Lymphocytic choriomeningitis virus

Lymphocytic choriomeningitis virus, abbreviated LCMV, is the prototype arenavirus and, more than any other single virus, the system in which the basic rules of cellular immunology were worked out. It is an Old World arenavirus whose natural host is the common house mouse, and it is distributed wherever that mouse lives, which is to say almost everywhere. Most human infection is silent or causes no more than a self-limiting febrile illness, and a minority develop aseptic meningitis, the presentation that gave the virus its name.

Its clinical weight lies at the two extremes of the immune spectrum. In the developing fetus it is a neurotropic congenital pathogen that mimics the classic congenital infections and can cause lasting brain and eye injury, a diagnosis often missed because it is not routinely sought. In the profoundly immunosuppressed, above all the organ-transplant recipient who acquires the virus from an infected donor, it produces a severe and frequently fatal multisystem disease. Between these poles sits a virus that rarely troubles the healthy adult but has an importance in the laboratory out of all proportion to the disease it causes.

Discovery and historical significance

LCMV was isolated in 1933 by Charles Armstrong and Ralph Lillie during an investigation of what was thought to be St. Louis encephalitis, and it was quickly recognised as a distinct agent and the cause of a form of aseptic meningitis. Its lasting significance, however, is as the workhorse of twentieth-century immunology, the virus in which several foundational concepts were first demonstrated.

Three of these stand out. Work on mice infected with LCMV before birth or in the newborn period, which become lifelong carriers with high levels of virus yet no disease, was central to the concept of immunological tolerance, the idea that the immune system learns not to attack antigens it meets very early. In the adult mouse the same infection is lethal, and it was shown that the fatal choriomeningitis is caused not by the virus destroying tissue but by the host’s own T cells attacking infected cells, the founding demonstration of immune-mediated disease, or immunopathology. Most influential of all, in 1974 Rolf Zinkernagel and Peter Doherty used LCMV to show that cytotoxic T cells recognise a viral target only when it is presented together with the body’s own major histocompatibility complex (MHC) molecules, the principle of MHC restriction that underlies all of T-cell recognition and brought them the Nobel Prize. The virus remains a central tool for studying T-cell memory and exhaustion.

Classification, structure, and genome

Classification

LCMV is the species Mammarenavirus choriomeningitidis in the genus Mammarenavirus, family Arenaviridae, and is the prototype of the Old World arenavirus complex that also contains Lassa and Lujo viruses. Unlike its African relatives it is not a haemorrhagic fever agent, and unlike them it is found worldwide, because its reservoir travels with humanity everywhere.

Virion structure

The particle is a characteristic arenavirus: pleomorphic and enveloped, bearing glycoprotein spikes over a lipid envelope, and carrying host ribosomes taken up during assembly that give the family its sandy electron-microscopic appearance.

Genome organisation

The genome follows the standard arenavirus plan, a bisegmented, ambisense, negative-sense RNA in a small and a large segment. The small segment encodes the nucleoprotein and the glycoprotein precursor, the large segment the polymerase and the Z matrix protein. Two laboratory strains have shaped immunology: the Armstrong strain, which causes an acute infection cleared by the mouse, and the Clone 13 variant derived from it, which differs by a few mutations and instead establishes a chronic infection, the pair now used as the standard model of acute versus persistent viral infection.

Replication cycle

Entry begins when the glycoprotein binds alpha-dystroglycan, the receptor shared with the other Old World arenaviruses, after which the virion is taken up by endocytosis and fuses with the endosomal membrane at low pH to release the genome into the cytoplasm. Transcription and replication proceed there by the arenavirus mechanism of cap-snatching, and progeny bud from the plasma membrane under the direction of the Z protein. A defining feature of LCMV is the ease with which it establishes non-cytolytic persistent infection, replicating without killing the cell, which is the cellular basis of its lifelong, symptomless carriage in the mouse and of the chronic-infection model in the laboratory.

Pathogenesis

The pathogenesis of LCMV is the clearest illustration in virology that disease and viral replication are not the same thing. In the immunocompetent host the virus is not itself very destructive; the illness is produced by the immune response to it. When adult mice are infected in the brain, it is the cytotoxic T-cell attack on infected meningeal and ependymal cells that causes the fatal choriomeningitis, and suppressing that T-cell response prevents the disease while allowing the virus to persist. Human aseptic meningitis is understood in the same way, as an immune-mediated inflammation, which is consistent with its appearance after the initial febrile phase and with the lymphocyte-rich cerebrospinal fluid.

The outcome depends entirely on when in life the host meets the virus. Infection of the fetal or newborn mouse, before the immune system has matured, produces tolerance and lifelong high-level carriage without disease, whereas the same infection in the adult is controlled, or fatal, through a vigorous immune response. This dependence on immune status explains the human disease pattern directly: silent or mild in the healthy adult, but severe where immunity is absent or suppressed.

The fetal brain is a specific target. The virus has a tropism for the dividing neuroblasts of the developing brain and retina, and infection there disturbs neuronal migration and damages the retina, producing the malformations of congenital LCMV rather than the destructive picture seen after birth.

Epidemiology

LCMV is distributed worldwide, following its reservoir, the house mouse (Mus musculus), which carries the virus persistently and sheds it lifelong in urine, saliva and droppings. Human seroprevalence is generally around 2 to 5%, higher in conditions of poor housing where contact with mice is greater. People acquire the virus by inhaling or ingesting material contaminated with rodent excreta, or through broken skin.

Beyond wild mice, two other sources matter. Pet rodents, particularly hamsters and mice, and laboratory rodent colonies are recognised sources of human infection, and have been the origin of clusters. Crucially, LCMV does not spread from person to person by ordinary contact: the only routes of human-to-human transmission are across the placenta and through organ transplantation, which shape its two most serious clinical settings.

