Lymphocytic Choriomeningitis Virus

Lymphocytic choriomeningitis virus (LCMV) is a single-stranded RNA virus transmitted to humans via rodents, the primary reservoir. Viral infections can occur through direct contact (such as through a break in the skin) with rodent urine, saliva, or droppings or via inhalation of aerosolized virus. Vertical transmission and, rarely, organ transplantation also lead to infections. The disease typically results in a self-limited, febrile, biphasic disease. In severe cases, patients can present with encephalitis, aseptic meningitis, or meningoencephalitis. Lymphocytic choriomeningitis virus infections of pregnant women have also been recognized as a significant teratogen resulting in fetal death or congenital defects. Diagnosis is by serology or RT-PCR. Management is supportive.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics

Basic features of lymphocytic choriomeningitis virus (LCMV)

  • Enveloped
  • Spherical
  • Midsize (diameter between 60 and 300 nm)
  • 2 viral surface glycoproteins on envelope: G1 and G2
  • Virus genome:
    • Encapsulated by a helical nucleocapsid
    • Segmented with:
      • A large (L) single-stranded, negative-sense RNA  
      • A small (S) ambisense RNA
    • Carries RNA-dependent RNA polymerase (RDRP)

Taxonomy:

  • Family Arenaviridae
  • Genus Mammarenavirus
  • Viruses contain host ribosomes, giving the virus a granular appearance (arenosus is Latin for “sandy”)
  • Other arenaviruses include:
    • Lassa virus (Lassa fever)
    • Junin virus (Argentine hemorrhagic fever)
    • Machupo virus (Bolivian hemorrhagic fever)
    • Guanarito virus (Venezuelan hemorrhagic fever)
    • Sabia (Brazilian hemorrhagic fever)
    • Chapare (Chapare hemorrhagic fever)
    • Lujo (Lujo hemorrhagic fever)
Electron micrograph of lymphocytic choriomeningitis virus

Electron micrograph of lymphocytic choriomeningitis virus

Image: “Negative stain electron micrograph of an arenavirus from a mouse that tested positive for LCM” by CDC. License: Public Domain

Epidemiology

  • Seroprevalence in the United States: approximately 5%
  • Disease found in:
    • North and South America
    • Europe
    • Australia
    • Japan
  • No racial or sexual predilection
  • Infections more common in young adults
  • Infections are more common in the fall and winter (when rodents seek shelter indoors).

Pathogenesis

Reservoir

Arenaviruses: cause chronic infections in rodents (house mouse, Mus musculus)

Transmission

  • Direct contact with material contaminated by feces/urine/saliva of infected rodents (through the eye, nose, mouth, a break in the skin, or animal bite) 
  • Inhalation of aerosolized virus 
  • Vertical transmission from mother to fetus
  • Organ transplantation (recipient of infected donor tissue)

Life cycle

  1. Virus attaches to host receptors through envelope glycoproteins. 
  2. Virus is subsequently endocytosed, thus gaining entry into the cell. 
  3. Viral fusion with an endosome follows. 
  4. The virus merges with the endosome membrane, allowing the release of the viral ribonucleocapsid into the cytoplasm. 
  5. The RDRP mediates the viral gene replication and transcription in the cytoplasm of the host. 
  6. New virions are assembled and budding occurs, releasing the virion to infect other cells. 
life cycle of lymphocytic choriomeningitis virus

Life cycle of lymphocytic choriomeningitis virus:
1: Virus attaches to host receptors through envelope glycoproteins.
2: Virus is subsequently endocytosed, thus gaining entry into the cell.
3: Viral fusion with an endosome follows.
4: The virus fuses with the endosome membrane, allowing release of the viral ribonucleocapsid (vRNP) into the cytoplasm.
5: The RDRP mediates the viral gene replication and transcription in the host cytoplasm.
6: New virions are assembled and budding occurs, releasing the virion to infect other cells.

Image: “Arenavirus life cycle” by Y Liang et al. License: CC BY 4.0

Host risk factors

  • Owners of pet mice or hamsters
  • Laboratory workers

Disease process

LCMV is not cytotoxic, but while the host immune response tries to eliminate the virus, this may also trigger immune-mediated disease. The immune response produces the different manifestations of the disease.

