Rabies Virus Genome: Pathogenesis, Evolutionary Origins, and Immunological Perspectives

Rabies is a highly fatal neurological disease caused by rabies virus infection. We will introduce the structure of the virus, its transmission pathways, key pathogenic factors, and how it evades the host immune system. Additionally, based on genomic research, we analyze the evolutionary patterns of the virus to better understand its spread and provide scientific insights for rabies prevention and treatment.This article aims to systematically explore the characteristics, pathogenesis, evolution, and interactions of the rabies virus with the host immune system.

Rabies Virus and Pathogenesis of Rabies

Basic Characteristics of Rabies Virus

Rabies virus belongs to the genus Rabies virus in the family Rhabdoviridae. It has a unique shape and is bullet-shaped or rod-shaped. The virion is surrounded by an envelope, which is inlaid with glycoprotein spikes. These spikes play a key role in the recognition and binding process between the virus and the host cell. The interior of the virus is a helically symmetric nucleocapsid structure, which is formed by closely binding single-stranded minus-strand RNA to nucleoproteins, phosphoproteins and large proteins. Its genome is about 12kb long and contains 5 major genes, encoding nuclear protein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and large protein (L). These five proteins perform their duties during the replication, assembly and pathogenesis of the virus, and jointly maintain the biological characteristics and pathogenicity of the virus.

Figure 1.The successful implementation of the RABV life cycle depends on the preservation of the neuronal network.(Lafon, M.,2014)

Physiological Process of Rabies Disease

Rabies virus usually invades the human body through damaged skin or mucous membrane. First, it proliferates in a small amount of muscle cells near the wound, can stay locally for 3 days or more, and then invades the peripheral nerves near the human body. The virus spreads centripetal towards the central nerve along the axon of the nerve at a fast speed, and thrives in large numbers to the dorsal root ganglia of the spinal cord. It invades the spinal cord and quickly reaches the brain, mainly invading nerve cells in the brain stem, cerebellum, etc. After the virus replicates in large quantities in the central nervous system, it spreads to the whole body along the efferent nerves, especially the salivary glands, tongue taste buds, olfactory nerve epithelium and other parts. When the virus damages the vagus, glossopharyngeal and sublingual brain nerve nuclei, it will cause spasm of the swallowing muscles and respiratory muscles, causing patients to experience symptoms such as water phobia, swallowing and difficulty breathing; when the sympathetic nerve is involved, saliva secretion and sweating increase; When the vagus ganglion, sympathetic ganglion and cardiac ganglion are damaged, it can cause cardiovascular dysfunction or even sudden death in the patient.

Key Factors Influencing Pathogenesis

Viral virulence is one of the important factors affecting the incidence of rabies. The virulence of different strains is different, and virulent strains are more likely to break through host defenses and cause disease. The infection site is also crucial. If the nerves are densely distributed at the site where the virus invades, the virus can easily enter the nerve tissue quickly, and the onset time may be shorter. For example, head and face bites have a higher risk than limb bites. The immune status of the host is also critical. For individuals with strong immunity, the immune system can recognize and fight the virus more quickly, which may delay or even prevent the spread and disease of the virus; for those with low immune function, such as those suffering from immunodeficiency diseases and receiving immunosuppression, it is difficult for people treated to effectively resist the virus, and the chance of the disease is greatly increased and the condition is often more serious. In addition, the treatment of wounds and whether they are vaccinated in a timely manner will also have an impact on the incidence of the disease. Timely and standardized treatment of wounds and vaccination can significantly reduce the risk of the disease.

Evolutionary Origins and Phylogeny of Rabies Virus

Early Origins and Historical Studies

Early research on the traceability of rabies virus mainly relied on traditional epidemiological investigations and analysis of the biological characteristics of the virus. Researchers tried to outline the origin and transmission route of the virus by tracing information such as the geographical distribution, transmission routes and host types of rabies cases. At the same time, viruses are classified and traced back to the origin based on differences in biological characteristics such as pathogenic manifestations and serological reactions of the virus in different hosts. These studies initially determined the widespread distribution of rabies virus around the world and found that there are certain differences in different regions and host groups. However, due to technical limitations, it was difficult for early research to delve into the genetic level of the virus, and the understanding of the evolutionary relationship of the virus was relatively vague, making it impossible to accurately reveal the origin and evolution of the rabies virus.

