Arenaviruses: New World and Old World

The arenaviruses are a family of rodent-borne, enveloped, single-stranded RNA viruses with a distinctive habit: each agent is maintained in nature by a single rodent species that it infects for life without obvious harm, shedding virus continuously in urine, and human infection is an accidental and usually dead-end spillover. The family name comes from the grainy appearance of the virion under the electron microscope, produced by host ribosomes taken up during assembly (Latin arena, sand). Several of its members, above all Lassa virus and the New World agents that cause the South American haemorrhagic fevers, sit among the most dangerous human pathogens known and are handled only at maximum laboratory containment.

The organising fact for the whole family is a deep evolutionary and geographic split into an Old World complex, found in Africa, and a New World complex, found in the Americas. That division is not merely taxonomic bookkeeping: it tracks which rodents carry the viruses, which cell-surface receptor they use to enter cells, and, to a useful degree, the shape of the disease they cause. Human pathogenicity has arisen independently more than once within the family, which is why a single clean rule linking group to disease does not quite hold, but the split remains the most useful first map of the arenaviruses.

Classification: the Old World and New World split

Current taxonomy places the mammalian arenaviruses in the genus Mammarenavirus, family Arenaviridae, with a separate genus for the reptile-associated arenaviruses. Within Mammarenavirus, the two serological and genetic subgroups are the Old World (Lassa and lymphocytic choriomeningitis) complex and the New World (Tacaribe) complex.

The Old World complex is associated with African Mastomys and related mice, with the worldwide exception of lymphocytic choriomeningitis virus, whose reservoir is the house mouse. Its human pathogens are Lassa virus and Lujo virus; lymphocytic choriomeningitis virus causes a different, mostly non-haemorrhagic illness; and several members (Mopeia, Mobala, Ippy) cause no known human disease.

The New World complex is carried by cricetid rodents of the Americas and is divided into three clades. All the human haemorrhagic fever agents fall in clade B: Junin, Machupo, Guanarito, Sabia and Chapare viruses. Clades A and C contain no confirmed human pathogens. A curiosity that underlines the rodent link is that the one clade-B member with a bat rather than a rodent host, Tacaribe virus, is not a human pathogen.

Virus	Complex	Reservoir	Region	Human disease
Lassa	Old World	Mastomys natalensis	West Africa	Lassa fever
Lujo	Old World	Unknown	Southern Africa	Haemorrhagic fever (2008 cluster)
Lymphocytic choriomeningitis	Old World	House mouse	Worldwide	Meningitis, congenital, transplant-transmitted
Junin	New World (clade B)	Calomys musculinus	Argentina	Argentine haemorrhagic fever
Machupo	New World (clade B)	Calomys callosus	Bolivia	Bolivian haemorrhagic fever
Guanarito	New World (clade B)	Zygodontomys brevicauda	Venezuela	Venezuelan haemorrhagic fever
Sabia	New World (clade B)	Unknown	Brazil	Brazilian haemorrhagic fever
Chapare	New World (clade B)	Unknown	Bolivia	Haemorrhagic fever (rare)

Structure, genome and replication

The arenavirus particle is pleomorphic and enveloped, usually 110 to 130 nanometres across, studded with club-shaped glycoprotein spikes and enclosing two circular nucleocapsids along with the non-functional host ribosomes that give the family its name. The genome is two single-stranded RNA segments, a large (L) and a small (S), and its defining feature is an ambisense coding strategy: each segment carries genes in both orientations, so part of the segment reads as negative sense and part as positive sense. The S segment encodes the nucleoprotein and the glycoprotein precursor, and the L segment encodes the RNA-dependent RNA polymerase and the small zinc-binding matrix protein Z.

The ambisense arrangement gives the virus temporal control of gene expression: the nucleoprotein and polymerase are made first from the incoming genome, and the glycoprotein and matrix protein only after an antigenomic template has been synthesised. Replication is entirely cytoplasmic, transcription is primed by cap-snatching from host messenger RNAs, and assembly occurs by budding from the plasma membrane. The virus establishes persistent, poorly cytolytic infection readily, which is the cellular basis of the lifelong carriage seen in reservoir rodents.

