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Flavivirus


The Flaviviradae is a large family of viral pathogens responsible for causing severe disease and mortality in humans and animals. The family consists of three genera: Flavivirus, Pestivirus and Hepacivirus. The Flavivirus genus, which is the largest of the three, contains more than 70 viruses including Dengue Virus (DV), Japanese Encephalitis Virus (JEV), West Nile Virus (WNV), Yellow Fever Virus (YFV) and Zika Virus (ZIKV). Flaviviruses show morphological uniformity with an icosahedral capsid and closefitting, spiked envelope. The size of the capsid is about 30 nm and the whole virion measures 45 nm. The genome of the flaviviruses is a singlestranded sense RNA about 10 kb in size. It codes for 3 structural proteins: capsid (C protein), membrane (M, which is expressed as prM, the precursor to M and envelope (E protein) and 7 nonstructural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5 (Figure 1 a.b).

Flavivirus particles (a), proteins (b) and life cycle (c)

Figure 1. Flavivirus particles (a), proteins (b) and life cycle (c).

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Flavivirus life cycle:
Virions attach to the surface of a host cell and subsequently enter the cell by receptor-mediated endocytosis (Figure 1c). Several primary receptors and low-affinity co-receptors for flaviviruses have been identified. Acidification of the endosomal vesicle triggers conformational changes in the virion, fusion of the viral and cell membranes, and particle disassembly. Once the genome is released into the cytoplasm, the positive-sense RNA is translated into a single polyprotein that is processed co- and post-translationally by viral and host proteases. Genome replication occurs on intracellular membranes. Virus assembly occurs on the surface of the endoplasmic reticulum (ER) when the structural proteins and newly synthesized RNA buds into the lumen of the ER. The resultant non-infectious, immature viral and subviral particles are transported through the trans-Golgi network (TGN). The immature virion particles are cleaved by the host protease furin, resulting in mature, infectious particles. Subviral particles are also cleaved by furin. Mature virions and subviral particles are subsequently released by exocytosis.

Flavivirus Epidemiology:
Mosquito-borne flaviviruses are transmitted in nature in one or more distinct or overlapping cycles that include a mosquito vector, generally Aedes mosquitoes for YFV and DENV and Culex mosquitoes for JEV and WNV, and a mammalian or avian host. Transmission between mosquitoes and vertebrate hosts is termed horizontal transmissions and causes disease in vertebrates. In contrast to horizontal transmission, mosquito-borne flaviviruses can be maintained in the environment through vertical, i.e., transgenerational, transmissions which allow the spread of flaviviruses solely in mosquitoes. The most direct evidence supporting the vertical transmission of mosquito-borne flaviviruses is derived from the isolation of virus from infected larvae presumably through transovarial transmission. This observation is consistent with the detection of viral antigens in ovarian tissues of infected mosquitoes. (Figure 2)

Three typical mosquitos that transmit disease

Figure 2. Three typical mosquitos that transmit disease.

Flaviviruses have a global distribution, and some members of the genus constitute a major public health issue (e.g., yellow fever virus [YFV], dengue virus [DENV], West Nile virus [WNV] and Japanese encephalitis virus [JEV]), with high morbidity and/or mortality. In the last decade, flaviviruses have demonstrated an increased prevalence, posing a risk for more than 3 billion people worldwide, which makes them a paradigm of emerging diseases.

In the last 50 years many flaviviruses, such as dengue, West Nile, and yellow fever viruses, have exhibited dramatic increases in incidence, disease severity and/or geographic range. Environmentally derived viral pathogens display relatively uniform epidemiologic characteristics. Mosquitoes, ticks, and biting flies serve as the vectors for most human viral diseases. Human disease occurs when vectors are active, typically in spring, summer, and fall in temperate climates, and often displays distinct epidemiological characteristics that correspond to the habitat of the vector (Figure 3).

The epidemic area of 5 typical flavivirus

Figure 3. The epidemic area of 5 typical flavivirus.

