Equine Encephalitis Viruses

Equine encephalitis viruses (EEVs), belonging to the Togaviridae family and Alphavirus genus, are mosquito-borne arboviruses that infect humans and cause minor illness or, in severe cases, encephalitis. The eastern equine encephalitis (EEE) virus complex consists of the EEE virus, found in North America and the Caribbean; and the Madariaga virus, found in South and Central America. Other viruses in this complex include western EEV and Venezuelan EEV. The virus is maintained in a cycle between mosquitoes and avian hosts, but can spread to humans via bridge vectors (other species of mosquitoes). Initial symptoms after the mosquito bite include fever, headache, and vomiting. A majority of patients recover, but the illness can progress to severe encephalitis. Diagnosis is by clinical findings and CSF analysis using serology, and also by virus antigen or genomic sequence detection. There is no specific treatment, and therapy is largely supportive. Prevention of mosquito bites is key in management.

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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 and Epidemiology

General features of equine encephalitis virus (EEV)

  • Family: Togaviridae
  • Genus: Alphavirus
  • Genome:
    • Positive-sense, ssRNA
    • 11–12 kb in size
  • Properties:
    • Enveloped
    • Lipid bilayer envelope has viral-encoded glycoproteins E1 and E2.
    • Small icosahedral capsid
  • Clinically relevant viruses and geographic distribution:
    • Eastern equine encephalitis virus (EEEV) complex:
      • Eastern equine encephalitis (EEE) virus: North America (Atlantic and Gulf coasts) and the Caribbean
      • Madariaga virus: South and Central America
    • Western equine encephalitis virus (WEEV): North and South America
    • Venezuelan equine encephalitis virus (VEEV): Central and South America

Epidemiology

  • In the United States:
    • EEEV is the most common of the 3 viruses.
    • Infections are rare and sporadic.
    • Peak incidence: August and September
  • Flooding increases breeding of mosquitoes → ↑ risk of infection
  • Both humans and horses can be infected and develop encephalitis.

Pathophysiology

Vector and transmission

  • Mosquitoes: primary arthropod vector
  • Virus has different reservoirs or amplifying hosts: domestic and wild birds, mammals
  • Transmission:
    • The virus is maintained by birds and mosquitoes (Culiseta melanura with EEEV infection) in a mosquito-bird-mosquito cycle.
    • Viral transmission between vertebrates is facilitated by bridge vectors (other mosquitoes or blood-feeding arthropods).
    • Species of mosquitoes that serve as bridge vectors:
      • Coquillettidia species
      • Aedes species
      • Culex species
    • Humans are infected by the human-biting bridge vectors.
      • While humans can develop illness, they are considered dead-end hosts.
      • Viremia in humans is generally insufficient to infect feeding mosquitoes/vectors.
  • The virus can also be used as a bioterrorism agent (via aerosol transmission).
Life cycle of arboviruses

Transmission cycles of arboviruses in nature:
Transmission of most arboviruses is covered by 2 major cycles, namely the mosquito-reservoir/host-mosquito cycle and the mosquito vector and humans/dead-end hosts.

Image: “Transmission cycles of arboviruses in nature” by Guey-Chuen Perng and Wei-June Chen. License: CC BY 3.0

Pathogenic features and viral infection

  • Infected female mosquito bites human → virus enters the bloodstream → entry into host cells (myeloid or lymphoid cells) via endocytosis
  • Envelope E1 and E2 viral proteins:
    • Aid in virus attachment and penetration
    • E1 can bring about hemagglutination by fusing to membrane lipids
  • Viral replication:
    • Occurs in the cytoplasm (viremic phase)
    • Positive-sense genomic RNA serves as the mRNA.
  • Virions mature by budding from plasma membranes → infect other cells
  • Neuroinvasion:
    • The virus crosses the blood-brain barrier and multiplies in the CNS.
    • Leads to neuronal necrosis/neuronophagia and meningeal irritation
    • Invasion depends on:
      • Level of viremia
      • Virulence of strain
      • Host immune response
    • Age-dependent risk for CNS infection, which is increased in:
      • Infants/young children
      • Elderly
Mosquito salivary gland - eastern equine encephalitis

Electron micrograph of the salivary gland of a mosquito containing the eastern equine encephalitis virus:
The mosquito is infected with the virus when it feeds on the blood of a viremic animal. The virus matures and disseminates in the organs and eventually accumulates in the salivary glands of the mosquito.

Image: “Colourised TEM micrograph” by Fred Murphy and Sylvia Whitfield – CDC. License: Public Domain

Diseases

Minor illness

  • 1st phase (from mosquito bite to viral replication in non-neural tissue)
  • Incubation period: 4–10 days following a mosquito bite
  • 7–10 day prodrome:
    • Fever
    • Headache
    • Nausea/vomiting
  • Most cases are subclinical or only produce low-grade fever.
  • Patients with minor viral illness (and no CNS involvement) recover within 1–2 weeks.

Major illness

  • 2nd phase: viral multiplication in the brain
  • Encephalitis or inflammation/swelling of the brain parenchyma affects 2% and 6% of infected adults and children, respectively.
    • Signs and symptoms include: 
      • Headache
      • High fever
      • Muscle pain
      • Photophobia
      • Altered mental status
      • Seizures and cranial nerve palsies in 50% of patients
      • May manifest as bulging fontanelle in infants
    • Mortality rate can reach 20%–30% depending on the EEV type and host factors.
    • Survivors have severe neurologic sequelae that can include: 
      • Intellectual impairment
      • Epilepsy
      • Paralysis
      • Deafness
      • Blindness

Diagnosis and Management

  • Diagnostic approach:
    • Clinical findings consistent with encephalitis
    • Laboratory findings:
      • Leukocytosis
      • Hyponatremia
      • CSF analysis: pleocytosis, ↑ protein concentration
    • Determination of virus:
      • Virus-specific IgM: < 4-fold rise in specific antibodies 
      • Viral antigen or genomic sequences (using PCR assays) in CSF, blood, or tissue
    • Imaging: MRI is more sensitive in showing abnormalities (focal lesions in basal ganglia, brainstem, and thalami).
  • Treatment: supportive (no specific treatment)
  • Prevention: 
    • Mosquito control
    • Avoidance of mosquito bites (protective clothing, mosquito repellants)

References

  1. Crosby, B., Crespo, M.E. (2020). Venezuelan Equine Encephalitis. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, from https://www.ncbi.nlm.nih.gov/books/NBK559332/
  2. Perng, G., Chen, W. (2013). Arboviral Encephalitis, Encephalitis, Sergey Tkachev, IntechOpen. https://www.intechopen.com/books/encephalitis/arboviral-encephalitis
  3. Peterson, L. (2021). Arthropod-borne encephalitides. UpToDate. Retrieved Apr 24, 2021, from https://www.uptodate.com/contents/arthropod-borne-encephalitides
  4. Riedel, S., Hobden, J.A., Miller, S., Morse, S.A., Mietzner, T.A., Detrick, B., Mitchell, T.G., Sakanari, J.A., Hotez, P, Mejia, R. (2019). Arthropod-borne and rodent-borne viral diseases. Jawetz, Melnick & Adelberg’s Medical Microbiology, 28e. McGraw-Hill.
  5. Ryan, K.J. (Ed.), (2017). Arthropod-borne and other zoonotic viruses. Sherris Medical Microbiology, 7e. McGraw-Hill.
  6. Simon, L.V., Coffey, R., Fischer, M.A. (2020). Western Equine Encephalitis. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, from https://www.ncbi.nlm.nih.gov/books/NBK470228/

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