Zika Virus (ZIKV)-Describe

Zika Virus (ZIKV)-Describe

The re-emerging arbovirus, Zika virus (ZIKV), was first identified in rhesus monkeys in the Zika forest, Uganda, about 70 years ago.

It is a single-stranded RNA virus of the Flaviviridae family, transmitted by the Aedes mosquito.

  • The two main geographically separated lineages include the Asian and African lineages; The African lineage of the virus affects monkeys and apes as primary hosts and humans as occasional hosts, while the Asian lineage affects humans as primary hosts.
  • The mature ZIKV resembles a golf ball shape with a smooth surface in which the major surface protein E lies parallel to the viral membrane.
  • The virus is 50 nm in size and contains 180 copies of the E and M proteins in its viral membrane.
  • It consists of a positive-stranded RNA genome with three structural proteins and a lipid envelope.
  • The E protein consists of 4 domains: stem transmembrane domain pair and 3 ectodomains I, II and III.
  • The E protein is dominant on the outer surface of the particle and about 50% of the protein is conserved in the ZIKV and Dengue (DENV) virus strains.
  • The smaller M protein lies beneath the larger E protein, where the 180 E and M proteins are arranged in a raft configuration.
  • The prM glycoprotein is attached to the viral membrane. The trimers of prM-E heterodimers form spiny protrusions arranged with icosahedral symmetry in immature ZIKV, assembling on the endoplasmic reticulum. The immature virion proceeds through the secretory pathway where the prM is cleaved by the host’s furin-like protease.
  • The mature virion has a relatively smooth surface composed of 90 E protein dimers oriented in a parallel plane with the viral membrane.
  • The ZIKV consists of a single positive-stranded RNA genome with a genome size of approximately 10.7 kbp encoding a single open reading frame.
  • It consists of two untranslated regions (UTRs) in each of its terminals.
  • The single polyprotein encodes three structural proteins, including capsid (C), pre membrane (prM), and envelope (E), and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). ).
  • The structural proteins form the structure of the virus, while the nonstructural proteins are involved in genome replication, viral polyprotein processing, and regulation of the host response.

Epidemiology of Zika Virus

  • The Zika virus was first isolated in Uganda in 1947 during a study of yellow virus fever and has been associated with causing sporadic human infections in Africa and Asia.
  • The first significant outbreak of the virus was identified in 2007 on the coast of Central Africa. Another outbreak was also identified in the same year in Micronesia.
  • Subsequent outbreaks were seen from 2013 to 2016 in French Polynesia and other Pacific islands, including New Caledonia, Easter Island, Cook Islands, Samoa, and American Samoa.¬†
  • The virus then rapidly spread through South and Central America. The United States detected its first locally transmitted Zika virus case in July 2016.
  • The actual incidence and prevalence of the virus can likely be underestimated due to the lack of routine laboratory testing for the pathogen.

Transmission of Zika Virus

ZIKV is mainly transmitted to humans through the bite of the infected Aedes aegypti mosquito.

Other Aedes species such as Aedes albopictus, A. africanus, A. luteocephalus, A. furcifer and A. taylori also contribute to transmission of the virus.

Other transmission routes of the virus are:

  • Through sexual intercourse with the infected person
  • Through blood transfusions and organ transplants
  • Congenital infection from mother to fetus as the virus can cross the placenta
  • Through accidental exposure to laboratory workers

Replication of Zika Virus

Viral replication occurs in the cytoplasm, however, the detection of virus-specific antigen in the nuclei of Zika virus-infected cells has questioned the role of the nucleus in viral replication. The mechanism of its replication includes:

Attachment/Adsorption

Viral binding occurs through the viral E proteins present in their envelope with the host receptors such as the C-type lectin receptors (CLRs) expressed in myeloid cells including monocytes, macrophages and dendritic cells.

Penetration

The virus is endocytosed by clathrin-mediated endocytosis aided by the mechanism of molecular mimicry.

Uncoating

The clathrin-coated vesicle is transported away from the plasma membrane and the clathrin is removed from it. The endocytic vesicle is then delivered to the early endosomes, which mature into late endosomes. Due to the variation in pH environment, the viral membrane then fuses with the endosomal membrane, releasing the viral genome into the cytoplasm.

