**3.1 Pathophysiology**

The most common entry point for RABV is through the bite of an infected individual as rabies resides in saliva [22]. However, transmission from organ transplants and aerosol droplets have also been recorded [23–25]. Upon entry, an incubation period often takes place in the myocytes, and rarely fibrocytes, where the virus attaches to the G-protein of the cells, enters through pinocytosis or fusion, and replicates in the cytoplasm of the cells [5, 24]. Virions will replicate with little to no immune response

#### *The Diagnosis, Clinical Course, Treatment, and Prevention of the Rabies Virus DOI: http://dx.doi.org/10.5772/intechopen.97691*

until the virus interacts with and infects a nerve cell. The rabies virus gains access to the nervous system by binding to the nicotinic acetylcholine receptors on the postsynaptic membrane at the neuromuscular junction [26]. From the point of nerve cell infection, the virus will travel via axon transport through the nervous system, eventually reaching the brainstem to give rise to either encephalitis or acute flaccid paralysis [7, 27]. The incubation periods are highly variable depending on the dosage of the virus. However, in humans, the incubation period is often >1–3 months. Canine incubation periods are most commonly less than 60 days [26, 28].

Once infection is recognized by the immune system, cytokine, IgM, and IgG antibody production increases [5]. Specific cytokines, Interleukin-1β (IL-1β) and TNFα, are thought to be the reason inflammation of the central nervous system occurs postexposure [29]. The presence of these cytokines initiate a cascade reaction, upregulating proteins necessary for the inflammatory response such as the major histocompatibility complex and adhesion molecules. These proteins then interact with leukocytes to allow the blood brain barrier to become more permeable, thus causing an immune response leading to encephalitis [30]. As for the natural defense against rabies, RABV signals a series of molecular cascades that initiates type I interferon responses that have antiviral properties, decreasing the pathogenicity of rabies [31]. However, to artificially aid the natural response, there is heavy research on the potential to activate dendritic cells which subsequently enhance the activity of interleukin proteins and high mobility group box 1 (HMBG1) to enhance immunogenicity [32, 33].
