Rabies is an ancient neuroinvasive viral (genus Lyssavirus, family
Rhabdoviridae) disease affecting approximately 59,000 people worldwide.
The central nervous system (CNS) is targeted, and rabies has a case
fatality rate of almost 100% in humans and animals. Rabies is entirely
preventable through proper vaccination, and thus, the highest incidence
is typically observed in developing countries, mainly in Africa and
Asia. However, there are still cases in European countries and the US.
Recently, demographic, increasing income levels, and the coronavirus
disease 2019 (COVID-19) pandemic have caused a massive raising in the
animal population, enhancing the need for preventive measures (e.g.,
vaccination, surveillance, animal control programs), post-exposure
prophylaxis, and a better understanding of rabies pathophysiology to
identify therapeutic targets, since there is no effective treatment
after the onset of clinical manifestations. Here we review the
neuroimmune biology and mechanisms of rabies. Its pathogenesis involves
a complex and poorly understood modulation of immune and brain functions
associated with metabolic, synaptic, and neuronal impairments, resulting
in fatal outcomes without significant histopathological lesions in the
CNS. In this context, the neuroimmunological and neurochemical aspects
of excitatory/inhibitory signaling (e.g., GABA/glutamate crosstalk) are
likely related to the clinical manifestations of rabies infection.
Uncovering new links between immunopathological mechanisms and
neurochemical imbalance will be essential to identify novel potential
therapeutic targets to reduce rabies morbidity and mortality.