Rabies Outbreak in Timor-Leste: Mechanisms, Prevention, and Research Solutions

Between May and June 2025, Timor-Leste reported four fatal human rabies cases within a single month. All patients had been bitten or scratched by dogs months earlier and did not receive timely post-exposure prophylaxis (PEP), leading to their deaths due to disease progression. On July 24, the World Health Organization (WHO) issued a statement classifying the public health risk at the national level as “high,” drawing global attention. Rabies is not unique to Timor-Leste; cases have been reported in many countries and regions worldwide. If bitten and the skin is broken, immediate medical attention to clean the wound, followed by prompt administration of rabies immunoglobulin and vaccine, is the only way to prevent rabies onset and save lives. Rabies remains one of the leading viral causes of human mortality, with an estimated 59,000 deaths globally each year, mostly among children.

Rabies is a zoonotic, viral, and fatal infectious disease caused by the rabies virus (RABV), primarily transmitted through the saliva of infected animals. Once the virus enters the body and triggers clinical symptoms, the mortality rate is nearly 100%. The virus invades the brain, replicating extensively, spreading, and destroying nerve cells, leading to symptoms such as agitation or paralysis, followed by throat muscle spasms, respiratory failure, and ultimately death.

RABV belongs to the order Mononegavirales, family Rhabdoviridae, genus Lyssavirus. The virus particle has a flat or slightly concave end and a hemispherical or bullet-shaped end, with a diameter of approximately 75–80 nm and a length of 170–180 nm. The virus is enveloped, with 6–7 nm spike-like protrusions on its surface, formed by trimeric viral glycoproteins (G protein). The inner layer of the envelope contains the matrix protein (M protein). The core consists of a tight, helical nucleocapsid, about 50 nm in diameter, composed of single-stranded RNA, nucleoprotein (N protein), large protein (L protein), and phosphoprotein (P protein).

N protein (P16285): Encapsulates the negative-strand RNA at a ratio of 9 nucleotides per N protein, forming a "pearl necklace"-like nucleocapsid (NC). It protects the RNA and serves as a template for transcription and replication.

P protein (P22363): Acts as a polymerase cofactor, stabilizing the L protein's binding to N-RNA, suppressing host interferon signaling, and promoting immune evasion.

M protein (P16287): Envelops the nucleocapsid, maintaining the virus's bullet-shaped structure, regulating transcription and replication, and inducing neuronal apoptosis.

G protein (P03524): Mediates viral binding to host receptors (e.g., nAChR, NCAM), triggering endocytosis and membrane fusion, facilitating viral entry.

L protein (P16289): An RNA-dependent RNA polymerase that catalyzes mRNA transcription, capping, and polyadenylation, driving viral gene expression.

The rabies virus (RABV) primarily enters the body through bites from infected animals. Initially, the virus remains latent at the wound site for days to weeks before migrating retrogradely along peripheral nerves to the central nervous system (CNS). Once in the CNS, it causes fatal, irreversible neurological damage and encephalitis. During this process, key viral proteins play critical roles: the P protein suppresses host interferon signaling, weakening innate antiviral immunity; the M protein induces neuronal apoptosis, impairing neurological function; and the G protein not only mediates viral entry into neurons but also facilitates trans-synaptic spread, a key factor in viral dissemination within the nervous system. Ultimately, the virus spreads to the salivary glands, where it replicates extensively in epithelial cells, particularly producing high levels of G protein to promote viral assembly and release into saliva. This makes the saliva of infected animals a primary transmission route through bites. Thus, salivary gland infection is a critical step in RABV transmission.

Once rabies symptoms appear, the disease is nearly always fatal. Neutralizing antibodies are currently the only way to clear the virus from the body. However, in 2004, a girl in the United States was successfully treated using the Milwaukee Protocol, offering a glimmer of hope for curing rabies. This protocol induces a coma to slow viral spread in the nervous system, using a combination of drugs including ketamine, antiviral agents (ribavirin, amantadine), sedatives, and anticonvulsants. By day 7, the patient began producing antibodies, awoke on day 10, and tested negative for the virus by day 31. Despite this success, the method is highly risky, its mechanisms are not fully understood, and subsequent attempts have largely failed, making it unsuitable as a standard treatment.

1. Vaccination: Traditional inactivated vaccines require multiple doses, while novel mRNA vaccines (e.g., RABV-G-LT) show greater protective potential by simultaneously inducing neutralizing antibodies and T-cell immunity.

2. Immune Mechanism Research: T-cell immunogens targeting conserved viral proteins (e.g., L protein) can enhance broad-spectrum protection against various strains.

The high lethality of rabies is closely tied to its sophisticated immune evasion mechanisms. In-depth analysis of viral protein structures and functions (e.g., G protein’s receptor-binding properties and L protein’s transcriptional regulation) provides targets for novel vaccine design and lays the foundation for developing targeted antiviral drugs. With advancements in mRNA vaccine technology and immune mechanism research, humanity may gradually shift from a reactive to a proactive stance against this deadly virus, opening new pathways for global rabies control.

abinScience, a France-based biotechnology company, specializes in developing and producing high-quality research reagents. We are committed to providing innovative and reliable tools and technical solutions for life science researchers worldwide. Below is a list of RABV-related protein and antibody products offered by abinScience:

References:
1. Ramzan, Y., Fadhl, B.M., Niazai, S. et al. Decoding the transmission and subsequent disability risks of rabineurodeficiency syndrome without recuperation. Sci Rep 15, 17322 (2025). https://doi.org/10.1038/s41598-025-01066-3

2. Bai, S., Pan, X., Yang, T. et al. Rabies virus large protein-derived T-cell immunogen facilitates rapid viral clearance and enhances protection against lethal challenge in mice. Commun Med 5, 127 (2025). https://doi.org/10.1038/s43856-025-00851-5