Natural history

After an incubation of about 1 to 2 weeks, most infections are either silent or cause a nonspecific febrile illness that resolves on its own. In a minority the illness is biphasic: a first phase of fever, malaise, headache and myalgia settles briefly, and is then followed by a second, meningitic phase. Aseptic meningitis is usually self-limiting and rarely fatal in the immunocompetent, and recovery is generally complete, though convalescence can be prolonged.

The natural history is wholly different when the virus is acquired before birth or by an immunosuppressed transplant recipient. In those settings there is no benign self-limiting course; congenital infection leaves fixed neurological and visual deficits, and transplant-acquired infection is a rapidly progressive and often fatal illness.

Clinical presentations and complications

Acquired infection and aseptic meningitis

In the immunocompetent, most infection is asymptomatic or an influenza-like illness with fever, headache, malaise and myalgia. Where the nervous system is involved, the usual presentation is aseptic meningitis, often after the biphasic course, with headache, neck stiffness and photophobia; less often the virus causes encephalitis, myelitis or a transient hydrocephalus. The outlook for acquired disease is generally good.

Congenital LCMV

Maternal infection during pregnancy can cross the placenta and injure the fetal brain and eye. The characteristic result is a triad of hydrocephalus or microcephaly, periventricular calcification, and chorioretinitis, together with seizures and later psychomotor impairment, and infection early in pregnancy may cause miscarriage. The picture closely mimics the classic congenital infections grouped as TORCH (toxoplasmosis, other, rubella, cytomegalovirus and herpes simplex), and LCMV is an under-recognised member of that differential: it should be considered in an infant with congenital hydrocephalus and chorioretinitis in whom the usual agents have been excluded, especially where there is a history of rodent exposure in pregnancy.

Transplant-transmitted LCMV

The most lethal presentation follows organ transplantation from an infected donor. In the profoundly immunosuppressed recipient the virus is not controlled, and it produces a rapidly progressive multisystem illness with fever, hepatitis, encephalopathy and multiorgan failure within weeks of transplantation. Recognised United States clusters illustrate the severity: across five donor-derived clusters, 17 recipients were infected and roughly 12 died, and the first recognised cluster was traced to a donor’s contact with a pet hamster. The same donor-derived, near-uniformly severe pattern was seen in a related Australian cluster.

Diagnosis

In acquired disease the pointer is the cerebrospinal fluid, which shows a marked lymphocytic pleocytosis, often with several hundred to over a thousand cells, together with a low glucose, a combination that in a returning febrile patient with an aseptic meningitis should raise LCMV. Confirmation is serological, by immunofluorescence or enzyme immunoassay for immunoglobulin M (IgM) and immunoglobulin G (IgG), and by reverse transcription polymerase chain reaction (RT-PCR) on cerebrospinal fluid or blood. Congenital infection is diagnosed within the TORCH workup, by detecting specific antibody in the infant or demonstrating the virus, once the commoner agents have been excluded in a child with the typical brain and eye findings. In the transplant setting the diagnosis is made by RT-PCR and immunohistochemistry on the recipient, with retrospective testing of donor material. LCMV is generally handled at moderate rather than maximum laboratory containment, unlike its haemorrhagic-fever relatives.

Management

Treatment is principally supportive, and most acquired disease, including aseptic meningitis, resolves without specific therapy. Ribavirin has activity against LCMV in the laboratory and has been used in severe and transplant-associated infection, together with reduction of immunosuppression where possible, but its benefit is not established and outcomes in the transplant setting remain poor. There is no specific antiviral of proven value and no established treatment that reverses the congenital injury, which is fixed by the time of birth.

Prevention and public health

Vaccination

There is no vaccine against LCMV, and none is in development; prevention rests entirely on avoiding exposure to the reservoir.

Infection prevention and control

Prevention is a matter of reducing contact with rodents and their excreta, which carries the greatest weight in two groups. Pregnant women should avoid handling wild or pet rodents and cleaning their cages, given the risk of congenital infection, and the same caution applies around immunosuppressed patients. In the laboratory, rodent colonies are screened and handled to prevent occupational infection. Organ transplantation poses a distinct and difficult problem, since donors cannot practically be screened for a rare infection they may carry silently, so donor-derived LCMV is recognised after the event rather than prevented, through vigilance for unexplained severe illness in clusters of recipients from a shared donor.

South African context

LCMV follows the house mouse and is therefore present in South Africa, though it is rarely sought and almost certainly under-recognised. Its practical relevance is twofold and mirrors the global picture. It belongs in the differential diagnosis of aseptic meningitis, particularly where there is rodent exposure, and, more importantly, it should be remembered as a cause of congenital hydrocephalus and chorioretinitis when the standard congenital-infection screen is negative, since the diagnosis is otherwise easily missed. No specific national programme addresses LCMV; the general counsel to avoid rodent contact in pregnancy is the main preventive measure, and diagnosis of suspected cases would draw on the reference virology laboratories.

References and recommended reading

• Bausch DG. Arenaviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. Washington: ASM Press; 2016. The source for the human clinical spectrum, congenital and transplant-transmitted disease, diagnosis and management.
• Radoshitzky SR, Buchmeier MJ, de la Torre JC. Arenaviridae: The Viruses and Their Replication. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2022. The reference for classification, genome organisation, receptor use and persistence, and for LCMV as an immunological model.
• Burrell CJ, Howard CR, Murphy FA. Arenaviruses. In: Fenner and White’s Medical Virology, 5th edition, Chapter 30. Elsevier / Academic Press; 2017. The concise account of the tolerance, immunopathology and MHC-restriction discoveries built on LCMV.