Biosynthesis

The ssRNA genome is then translated into a single polyprotein, which is cleaved into structural and non-structural proteins. Viral replication occurs at the surface of the endoplasmic reticulum and a dsRNA genome is synthesized from the positive-stranded ssRNA. The dsRNA yields the viral mRNA and new ssRNA products through transcription and replication.

Assembly

Viral assembly occurs at the endoplasmic reticulum where it buds off and then enters the Golgi apparatus.

Maturation

Virus maturation takes place in the Golgi apparatus where the prM protein of the immature virion is cleaved and the mature virus particle is released into the cytoplasm.

Release

The virus particle is released from the cell through the process of exocytosis.

Pathogenesis of Zika Virus

  • There is a lack of sufficient data on the pathogenesis of the Zika virus.
  • The human dermal fibroblasts, epidermal keratinocytes, immature dendritic cells, monocytes and macrophages act as receptor cells for the virus.
  • Adhesion/entry factors such as DC-SIGN, Tyro, AXL and TIM-1 help the virus enter cells.
  • ZIKV replication induces the production of type I interferons in the infected cells while activating an antiviral immune response.
  • From the skin, the virus spreads to the lymph nodes, replicates, and causes primary viremia. The virus spreads to other visceral organs through the hematogenous circulation.
  • The ZIKV RNA can be detected in the blood within 10 days after infection. If viremia persists, higher virus titers are observed.
  • Virus shedding occurs at high levels in urine, saliva, and other body fluids such as semen, tears, and cervical mucus.
  • Studies have shown that the virus can still be shed in semen months after it has been removed from the blood.
  • After infection, both humoral and cell-mediated immune responses are induced.
  • IgM antibodies produced against the virus are usually detectable for 2-3 months to over a year, while IgG antibodies remain detectable for months or years and are believed to confer lifelong immunity.

Clinical Manifestations of Zika Virus

Zika virus infection may be asymptomatic, or if symptoms occur, are usually mild that arise 3-14 days after infection lasting for 2-7 days.

 The general symptoms include:

  • Fever
  • The appearance of maculopapular rash
  • Joint pain
  • Conjunctivitis
  • Muscle pain
  • Headache
  • Pain behind the eye
  • Vomiting

Other symptoms and complications include:

  • Myalgia
  • Asthenia
  • Peripheral edema
  • Gastrointestinal disturbances (abdominal pain, nausea, diarrhea)
  • Congenital microcephaly
  • Guillain-Barr√© syndrome
  • Fetal losses in women infected during pregnancy
  • Acute myelitis
  • Meningoencephalitis
  • Axillary and/or inguinal lymphadenopathy
  • Leukopenia with monocytosis
  • Thrombocytopenia

Diagnosis of Zika Virus

Culture

The virus can be cultured and isolated by inoculation into chick embryo yolk sac, allantoic sac and chorioallantoic membrane and in cell culture in Vero, rhesus monkey and pig kidney cells. It can also be inoculated into lactating mice but shows lower sensitivity than the cell cultures. The ZIKV has been successfully cultured from human blood, semen and urine.

Molecular detection of ZIKV RNA

The ZIKV RNA viruses can be detected by gene amplification in a two-step process involving the reverse transcription of genomic RNA into single-stranded DNA (cDNA), followed by conversion to double-stranded DNA and amplification of the DNA. Real-time PCR can be performed for faster detection than traditional PCR.

Serological diagnosis

The serological test for ZIKV is performed by ELISA and the test is confirmed by PRNT (Plaque Reduction Neutralization Test) according to standard protocols. PRNT is considered the “gold standard” for differentiation of anti-flavivirus antibodies. The IgM antibody response in the primary flavivirus was found to be specific for ZIKV with limited cross-reactivity to other flaviviruses. However, a high level of serological cross-reactivity was observed during flavivirus secondary infection with other flaviviruses using both IgM-ELISA and PRNT90. However, PRNT is expensive and only performed in highly specialized laboratories.

Diagnosis of ZIKV in endemic countries

In countries with limited access to molecular testing methods, diagnosis is often made by serological testing using IgM ELISA or rapid tests. A combined NS1 antigen and IgM antibody test increase the sensitivity and specificity of dengue fever diagnostics. If several patients test negative in the DENV NS1 test, Zika and other flavivirus infections are suspected.

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Zika Virus (ZIKV)-Describe

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