  • Incubation period: up to 13 days
  • Primary viremia ensues → dissemination to other organs
  • The virus reaches the CNS (meninges, choroid plexus, and ventricular ependymal lining), leading to infiltration of inflammatory cells.

Clinical Presentation

Acquired lymphocytic choriomeningitis virus infection

Infection with LCMV results in a biphasic illness.

Symptom onset:

  • Occurs 8–13 days after exposure
  • 1st symptoms may last 5–7 days.
  • 33% are asymptomatic.
  • 50% have febrile illness without neurologic involvement.

1st-phase symptoms:

  • Fever
  • Lack of appetite
  • Headache
  • Muscle aches
  • Malaise
  • Nausea and/or vomiting
  • Lymphadenopathy
  • Maculopapular rash

2nd-phase symptoms:

Following a few days of recovery, 2nd-phase symptoms may start, which include neurologic symptoms (typical of meningitis and/or encephalitis).

  • Increased headache, photophobia
  • Nuchal rigidity
  • Change in mental status (lethargy, coma)

Other less frequent findings:

  • Orchitis
  • Myocarditis
  • Arthritis
  • Parotitis
  • Pneumonitis

Congenital lymphocytic choriomeningitis virus infection

Women who become infected with LCMV during pregnancy can pass the infection to the fetus.

  • Infections occurring during the 1st trimester may result in fetal death or spontaneous abortion.
  • Infections in the 2nd and 3rd trimesters can result in birth defects, including:
    • Blindness: Chorioretinitis is a common finding in children.
    • Mental retardation
    • Hydrocephalus 
    • Epilepsy

Organ transplant lymphocytic choriomeningitis virus infection

Significant immunosuppression in transplant recipients play a role in the development of disease:

  • Encephalopathy
  • Respiratory failure
  • Renal/hepatic impairment
  • Graft dysfunction
  • Coagulopathy
  • Thrombocytopenia
  • Fever

Diagnosis

Diagnostic tests

  • Confirmatory tests for the LCMV include:
    • Detecting IgM and IgG antibodies in the CSF and serum
    • RT-PCR
    • CSF viral culture
  • For congenital LCMV infection, babies may not have the virus anymore, so IgM and IgG levels are used.
  • Common findings in the CSF include:
    • Increase in protein levels
    • Lymphocytic pleocytosis
    • Decrease in the glucose levels

Additional findings

During the 1st phase of the disease, the most common laboratory abnormalities are

  • CBC:
    • Leukopenia
    • Thrombocytopenia
  • Elevated liver enzymes

Management

  • Patients with aseptic meningitis, encephalitis, or meningoencephalitis require: 
    • Hospitalization
    • Supportive treatment based on severity
  • Recovery generally takes up to 3 weeks.
  • Mortality rate:
    • Acquired LCMV infection: approximately 1%
    • Congenital LCMV infection: can reach 35% depending on the associated disorders

Comparison of Species

Arenaviruses can cause neurologic disease (LCMV) and/or hemorrhagic fevers, for which one of the major etiologies is the Lassa virus.

Table: Comparison of lymphocytic choriomeningitis virus (LCMV) and Lassa virus
OrganismLCMVLassa virus
FamilyArenaviridae
GenusMammarenavirus
Characteristics
  • Enveloped
  • Midsize
  • Spherical
  • Segmented genome
  • Single-stranded RNA (ssRNA)
  • Enveloped
  • Midsize
  • Spherical
  • Segmented genome
  • ssRNA
ReservoirRodents
Transmission
  • Aerosols
  • Direct contact
  • Vertical transmission
  • Organ transplantation
  • Aerosols
  • Direct contact
  • Ingestion
  • Person to person (through exposure to blood, secretions, tissue of infected individual)
Clinical courseBiphasic:
  • Flu-like illness
  • Meningitis, encephalitis
  • Majority of cases asymptomatic or only mild symptoms
  • Hemorrhagic manifestations
  • Deafness is common.
Diagnosis
  • Serology
  • RT-PCR
Management Supportive
  • Supportive
  • Ribavirin
Prevention Avoid contact with rodents and their body fluids.
  • Avoid contact with rodents and their body fluids.
  • Personal protective equipment

Differential Diagnosis

The following selected RNA viruses can also lead to CNS infection. 

