Every year in the spring and summer, china's northeast region, including the Daxing'an Mountains and changbai mountains, should be vigilant against a blood-sucking ectoparasite, the tick. Tick bite-borne flavivirus tick-borne encephalitis virus (TBEV), infection of people can lead to encephalitis, meningitis and other central nervous system diseases and death.
The tick-borne encephalitis virus was discovered in the 1930s and was first isolated in 1937. This neurotropic virus, belonging to the flaviviridae genus flaviviridae of the flaviviridae family, has a spherical lipid-encapsulated single positive chain RNA virus. Structural proteins consist of capsid proteins (C), membrane proteins (M), and envelope glycoproteins (E), where E protein is an important antigen capable of inducing hosts to produce neutralizing antibodies. The virus has three genotypes: the European subtype, the Siberian subtype, and the Far East Asian type.
Tick-borne encephalitis (TBE) is highly prevalent in Europe, Siberia, northern China and Japan, and the case fatality rate of this acute infectious disease is as high as 10%-20%, which is the focus and difficulty of virology expert research in recent years. In addition to humans, the virus can also infect a large number of forest animals, such as bears, wild boars, horses, deer, squirrels, marmots and various birds, so it is also known as forest encephalitis.
From a preventive point of view, tick-borne encephalitis has a variety of inactivated and attenuated vaccines. Just in August 2021, the U.S. Food and Drug Administration (FDA) approved the Pfizer TICAVAC vaccine for the prevention of tick-borne encephalitis (TBE) infection in people 1 year of age and older. The TICOVAC vaccine is also the only FDA-supported tick-borne encephalitis vaccine in the United States. In general, tourists, loggers, etc. who travel to forest areas are best vaccinated to prevent infection.
However, the team of Cui Zongqiang, Wuhan Institute of Virology/Big Science Center for Biosafety, Chinese Academy of Sciences, mentioned in a recently published study that there are more than 13,000 clinical cases of tick-borne encephalitis worldwide every year, and the number of cases has increased in the past few decades. Despite the availability of a vaccine against the virus, it remains one of the leading pathogens of central nervous system infections in Europe and Northeast Asia. As of now, there is no specific and effective treatment for this virus.
Tick-borne encephalitis viruses have been discovered for more than 80 years, but their cell receptors are unknown, hindering the understanding of the pathogenic mechanisms of viral infections and the development of antiviral drugs. Cui Zongqiang's team's research is the first to find that T-cell immunoglobulin domain mucin domain protein-1 (TIM-1) is a functional receptor for tick-borne encephalitis virus, revealing a key mechanism for tick-borne encephalitis virus invasion.
The study has been officially published in mBio, an authoritative journal in the field of microbiology research, and Cui Zongqiang is the corresponding author of the study. The research has been supported by the Strategic Pilot Science and Technology Project of the Chinese Academy of Sciences, the National Natural Science Foundation of China, the Frontier Science Key Research Project of the Chinese Academy of Sciences, and the Open Project Fund of the Key Laboratory of Molecular Viruses and Immunology of the Chinese Academy of Sciences.
Previous studies have shown that the life cycle of tick-borne encephalitis virus begins with virions attaching to receptors on the surface membrane of host cells, which subsequently leads to receptor-mediated endocytosis. The process by which a tick-borne encephalitis virus enters a target cell requires it to act as a host molecule that enters a factor or cell receptor.
Cui Zongqiang et al. mentioned that although some cell surface molecules are thought to play a role in virion attachment, little is known about the intermolecular interactions that mediate the entry of tick-borne encephalitis viruses, and the host factors involved in tick-borne encephalitis virus entry have not been identified and characterized. In this study, the team provided several pieces of evidence that TIM-1 is a key host factor for tick-borne encephalitis virus entry.
According to the introduction of the study by the Wuhan Institute of Virology of the Chinese Academy of Sciences, through mass spectrometry analysis of virus-binding cell membrane proteins, the research team screened out a host protein TIM-1 that can bind to tick-borne encephalitis virus particles. Ectopic expression of TIM-1 significantly enhances the susceptibility of nonsensitive cells to tick-borne encephalitis virus.
Subsequently, through gene knockout and viral genomic RNA transfection tests, the research team confirmed that TIM-1 plays a role in the invasive phase of the viral replication cycle. TIM-1 and virions can be co-internalized into host cells. Inhibition of TIM-1 protein function through gene knockout, gene knockout, antibody blocking, etc., can significantly inhibit viral infection with cells such as A549 and Vero. In primary tubular epithelial cells (RTEs) expressing TIM-1, antagonism to TIM-1 also significantly reduces the level of viral infection.
Further, the research team constructed a mouse model of TIM-1 gene knockout, confirming the role of TIM-1 receptors in viral infection and pathogenesis in animals. Simulating the tick bite pathway, infecting mice with virus through foot pad injection, it was found that TIM-1 gene knockout can significantly inhibit the infection and replication of viruses in peripheral blood and brain, kidney, lung and other tissues and organs. Compared with normally functioning mice, TIM-1 gene knockout significantly reduced mortality, prolonged survival, and alleviated neurological symptoms such as muscle tremor, hindlimb paralysis, and ataxia.
TIM-1 mediates tick-borne encephalitis virus invasion.
At the same time, it is worth noting that the paper also mentions that anti-TIM-1 antibodies do not completely inhibit tick-borne encephalitis virus infection. In addition, comparable levels of viral load can be detected in both TIM-1 knockout and normally functioning spleens, suggesting that there may be other pathways of entry.
Therefore, the research team believes that the TIM-1-mediated entry may be one of the main mechanisms of tick-borne encephalitis virus entry, but not the only way.
The research team concluded that the study found the first functional receptor of TBEV, revealing the key role of TIM-1 receptors in mediating viral invasion, which has implications for understanding the mechanism of infection and transmission of viruses, and helps to develop new antiviral targets and strategies.
Thesis link: https://journals.asm.org/doi/10.1128/mbio.02860-21