Vesicular stomatitis virus (VSV)

Blistering stomatitis is an acute, highly contagious zoonotic infectious disease, especially in domestic animals such as horses, cattle and pigs. The disease is caused by the vesicular stomatitis virus and has been listed as one of the notifiable diseases under the International Office of Epizootics (OIE). VSV is widely used in a wide range of mammals, and its clinical manifestations are similar to those of foot-and-mouth disease and swine vesicular disease, so it is highly confusing in the process of disease diagnosis. Accurate diagnosis is important to control the outbreak and spread of this disease.

The clinical symptoms caused by VSV infection are mostly blisters in the mouth, tongue, nose, hooves and other parts, which seriously affects the health and economic benefits of animals. Although VSV is rarely endemic in humans, it can occasionally be contracted by experimenters and people who have close contact with infected animals. VSV is not only significant in the veterinary field, but also of interest in the biomedical field due to its potential oncolytic properties.

What is vesicular stomatitis virus?

Vesicular stomatitis virus (VSV) is a non-pathogenic, enveloped, negative-strand RNA rhabdovirus that mainly infects rodents, cattle, pigs, and horses, among others, and has a very low prevalence in the human population, with only a few cases of infection among animal keepers and laboratory personnel. Symptoms are mild or asymptomatic after infection.

VSV can infect almost all types of cells, but cannot trigger a productive infection in healthy cells due to a type I interferon (IFN)-mediated antiviral response. However, defects in IFN signaling often occur at the same time as tumorigenesis. Therefore, VSV is able to infect and selectively destroy cancer cells with minimal damage to normal cells, and at the same time, the general population has low anti-VSV immunity, which makes it an ideal oncolytic viral therapeutic.

Transmission of VSV

VSV can be transmitted in a variety of ways, mainly infecting mammals and insects. Naturally infected livestock include horses, cattle, sheep and pigs. Serological tests have shown that wild animals such as wild boars, raccoons, and deer can also be naturally infected with VSV. Antibodies to IND-1 VSV have been found in the blood of arboreal and semi-arboreal animals in Panama, while antibodies to NJ VSV have been found in bats, carnivores, and some rodents.

In humans, VSV infection occurs mainly in people who are in close contact with domestic animals, such as farm workers, animal keepers, and laboratory researchers. Although VSV is less transmissible in humans, mild infections may occur after contact with infected animals in endemic areas.

Vesicular stomatitis virus genome

The total length of VSV genome is 11161nt, From the 3' end to the 5' end, five proteins are encoded: Nucleocapsid Protein(N), Phosphor Protein(P), Matrix Protein(M), Glycol Protein(G), and Large Polymerase Protein(L). The G protein on its envelope initiates the viral infection process by binding to a variety of molecules that are widely present on the surface of the cell membrane. M proteins have been shown to inhibit innate antiviral responses and alter host transcriptional mechanisms, ultimately forcing tumor cell apoptosis. VSV's extensive cytotropism is based on G proteins, and in order to improve the safety and selectivity of VSV's oncolytic vectors, membrane proteins of other viruses are usually substituted.

Fig.1 The structure of VSV and its genome. (Liu Guodong, et al., 2021)

Vesicular stomatitis virus protein

VSV is made up of five main proteins: N, P, M, G, and L proteins. These proteins work closely together to ensure viral replication, transcription, assembly, and budding. The N protein encapsulates viral RNA to form a nucleocapsid to protect RNA stability. The P protein is part of the viral polymerase complex and helps RNA replication and transcription. The M protein not only plays a key role in viral assembly, but also inhibits the host's antiviral response. The G protein triggers viral infection by binding to receptors on the surface of host cells. The L protein is responsible for the replication of the viral genome and the synthesis of mRNA.

Treatment for vesicular stomatitis virus

Currently, treatment for vesicular stomatitis virus is focused on the study of vaccines and antiviral drugs. Despite the transmissibility of VSV, there is currently no widely effective vaccine that can completely control the spread of VSV.

VSV vaccine

Due to the widespread infectivity and variability of VSV, the development of safe and effective vaccines has been a challenge. Currently, there is no commercially available VSV vaccine on the market. Although both live (attenuated) and inactivated vaccines have been developed, they have not been widely promoted due to their potential safety concerns and unsatisfactory vaccine protection. Some studies have explored the possibility of recombinant vaccines, such as vaccinia virus vaccines expressing the VSV G protein gene, which have shown some protective effect in experiments, but have not been widely used due to their pathogenicity to humans. In addition, research on DNA-based vaccines and protein-based vaccines is also ongoing, but the immune effect in cattle, horses and other animals still needs to be further verified.

In some countries in South America, such as Guatemala, Colombia and Venezuela, inactivated oil seedlings produced from chicken embryos have been used, but because their effects have not been rigorously tested, standardized vaccine prevention and control measures have not yet been formed. Therefore, in the event of a VSV outbreak, the first measures remain isolation, lockdown and disinfection. In addition, control against insects and parasites that transmit VSV is also considered an important preventive measure.

Antiviral therapy

Antiviral therapy for VSV focuses on drugs that inhibit viral replication and alleviate symptoms of infection. The following compounds have demonstrated experimental activity against VSV:

Diphyllin: Aryl naphthalene lignans extracted from the plant Justicia procumbens, is a potent HIV-1 inhibitor with activity against both vesicular stomatitis virus and influenza viruses. Diphyllin blocks viral replication by inhibiting the activity of V-ATPase. In addition, Diphyllin also exhibits certain anticancer and anti-inflammatory activities.

Octyl Gallate (Progallin O): A commonly used food additive with antibacterial and antioxidant effects. Experiments have shown that Octyl Gallate has significant antiviral activity against VSV, as well as inhibitory effects on HSV-1 (herpes simplex virus) and poliovirus.

UNC0638: It selectively inhibits G9a and GLP histone methyltransferase with IC₅₀ of 15 nM and 19 nM, respectively. UNC0638 has anti-FMDV (foot and mouth disease virus) and anti-VSV activities.

Summary

Vesicular stomatitis virus is a highly contagious virus that widely infects a wide range of mammals. Although rare in humans and mild in symptoms, it can cause serious economic losses in domestic animals. Through in-depth research on the genome, protein composition and transmission pathways of VSV, scientists have gradually revealed the pathogenic mechanism and transmission mode of the virus. However, there are still many challenges in the development of vaccines and antiviral treatments for VSV. With the advancement of oncolytic virus research, the potential application of VSV will not be limited to the field of veterinary medicine, but is expected to play a greater role in cancer treatment in the future.

Reference

• Liu, Guodong, et al., Vesicular stomatitis virus: from agricultural pathogen to vaccine vector. Pathogens 10.9 (2021): 1092.

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