isolated in Brazil

  • Human contact - Single natural human infection, as well as 2 laboratory infections

• Tacaribe virus

  • Rodent -Artibeus species (ie, fruit-eating bat)

  • Location - Trinidad

  • Habitat - Tropical forest

  • Human contact - Unclear

Clade C

• Latino virus (Bolivia, Brazil)

• Oliveros virus (Argentina)

Other New World arenaviruses of questionable taxonomic status

• Chapare virus

  • Rodent – Unknown

  • Location – Higher altitudes near Cochabamba Bolivia

  • Habitat – Unclear

  • Human contact – Unclear

• Tamiami virus

  • Rodent -Sigmodon hispidus (ie, hispid cotton rat)

  • Location - Florida

  • Habitat - Grasslands, marsh

  • Human contact – Unclear

• Whitewater Arroyo

  • Rodent -Neotoma albigula (ie, white-throated wood rat)

  • Location - California, New Mexico

  • Habitat - Grasslands

  • Human contact - Unclear

• Bear Canyon (United States)

• Catarina virus (United States)

• Pinhal virus (Brazil)

• Skinner Tank virus (United States)

• Tonto Creek virus (United States)

• Big Brushy Tank virus (United States)

Viral characterization

Arenaviruses are host plasma membrane-enveloped, spherical-to-pleomorphic particles that range in size from 50-300 nm. The envelope that surrounds the virion contains 2 major glycoprotein components (ie, GP1, GP2) that appear as spikelike or clublike projections with variable spacing along the virus lipid coat.

The Arenaviridae generally have been considered negative-sense RNA viruses that contain 2 subgenomic segments, referred to as L (large) and S (small), composed of 2.4 million bases and 1.3 million bases, respectively. The 5' ends of both the L and S strands contain positive-sense RNA; therefore, the viruses are best considered ambisense. Each of the RNA segments consists of 2 nonoverlapped long open reading frames with opposite polarity. The L segment encodes for the viral RNA-dependent RNA polymerase and for the Z protein important for viral budding and other intracellular functions. The S segment encodes for the nucleocapsid protein (N) and the glycoprotein precursor polypeptide (GPC) that is differentially cleaved and glycosylated to form the spike glycoproteins. The N protein is the most antigenic and thus usually measured in the diagnostic indirect fluorescent antibody (IFA) test.

A distinguishing characteristic of arenaviruses is the presence of internal granular structures 20-25 nm in size. On electron microscopy, these structures appear sandlike. The family name, Arena, is derived from the Latin root (arenosos), meaning sand. These sandlike components are host cell–derived ribosomes, which are incorporated into the virus during budding, but apparently not biologically functional.

Genetic susceptibility

The Human Genome Project (HGP) began in 1989 as an international scientific research project with a primary goal of determining the sequence of chemical base pairs that make up human DNA from both a physical and functional standpoint. ^[2] The essentially complete genome was published in April 2003, save for the highly repetitive sequences surrounding the centromere and telomere. This database of genes has, when possible, been used to link disease with relevant genes in the human genome. The arenaviruses are no exception.

The DAG1 gene, located at 3p21 for example, encodes for 2 dystroglycan proteins, alpha and beta. Alpha dystroglycan appears to be necessary for infection with viruses of the LCMV-Lassa complex and some New World arenaviruses (Oliveros and Latino) because null mutants were resistant to infection.

The transferrin receptor gene 1, located at 3q29 is a cell surface glycoprotein transferrin receptor that also appears to enhance susceptibility to infection with those of the Tacaribe virus complex.

Pathogenesis (in humans)

Little data are available regarding the pathogenesis of fatal LCM infection, but marked neuronal infection is seen in human encephalitis. In the case of arenavirus hemorrhagic fevers, pathogenesis likely results from direct viral infection of endothelial cells resulting in vascular dysfunction and shock. Immunopathologic events seem less likely, although as seen in most viral infections, high levels of circulating endogenous interferon-alpha and pro-inflammatory cytokines are present that may prove detrimental rather than beneficial in arenavirus infections.