Cell entry marks the sharpest molecular line between the two groups. The Old World viruses and the non-pathogenic clade C use alpha-dystroglycan as their receptor, whereas the pathogenic New World clade-B viruses use transferrin receptor 1 (TfR1), a protein involved in cellular iron uptake. The nucleoprotein of many arenaviruses actively suppresses innate immunity by blocking the transcription factor nuclear factor kappa B (NF-kappa-B) and interfering with interferon induction, contributing to the immunosuppression seen in severe disease.

Reservoir ecology and transmission

Each arenavirus is tied to a particular rodent host, which it infects persistently and for life, shedding virus in urine, saliva and faeces. People are infected by contact with rodent excreta, through inhalation of contaminated dust, ingestion of contaminated food, or contamination of skin abrasions, so exposure follows rodent ecology and human behaviour: peridomestic rodents drive household transmission of Lassa, while the field rodents of the South American agents put agricultural workers at risk during harvest.

A biological contrast tracks the Old World and New World divide. The Old World viruses do not harm their rodent hosts, but Junin and Machupo do, causing haemolytic anaemia and reduced fertility in their Calomys reservoirs, which in turn regulates the shedding population. Most arenaviruses spread poorly between people, but Lassa is the important exception, with well-documented person-to-person and nosocomial transmission, and Lujo also spread nosocomially in its single outbreak. Human arenaviruses are biosafety level 4 pathogens, with the partial exception of lymphocytic choriomeningitis virus, some strains of which are handled at lower containment.

Lymphocytic choriomeningitis virus: the immunology model

Lymphocytic choriomeningitis virus (LCMV) is the prototype arenavirus and, more than any other virus, the system in which cellular immunology was worked out. Its natural reservoir is the house mouse, and human infection, acquired from mice or pet rodents, is often subclinical or produces a self-limiting influenza-like illness that occasionally progresses to aseptic meningitis. It matters clinically for two special situations. Congenital infection in pregnancy can cause fetal death, hydrocephalus and chorioretinitis, so LCMV belongs in the differential of congenital infection alongside the more familiar agents. Transplant-transmitted infection is rare but devastating: in three clusters in the United States between 2005 and 2010, nine of ten organ recipients who acquired LCMV from their donors died.

The virus earned its place in immunology because its outcome in mice depends entirely on the host immune response. Infection of a newborn or fetal mouse produces lifelong tolerant infection, the observation from which Burnet and Fenner built the concept of immunological tolerance. In the adult mouse, by contrast, the cytotoxic T-lymphocyte response both clears the virus and, in the meninges, causes the fatal disease, the demonstration that a virus-specific T-cell response can be the agent of immunopathology rather than only of protection. Work in this system established that cytotoxic T lymphocytes recognise viral peptides only in the context of self major histocompatibility complex (MHC) molecules, the principle of MHC restriction that earned Doherty and Zinkernagel the Nobel Prize.

Old World haemorrhagic fevers: Lassa and Lujo

Lassa fever is the most important arenaviral disease by burden, endemic across rural West Africa from Nigeria to Guinea, where its reservoir, the multimammate rat Mastomys natalensis, lives in and around houses. Estimates of the burden are uncertain but commonly put it at 100,000 to 300,000 infections and several thousand deaths a year. Most infections are mild or subclinical; the case fatality is around 15% among patients ill enough to reach hospital, and higher in some outbreaks.

After an incubation of about 10 days, within a range of 3 to 21 days, illness begins insidiously with fever, headache, sore throat and malaise, and in a florid minority progresses to facial and neck swelling, mucosal bleeding, hypotension, pleural effusions and encephalopathy. Two features are distinctive. Sensorineural hearing loss affects roughly a quarter to a third of survivors of clinical disease, is often permanent, and makes Lassa a leading cause of acquired hearing loss in the endemic region; because most infections are mild or subclinical, the proportion is much lower when counted against all infections rather than against clinical cases. In pregnancy the disease is far more severe, with fetal death approaching 100% in the third trimester and high maternal mortality. Unlike the filoviruses, disseminated intravascular coagulation is not prominent until the terminal phase; the liver is the main target, with multifocal hepatocellular necrosis that looks like a direct viral cytopathic effect rather than immune injury. A rising aspartate aminotransferase and a high viraemia both predict a poor outcome, and high-dose intravenous ribavirin, given early, reduces mortality.

Lujo virus is the southern African member of the group. It is known from a single event, the 2008 nosocomial cluster that began in a patient airlifted from Zambia to Johannesburg and spread to healthcare workers, with four of the five people infected dying. Its reservoir has never been identified, and no further cases have been recorded, but it remains relevant to South African practice as a locally acquired arenaviral haemorrhagic fever.