Manifestations:
Flaviviruses vary widely in their pathogenic potential and mechanisms for producing human disease (Table 1). Human infection with both mosquito-borne and tick-borne flaviviruses is initiated by deposition of virus through the skin via the saliva of an infected arthropod. Virus replicates locally and in regional lymph nodes and results in viremia. Major syndromes and examples of causative flaviviruses include: encephalitis (Japanese encephalitis), febrile illness with rash (dengue virus), hemorrhagic fever (Kyasanur Forest disease virus and sometimes dengue virus), and hemorrhagic fever with hepatitis (yellow fever virus).

Table 1 Overview of the Most Important Flaviviruses

Viral species Transmitting vector Geographic spread Syndrome
Yellow fever Mosquito (Aedes) See Figure 3a Hemorrhagic fever
Dengue Mosquito
(Aedes, Stegomyia)
See Figure 3b Dengue syndrome,
DHF, DSS
West Nile fever Mosquito (Culex),
ticks (Argasidae)
See Figure 3c Dengue syndrome,
encephalitis
Japanese encephalitis Mosquito (Culex) See Figure 3d Encephalitis
Zika Mosquito (Aedes) See Figure 3e Microcephaly

Diagnostics:
The clinical diagnosis of the different flaviviruses is not reliable owing to the unspecific symptoms, and laboratory diagnosis is mandatory to confirm the etiology of the disease. In flavivirus infections, the virus can be found in serum or plasma, generally 2–7 days following disease onset, and the duration of this viremic phase and the viral load detected vary depending on the infecting virus (Table 2). Commonly, after 5–7 days from onset, an immune response against the infection arises, with IgM antibodies peaking after 15 days. These IgM antibodies could last from months (as in the case of DENV) to years (as in the case of WNV infections). The appearance of IgG occurs after 8–10 days from the onset and can be detected throughout life. The particular features of each flavivirus markedly influence the diagnostic algorithms to be applied in the identification of flaviviral infections. In general, many laboratories have chosen serological tests to diagnose infections caused by flaviviruses, owing to their accuracy and the availability of commercial tests based on high quality standards. However, the presence of serological cross-reactions among the different viruses, and the time necessary for detecting the antibodies in some infections, hamper the usefulness of serology as a diagnostic tool for acute flavivirus infections. Viral isolation constitutes the 'gold standard' method to achieve a confirmed flavivirus diagnosis.

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Table 2. Flavivirus diagnosis algorithms.

Acute phase Convalescent phase Preferred sample Viral load expected
YFV RT-PCR, RT-qPCR, IgM, virus isolation IgM, IgG Serum, plasma and tissue High
DENV RT-PCR, RT-qPCR, NS1 Ag, IgM, virus isolation IgM, IgG Serum, plasma, CSF and PBMCs Up to 106 virions/ml
WNV RT-PCR, IgM, IgG IgM, IgG CSF and serum Low
JEV RT-PCR, IgM, IgG IgM, IgG CSF, serum, blood and PBMCs Low
ZIKV RT-PCR, IgM, IgG IgM, IgG CSF and serum Low

Reference:

1. Gould E A, Solomon T. Pathogenic flaviviruses [J]. The Lancet, 2008, 371(9611): 500-509.
2. Gaunt M W, Sall A A, de Lamballerie X, et al. Phylogenetic relationships of flaviviruses correlate with their epidemiology, disease association and biogeography [J]. Journal of General Virology, 2001, 82(8): 1867-1876.
3. Kuno G, Chang G J J, Tsuchiya K R, et al. Phylogeny of the genus Flavivirus [J]. Journal of virology, 1998, 72(1): 73-83.
4. Mukhopadhyay S, Kuhn R J, Rossmann M G. A structural perspective of the flavivirus life cycle[J]. Nature Reviews Microbiology, 2005, 3(1): 13-22.
5. Huang Y J S, Higgs S, Horne K M E, et al. Flavivirus-mosquito interactions[J]. Viruses, 2014, 6(11): 4703-4730.

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