  • Tick-borne encephalitis virus: due to a single-stranded RNA virus of the genus Flavivirus. Transmission primarily occurs via Ixodes ticks found in Europe, Russia, and Asia. Most patients are asymptomatic, but symptomatic individuals may experience a biphasic illness. Patients can develop neurologic manifestations, such as meningitis, encephalitis, or meningoencephalitis. Serology or PCR can confirm the diagnosis. There is no effective antiviral therapy for tick-borne encephalitis virus infections, so management is supportive
  • Equine encephalitis viruses: mosquito-borne arboviruses (belonging to Togaviridae, genus Alphavirus) that can cause minor viral illness and, in severe cases, encephalitis in humans. The virus is a positive-sense, single-stranded RNA. The eastern equine encephalitis virus is the most clinically relevant in the United States. The virus is maintained in a cycle between mosquito and often avian hosts but spreads to humans via bridge vectors. Symptoms include fever, headache, and vomiting, with the majority of patients recovering. The illness can progress to severe encephalitis. Diagnosis is by CSF studies, with serology and virus antigen or genomic sequence detection. There is no specific treatment, and therapy is largely supportive.
  • West Nile Virus: can cause neuroinvasive disease, including meningitis, encephalitis, and acute flaccid paralysis. The virus is an enveloped, positive-sense, single-stranded RNA virus of the genus Flavivirus. The primary hosts are birds, and the disease is most often transmitted by Culex mosquitoes. Most people infected with the virus are asymptomatic. Some patients will have a self-limited febrile illness, termed West Nile fever. The diagnosis is confirmed with serum or CSF serology or RT-PCR. Management is generally supportive. Prevention is aimed at local mosquito control and protection from mosquito bites. 
  • Saint Louis encephalitis virus: enveloped, positive-sense, single-stranded RNA virus belonging to the genus Flavivirus and causing St. Louis encephalitis. Transmission is by Culex mosquito species. Most infections are asymptomatic. Symptomatic individuals may have flu-like symptoms, aseptic meningitis, encephalitis, or meningoencephalitis. The diagnosis is confirmed with serology. There is no effective antiviral treatment, so management is supportive. Prevention is aimed at local mosquito control and personal protection with insect repellent and protective clothing. 

References:

  1. Bonthius D.J. (2012). Lymphocytic choriomeningitis virus: an underrecognized cause of neurologic disease in the fetus, child, and adult. Seminars in Pediatric Neurology 19:89–95. https://doi.org/10.1016/j.spen.2012.02.002
  2. Centers for Disease Control and Prevention. (2013). Viral hemorrhagic fevers. Retrieved May 20, 2021, from https://www.cdc.gov/vhf/virus-families/arenaviridae.html
  3. Centers for Disease Control and Prevention (2008). Brief report: Lymphocytic choriomeningitis virus transmitted through solid organ transplantation. MMWR Morb Mortal Wkly Rep 57:799–801.
  4. Centers for Disease Control and Prevention. (2014). Lassa fever. https://www.cdc.gov/vhf/lassa/symptoms/index.html
  5. Emonet, S., Retornaz, K., Gonzalez, J.P., de Lamballerie, X., Charrel, R.N. (2007). Mouse-to-human transmission of variant lymphocytic choriomeningitis virus. Emerg Infect Dis 13:472–475. https://doi.org/10.3201/eid1303.061141
  6. McDonald, P., Chandrasekar, P. (2017). Lymphocytic choriomeningitis virus (LCMV) infection. Medscape. Retrieved May 20, 2021, from https://emedicine.medscape.com/article/220796-overview
  7. Ryan K.J. (2017). Arthropod-borne and other zoonotic viruses. Chapter 16 of Sherris Medical Microbiology, 7th ed. https://accessmedicine.mhmedical.com/content.aspx?bookid=2268&sectionid=176083946
  8. Shao, J., Liang, Y., Ly, H. (2015). Human hemorrhagic fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis. Pathogens 4:283–306. https://doi.org/10.3390/pathogens4020283

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