Flavivirus

Flavivirus is an enveloped single-strand positive-strand RNA virus, which is transmitted by mosquito bites and is an important pathogen of emerging infectious diseases, which seriously threatens human health. Although the clinical illness caused by different flaviviruses is different, there are some similarities in their clinical symptoms, with fever being the most common symptom of flavivirus infection and often presenting with high fever. This article will discuss in detail the characteristics, classification, clinical disease caused, and treatment strategies of Flavivirus.

What is flavivirus?

Flavivirus is a large group of single-positive-stranded RNA viruses with an envelope. These viruses are usually transmitted by blood-sucking arthropods (mosquitoes, ticks, sandflies, etc.). These viruses are structurally similar, and most of them are enveloped RNA viruses with 20-hedral stereo symmetry. They can multiply in arthropods and are not pathogenic to arthropods, but can be transmitted to vertebrates or humans through insect bites, causing natural infectious diseases. Most viruses cause zoonotic, naturally occurring diseases with a variety of clinical manifestations, including encephalitis or encephalomyelitis and systemic infections. Since arthropods are both storage hosts and vectors, their distribution is affected by geography and climate, so the diseases caused by arthropods are obviously seasonal and regional.

Characteristics of Flavivirus

1. The virus is a small spherical shape, with a diameter of 40~70nm, the surface of the virus has a lipid envelope, which is embedded with a spike composed of glycoproteins, and the envelope is a 20-sided symmetrical nucleocapsid protein, and the center contains viral RNA.

2. Viral genomic nucleic acids are single-stranded positive-strand RNA. Viruses all proliferate in the cytoplasm.

3. The virus is sensitive to heat, lipid solvents and sodium deoxycholate, and is unstable under the condition of pH of 3~5.

4. The vector of transmission of the virus is arthropods (mosquitoes, ticks, sandflies, etc.). These arthropods are also reservoirs for viruses and are infected by the bites of humans, domestic animals, wild animals and birds.

Flavivirus genus

The genome of Flavivirus is a single-stranded positive-strand RNA, typically 9.6-12 kb in length. The genome has non-coding regions (UTRs) at each end, with the 3' end usually having a poly(A) tail. The genome of Flavivirus acts directly as mRNA, directing the synthesis of viral proteins. The proteins it encodes can be divided into three categories: structural proteins (C, prM, and E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). E protein is an important factor in the binding of viruses to host cells, and is responsible for the attachment and entry of viruses. NS3 and NS5 are key enzymes of Flavivirus and are involved in viral replication and transcription.

Fig.1 Structure of infectious particles of flavivirus. (Zhang Xingcui, et al., 2021)

Classification of Flaviviruses

The Flaviviridae family includes three genera, namely flavivirus, pestivirus and hepacivirus, with a total of more than 70 viruses. Because flaviviruses are similar to group A viruses in the family Phiviridae in terms of virion morphological structure, transmission vectors, and diseases caused, they were once classified as flaviviruses in the family Togaviridae. According to the characteristics of flavivirus genome structure, replication mode and morphogenetics, it was independently named Flaviviridae by the International Committee on Nomenclature of Viruses in 1986. It mainly includes Forest encephalitis virus, dengue virus, Japanese encephalitis virus and hepatitis C virus.

Tick-borne encephalitis virus

Forest encephalitis, also known as tick-borne encephalitis, tick-borne encephalitis virus belongs to the Flaviviridae family, a single-stranded positive-stranded RNA virus, spherical particles with a diameter of about 50 nm, symmetrical capsid icosahedron, and hemagglutinin glycoprotein expressed on the envelope, which is divided into European subtypes, Siberian subtypes and Far East Asian types. Far East Asian type, also known as Russia spring-summer encephalitis subtype, has more severe symptoms and a mortality rate of 5~35%. TBE is an acute infectious disease of the central nervous system caused by tick-borne encephalitis virus of the genus Flavivirus, with ticks as its transmission vector, clinically characterized by sudden high fever, meningeal irritation, impaired consciousness and paralysis, and often has sequelae. The disease was first documented in 1931, and in 1939 the Soviet scientist Zilber proved that the disease is transmitted to humans by ticks.

Flavivirus-related diseases

The diseases caused by flavivirus are diverse, and common clinical symptoms include fever, rash, headache, and muscle pain. Different Flaviviruses cause different diseases, but the most common ones are:

Dengue fever: Caused by the Dengue virus, which is mainly transmitted by Aedes mosquitoes. Dengue fever is characterized by fever, rash, and severe muscle and joint pain, and in severe cases, it can progress to dengue hemorrhagic fever or dengue shock syndrome, with a high case fatality rate.

Yellow fever: Caused by the yellow fever virus, mainly transmitted by the Egypt Aedes mosquito. Yellow fever is characterized by sudden onset of high fever, jaundice, and hemorrhage, and in severe cases, liver and kidney failure may occur, with high mortality.

Zika virus infection: Zika virus infection usually causes mild fever, rash, and arthralgia, but infection in pregnant women can lead to fetal microcephaly and other serious birth defects.

Treatment of Flavivirus

At present, there are no specific antiviral treatments for the diseases caused by Flavivirus, but a variety of drugs have been shown to have inhibitory effects on Flavivirus.

Tiratricol: An orally active thyroid hormone analogue that inhibits pituitary thyroid-stimulating hormone secretion. Tiratricol is also an intracellular toxin neutralizer that inhibits the cytotoxicity of LPS and lipid A with IC₅₀ of 20 μM and 32 μM, respectively. Tiratricol reduces TNF production in lipopolysaccharide-stimulated macrophages. Tiratricol also has antiviral activity and is an inhibitor of Flavivirus that binds to the RdRp domain of the viral NS5 protein to hinder YFV replication.

KIN1400: A potent IRF3 activator. KIN1400 triggers IRF3-dependent innate immune antiviral genes (RIG-I, MDA5, IFIT1, and Mx1) and IFN-β expression. KIN1400 inhibits WNV and DV, two mosquito-vector members of the genera Flaviviridae and Flavivirus. KIN1400 also inhibits HCV replication. KIN1400 Induction of innate antiviral immunity via the MAVS-IRF3 axis.

Lanatoside C: A cardiac glycoside that can be used in the study of congestive heart failure and arrhythmia, Lanatoside C acts on HuH-7 cells and is anti-dengue virus infection with an IC₅₀ of 0.19 μM.

Summary

As an important emerging infectious pathogen, Flavivirus is widely distributed in many regions of the world and poses a serious threat to human health. Although there are currently limited treatments for Flavivirus, scientists are working to develop more effective antiviral drugs and vaccines by studying its genome structure and infection mechanisms. With the deepening of research on Flavivirus, we are expected to effectively control the infectious diseases caused by Flavivirus in the future and reduce its threat to global public health.

Reference

• Zhang, Xingcui, et al., Structure and function of capsid protein in flavivirus infection and its applications in the development of vaccines and therapeutics. Veterinary research 52 (2021): 1-14.

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