Genomic Insights into Rabies Evolution

With the development of gene sequencing technology, it has become possible to use genomic data to study the evolution of rabies virus. Complete gene sequence information was obtained by sequencing the entire genome of rabies viruses from different regions and different host sources. Then, bioinformatics methods are used to compare and analyze these sequences to build a phylogenetic tree. In the phylogenetic tree, the genetic relationship of different virus strains is clear at a glance, and the evolutionary branches and trends of the virus can be clearly seen. At the same time, combined with information such as the sampling time and location of the virus, the evolution rate of the virus can be estimated and its spread and evolution in different historical periods can be inferred. Genome-based evolutionary analysis provides an accurate and comprehensive perspective for an in-depth understanding of the evolutionary history and laws of rabies virus, and helps reveal the origin, transmission path and genetic relationships between different strains of the virus.

Figure 2.ML consensus phylogenetic tree of canine RABV sequences.Holtz, A., et.al,2023)

Critical Evolutionary Milestones

During the evolution of rabies virus, multiple key mutations and branching events occurred. For example, mutations at certain gene loci lead to changes in the structure of viral glycoproteins, affecting the ability of the virus to bind to host cell receptors, thereby changing the host range and pathogenicity of the virus. These key mutations may adapt the virus to a new host environment and trigger new epidemics. In terms of evolutionary branches, viruses in different geographical areas have gradually formed unique evolutionary branches, reflecting that the virus is affected by factors such as geographical isolation and host differences during its spread. These key nodes not only record the evolutionary history of the virus, but also provide clues for understanding the epidemic laws of rabies. Studying these key nodes will help predict the evolutionary trend of the virus and provide scientific basis for the formulation of rabies prevention and control strategies.

Immunological Perspectives on Rabies

Initial Immune Response to Rabies Virus

When a human body is first exposed to the rabies virus, the immune system quickly activates defense mechanisms. First, physical barriers such as skin and mucous membranes will try to block virus invasion. If the virus breaks through this line of defense, inherent immune cells will immediately take effect. Dendritic cells act as the "sentinel" of the immune system, ingest and process rabies virus antigens and migrate to local lymph nodes. Here, dendritic cells present viral antigen information to naive T cells, activating the T cells 'immune response. At the same time, macrophages also devour viruses and release cytokines such as interferons. These cytokines not only inhibit virus replication, but also recruit more immune cells to the infection site to enhance the immune response. In addition, the complement system is also activated to help clear the virus through a series of cascade reactions, laying the foundation for subsequent specific immune reactions.

Role of Immune Cells in Rabies Defense

CD4+ T cells and B cells are pivotal for neutralizing antibody production, targeting the G protein to block viral entry. CD8+ T cells infiltrate infected neurons but often cause immunopathology due to delayed activation. Microglia and astrocytes contribute via cytokine release (e.g., IL-6, TNF-α), though excessive inflammation exacerbates neuronal damage. Passive immunization with rabies immunoglobulins (RIG) remains critical post-exposure, bridging the gap until vaccines induce active immunity.

Immune Evasion and Viral Persistence

Rabies virus has multiple strategies to evade attacks by the body's immune system, leading to persistent infection. On the one hand, viruses can change their own antigenic epitopes through genetic mutations, making them difficult for the immune system to recognize. For example, mutations in viral glycoproteins may prevent antibodies from effectively binding, reducing immune clearance. On the other hand, rabies virus can interfere with the function of immune cells. It can inhibit the expression of co-stimulatory molecules on the surface of immune cells and hinder the activation of T cells; it can also secrete some immunosuppressive factors and inhibit the activity and function of immune cells. In addition, rabies virus mainly replicates in nerve cells, and MHC-class I molecules on the surface of nerve cells are low expressed and are not easily recognized and killed by CTLs, which allows the virus to persist in nerve tissue. These immune escape mechanisms allow the rabies virus to evade the monitoring and clearance of the human immune system, continue to infect in the body, and ultimately cause severe rabies symptoms.

References:

1. Lafon, M. (2014). Rabies: Neurobiology. In: Bentivoglio, M., Cavalheiro, E., Kristensson, K., Patel, N. (eds) Neglected Tropical Diseases and Conditions of the Nervous System. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8100-3_14
2. Holtz, A., Baele, G., Bourhy, H. et al. Integrating full and partial genome sequences to decipher the global spread of canine rabies virus. Nat Commun 14, 4247 (2023). https://doi.org/10.1038/s41467-023-39847-x