Host-Response Inhibitors

Rabies encephalitis is not just an invariably deadly disease, patients with rabies experience an agonizing final stage of their life, due to the effect of the virus infection on neuronal function. Patients with rabies are fully aware of their neurological symptoms before succumbing to coma and death. Histopathological changes in the form of inflammation or cell death are not evident in the majority of rabies victims.

Several lines of research suggest that RABV interferes with neuronal function; however the pathogenesis of rabies is not completely elucidated. ASKLEPIOS partners are in close collaboration with other EU- funded projects (ANTIGONE), in which mechanisms that govern the pathogenesis of lyssaviruses are being elucidated and in particular mechanisms of cell death and innate immune response.

It is already known that neither necrosis, nor caspase-9 dependent apoptosis play an important role in RABV infections. Within “ANTIGONE”, evidence has been acquired that a novel mechanism of cell death named pyroptosis is associated with RABV infections. This obligatory pro-inflammatory pathway is associated with Caspase-1 (CASP-1) induction and production of proinflammatory cytokines IL1β and IL18. This pathway has been involved in the pathogenesis of bacterial infections and inhibition of key molecules such as CASP-1 improves disease outcome in in vivo models of bacterial infection. Pyroptosis is also involved in neurodegenerative diseases and in animal models of ischemic brain injury, and inhibition of CASP-1 induced cell death has been proven neuroprotective.

Genomic profile signatures of RABV and other lyssavirus infections have also shown up-regulation of genes in the brains of infected animals that in spite of being part of the host immune response, could be harmful when expressed in excess amounts. For instance, high levels of the inflammatory cytokines TNF-α and IL-6 have been associated with detrimental outcome of dengue virus infections as well as neurodegenerative autoimmune diseases such as multiple sclerosis. The pathogenesis of several neurodegenerative diseases is attributed to detrimental host responses. A successful example of inhibition of host response has been shown with p38 MAP kinase, which is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. Besides key regulator effects of cellular signalling, MAP kinase pathways may contribute to virus replication. Inhibition of p38 activity reduces influenza virus replication; therefore it is a potential novel antiviral therapy for influenza. p38 inhibitors can reduce neuronal sensitization in animal models of neuropathic pain. While ANTIGONE will identify host responses involved in the pathogenesis of rabies encephalitis, ASKLEPIOS will take this knowledge a step further, to validate the therapeutic potential of inhibiting such responses. Investigations will be focused on the effect of MAP kinase inhibition on the replication of RABV in the host cells in vitro, as well as the effect on the course of rabies encephalitis in the in vivo mouse model.