Subversion of the Immune Response by Rabies Virus

Rabies is one of the oldest known zoonoses and poses significant challenges due to the limited understanding of how rabies virus (RABV) evades the immune system and kills its host.
This review discusses the complex interactions between RABV and the immune system, methods of immune evasion, and other influential factors that affect morbidity and mortality.
Focus on the various proteins of RABV, their role in immune evasion, and highlights important therapeutic targets for rabies treatment.

Rabies has affected mankind for centuries despite advancements such as the development of the first rabies vaccine by Louis Pasteur.
Majority of human cases result in death due to circulatory insufficiency, but the mechanism of viral infection leading to this outcome is poorly understood.
Exploration of immune evasion tactics by RABV and multiple aspects of the virus's interaction with the immune system.

Younger individuals are more susceptible to RABV infections, shown through studies with mice, dogs, and cats demonstrating age-related variations in immune response levels.
Extended age also leads to a gradual decline in immune responses, and older individuals exhibit lower vaccine response.

The efficacy of rabies vaccines is highly dependent on their administration timing relative to exposure.
Vaccination post-exposure can prevent symptoms only if administered before the onset of clinical signs.

Sexual dimorphism plays a critical role in immune response, with males generally being more susceptible to infections.
Studies show female mice outperformed males in resisting RABV infections after equal challenge doses.

Ambient temperature affects immunity; optimal conditions lead to better immune response efficiency.
Mice housed at optimal temperatures show reduced incubation periods and lower mortality rates from RABV inoculation.

Genetic variations among different strains can cause varying immune responses to RABV. Certain inbred mouse strains show significant resistance or susceptibility to infection.

Study results can vary significantly depending on animal models used (canine vs. murine). Murine models are often easier to manage but may not accurately reflect RABV paths in natural infections.

Lateralization affects behavior and immune responses, with differences noted in various species, including dogs.
Studies show left-pawed dogs expressed lower levels of neutralizing antibodies compared to right-pawed individuals, indicating paw preference correlates with immune response.

RABV enters the host typically via bites, with glycoproteins binding to acetylcholine receptors allowing it to evade early immune responses.
Initial low-level replication in muscle delays immune detection, facilitating neuroinvasion.

RABV can replicate in lymphocytes and may use immune cells like dendritic cells as carriers to infect nervous tissues.
Active infection and replication from macrophages may depend on the host’s age and immune cell maturity.

Apoptosis can inhibit viral replication or serve as an immune evasion strategy, depending on the context.
The relationship between RABV proteins, apoptosis levels, and immune response effectiveness varies between pathogenic and attenuated strains.

Apoptosis is proposed to limit virus spread by eliminating infected neurons, but findings vary widely based on species and strain.

RABV may intentionally induce apoptosis in infiltrating immune cells to prevent viral clearance while preserving infected neurons for replication.

The P protein of RABV interferes with the IFN signaling pathway, impairing both innate and adaptive immune responses.

The N protein encapsidates viral RNA, preventing recognition by the innate immune system and aiding in immune evasion.

The M protein assists in viral replication and also plays a role in immune interception.

RABV inhibits innate responses early in infection to facilitate rapid infection, subsequently manipulating adaptive immune responses for its advantage.

RABV uses various strategies to exploit and evade the immune system effectively to ensure replication and survival.
Continued research into RABV's mechanisms and potential therapeutic interventions is critical as rabies remains a global health priority.