A plethora of lyssaviruses, mostly associated with bats its ancestral reservoir host, are known today. All of those are potentially capable of causing rabies, a fatal zoonotic disease. Occasional spillover infections from bats to other mammals and human cases demonstrate the permeability of the species-barrier and highlight the zoonotic potential of bat-related lyssaviruses. To further characterize lyssavirus isolates particularly in regards to their pathogenicity and shedding, we established a standardized mouse infection model, using different inoculation routes and doses. Clinical sings, incubation periods and survival were used as parameters for a novel pathogenicity matrix to classify lyssavirus isolates. Using a total of 13 isolates from ten different phylogroup I lyssaviruses, this virulence index varied within and between virus species. Interestingly, Irkut virus (IRKV) and Bokeloh bat lyssavirus (BBLV) had higher virulence scores (1.14, 1.06) compared to the rabies viruses ranging between 0.85 and 0.19. On the contrary, shedding of viable virus was exclusively associated with RABV, thus providing a potential explanation for sporadic spillover infection of other bat lyssaviruses. Imaging of a selected panel of brain samples demonstrated for the first time that both neurons and astrocytes are infected by bat lyssaviruses.Altogether, our findings demonstrate a high diversity among lyssavirus isolates in our mouse model in regards to survival, incubation period and clinical signs. Our study design and matrix can provide the basis for a better comparison and risk assessment of lyssaviruses.
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