Frequency

United States

The number of cases of LCMV infection is unclear, but a number of clusters have been reported related to pet hamsters or laboratory animals. Recently, 3 fatal cases of infection with a virus similar to Whitewater Arroyo virus were reported in California.

International

Scattered outbreaks of Lassa fever in western Africa and South American hemorrhagic fever occur, representing local public health problems. Public health officials in nonendemic areas must remain vigilant for these infections because imported cases have been described, presumably due to person-to-person spread. ^[3]

A nosocomial outbreak of disease involving 5 patients, 4 of whom died, occurred in South Africa from September-October 2008 after the index patient was transferred there from Zambia for medical management. The source of infection was never determined, but a novel arenavirus determined by nucleotide sequencing and phylogenetic analysis, since named Lujo virus, was determined to be the cause.

In December 2003 and January 2004, a small number of hemorrhagic fever cases with classical presentation were reported in rural Bolivia. The virus was isolated from 2 of the patients and was identified as an arenavirus using polymerase chain reaction (PCR). Subsequent genome analysis showed it most closely related to Sabiá virus, but it was distinct enough to be anointed a new species named Chapare virus.

Mortality/Morbidity

Arenaviruses persist in nature by infecting rodents, primarily through a one-virus, one-rodent species relationship. Arenaviruses are transmitted to humans through aerosolization of dried excreta, especially urine that has been deposited in the environment. The distribution of the host dictates the distribution of the virus, but with environmental change due global warming and human factors and with the contemporary ease of international travel, they may occur anywhere in the world.

LCMV

Infection occurs wherever either of the 2 closely related species of the common house mouse (M musculus, M domesticus) exists. The areas include Europe, the Americas, Australia, and Japan. Human infection is more common in rural areas, where a higher rate of infection exists in mice. Sporadic human LCMV infections have autumn/winter predominance, when mice are more likely to seek human dwellings for shelter and food. The incubation period varies but most often ranges from 5-10 days, unless presenting with nervous system signs, then exposure likely occurred 2-3 weeks prior. Hamsters also can be infected and are more significant disease vectors in laboratory workers and pet owners.

Lassa virus (ie, Lassa fever)

Lassa fever is endemic to West Africa. Originally found in Nigeria, outbreaks have been reported from Sierra Leone, Liberia, and Guinea. Lassa virus was isolated from rodents of the genus Mastomys, members of which aggressively invade houses. Lassa fever is common in the dry season. This viral agent is noteworthy because of its ability to spread from person to person. This also occurs to some degree with South American viruses. ^{[4, 5, 6]} The incubation period varies from 3-16 days, and overall mortality rate is estimated to be 1%. The mortality rate is more than 80% in pregnant women in their third trimester and nearly always results in fetal death. Abortion decreases the risk of death to the mother.

South American viral hemorrhagic fevers

These are diseases of South American countries, including Argentina, Bolivia, and Venezuela, caused by the viruses Junin, Machupo, and Guanarito, respectively. Mortality rate in each is about 15-30%.

For Argentine hemorrhagic fever, the main reservoir rodent is C masculinus. This rodent is found in the cornfields, especially from February through May. Therefore, men harvesting corn are particularly at risk. Infectious aerosols are thought to be the most common mode of transmission, but food contamination and direct contact of abraded fingers with blood or tissue from rodents may occur.

Bolivian hemorrhagic fever is found in the tropical savanna of the Beni region in northeastern Bolivia. The reservoir rodent is C callosus, which travels freely around this area. Bolivian hemorrhagic fever is commonly found from April to July. Transmission is believed to occur through aerosols from infected rodents or, possibly, through food contaminated by rodent urine.

Venezuelan hemorrhagic fever, caused by the Guanarito virus, has the cane mouse Zygodontomys brevicauda as a reservoir. People who have moved to the cleared forest areas for agricultural work are most at risk.

Age

The risk of human acquisition of Arenavirus infection is related to age, race, or sex only to the degree that these variables impact contact with dried rodent urine.