Comparative pathogenesis of different phylogroup I bat lyssaviruses in a standardized mouse model

Abstract

A plethora of bat-associated lyssaviruses potentially capable of causing the fatal disease rabies are known today. Transmitted via infectious saliva, occasionally-reported spillover infections from bats to other mammals demonstrate the permeability of the species-barrier and highlight the zoonotic potential of bat-related lyssaviruses. However, it is still unknown whether and, if so, to what extent, viruses from different lyssavirus species vary in their pathogenic potential. In order to characterize and systematically compare a broader group of lyssavirus isolates for their viral replication kinetics, pathogenicity, and virus release through saliva-associated virus shedding, we used a mouse infection model comprising a low (102 TCID50) and a high (105 TCID50) inoculation dose as well as three different inoculation routes (intramuscular, intranasal, intracranial). Clinical signs, incubation periods, and survival were investigated. Based on the latter two parameters, a novel pathogenicity matrix was introduced to classify lyssavirus isolates. Using a total of 13 isolates from ten different virus species, this pathogenicity index varied within and between virus species. Interestingly, Irkut virus (IRKV) and Bokeloh bat lyssavirus (BBLV) obtained higher pathogenicity scores (1.14 for IRKV and 1.06 for BBLV) compared to rabies virus (RABV) isolates ranging between 0.19 and 0.85. Also, clinical signs differed significantly between RABV and other bat lyssaviruses. Altogether, our findings suggest a high diversity among lyssavirus isolates concerning survival, incubation period, and clinical signs. Virus shedding significantly differed between RABVs and other lyssaviruses. Our results demonstrated that active shedding of infectious virus was exclusively associated with two RABV isolates (92% for RABV-DogA and 67% for RABV-Insectbat), thus providing a potential explanation as to why sustained spillovers are solely attributed to RABVs. Interestingly, 3D imaging of a selected panel of brain samples from bat-associated lyssaviruses demonstrated a significantly increased percentage of infected astrocytes in mice inoculated with IRKV (10.03%; SD±7.39) compared to RABV-Vampbat (2.23%; SD±2.4), and BBLV (0.78%; SD±1.51), while only individual infected cells were identified in mice infected with Duvenhage virus (DUVV). These results corroborate previous studies on RABV that suggest a role of astrocyte infection in the pathogenicity of lyssaviruses.

From Field Tests to Molecular Tools—Evaluating Diagnostic Tests to Improve Rabies Surveillance in Namibia

“…Besides molecular confirmation, we also anticipated an increase in the level of surveillance by decentralized testing using LFDs. Generally, Anigen/Bionote rabies LFD performance demonstrated an almost perfect agreement compared to the FAT ( Table 3 ) which partly corresponds to previous assessments, e.g., [ 28 , 29 , 30 ], whereas other studies found a poorer sensitivity [ 21 , 31 ]. The results indicate that testing of fresh brain samples in the field results in higher sensitivity compared with testing at a later time point at a central veterinary laboratory ( Figure 2 ).…”

Structural Determination of the Australian Bat Lyssavirus Nucleoprotein and Phosphoprotein Complex

“…Because ABLV also has serines at positions 63, 210, and 271, it may also be phosphorylated in a similar manner. Although, clearly, further research is needed to understand non-RABV lyssaviruses like ABLV, there may be differences because when compared in terms of pathogenicity and replication kinetics, ABLV grows more slowly than RABV, and the incubation period can be as long as 27 months [ 49 , 50 ].…”

Glu333 in rabies virus glycoprotein is involved in virus attenuation through astrocyte infection and interferon responses

“…Evidently, ERA strain comprising Arg 333 in the G protein showed diminished infection of astrocytes ( Potratz et al., 2020 ), which further supports the G333-dependent astrocyte infection. Controversially, recent studies have shown that other field RABV strains or even some bat-associated lyssaviruses could cause infection in astrocytes regardless of the amino acid at G333 or pathogenicity ( Potratz et al., 2020 ; Klein et al., 2022 ). Based on these previous findings, we note that the amino acid at position 333 alone is not sufficient to determine astrocyte tropism of all RABV strains.…”