New World haemorrhagic fevers

The pathogenic clade-B viruses each cause a haemorrhagic fever named for its country: Argentine (Junin), Bolivian (Machupo), Venezuelan (Guanarito) and Brazilian (Sabia) haemorrhagic fever, with Chapare virus responsible for rare Bolivian cases. Each has a separate range and reservoir rodent, and human infection is largely rural and occupational, as when the field mouse Calomys musculinus brings Junin into contact with Argentine farm workers at harvest.

The clinical picture, best defined for Argentine haemorrhagic fever, is broadly shared. After an incubation of about 6 to 14 days, a gradual onset of fever, malaise and myalgia gives way to facial flushing, conjunctival injection and a petechial or maculopapular rash, with falling platelet and white cell counts. A prominent neurological component, with tremor, ataxia and in severe cases delirium and seizures, is more characteristic than in Lassa. Most patients improve in the second week, but a fifth to a third progress to severe haemorrhagic and neurological disease and shock. The historical case fatality of around 15 to 30% has been cut dramatically for Argentine haemorrhagic fever by two interventions: the live-attenuated Junin vaccine Candid #1, in use since the late 1980s, and early transfusion of immune convalescent plasma, which reduces mortality when given within the first week. Ribavirin is a further option.

What the split means clinically

The Old World and New World division is worth carrying as a clinical shorthand, provided its limits are kept in view. Old World disease is dominated by Lassa, in which bleeding is a late feature, hepatic injury and capillary leak drive severe cases, and sensorineural deafness is the signature sequela. New World disease carries a more prominent haemorrhagic and neurological picture from the outset, and has a specific countermeasure in the Junin vaccine and immune plasma. The two groups also differ mechanically, using different cellular receptors and behaving differently in their reservoirs. The caveats are real: lymphocytic choriomeningitis virus sits in the Old World group yet causes neither haemorrhagic fever nor deafness, and human pathogenicity evolved separately in the two lineages, so the split predicts the classical pattern rather than an invariable rule.

Diagnosis, treatment and prevention

Diagnosis rests on reverse transcription polymerase chain reaction (RT-PCR) and antigen detection in the acute phase, since a serological response is slow and, for Lassa, immunoglobulin M can persist for months, making it an unreliable marker of recent infection. Virus isolation is possible but is confined to maximum containment. Early Lassa fever is readily mistaken for severe malaria, which must be excluded in parallel.

Treatment is supportive, with ribavirin the main specific drug for Lassa fever and a backup for the South American agents, and immune convalescent plasma established for Argentine haemorrhagic fever. Prevention is built on rodent control and on avoiding contact with rodent excreta, which is difficult where the reservoir is peridomestic. The only licensed arenavirus vaccine is Candid #1 against Argentine haemorrhagic fever; there is no licensed Lassa vaccine, though candidate vaccines, led by a recombinant vesicular stomatitis virus construct, are in clinical trials in West Africa.

South African context

Two arenaviruses bear on South African practice. Lujo virus is the only arenavirus to have emerged within the region, in the 2008 Johannesburg nosocomial cluster, and although it has not reappeared it is the reason arenaviral haemorrhagic fever is part of the local differential and biosafety planning. Lassa fever is not endemic to South Africa but is an importation risk in travellers and evacuees from West Africa, where it is common, and any suspected case is managed through the same national viral haemorrhagic fever pathway of isolation, safe specimen handling and reference-laboratory testing. Both are handled at maximum containment, and confirmatory testing is centralised at the national reference laboratory.

References and recommended reading

• Burrell CJ, Howard CR, Murphy FA. Arenaviruses. In: Fenner and White’s Medical Virology, 5th edition, Chapter 30. Elsevier / Academic Press; 2017. The reference account of arenavirus classification, the lymphocytic choriomeningitis immunology model, and the Old World and New World diseases.
• Carson G, Bray M, Roth C. Viral Haemorrhagic Fevers. In: Clinical Virology, 4th edition, Chapter 9. ASM Press; 2016. The comparative VHF context and the transferrin receptor 1 usage of the pathogenic New World viruses.
• Hewson R. Understanding Viral Haemorrhagic Fevers: Virus Diversity, Vector Ecology, and Public Health Strategies. Pathogens. 2024;13(10):909. Current taxonomy, reservoir ecology and the vaccine-development landscape.