Lyssavirus phosphoproteins reorganize microtubule architecture

Rabies is a viral infection 100% fatal in non-immunized mammals, including humans. The rabies lyssavirus causes severe neurological disease with over 60,000 human deaths each year. Currently, the approved treatment is only a suboptimal 4-dose regimen over 2-3 weeks and not readily available in the countries where the virus is prevalent. To develop a more effective treatment, we should first understand the viral mechanism for disease progression at the molecular level. From an imaging perspective, super-resolution single molecule localization techniques are ideal for subdiffraction ( > 200 nm resolution) visualization of changes to cellular structures and function, inflicted by viral agents. For example, the microtubule (MT) network is a common target for viral hijacking to subvert and inhibit MT-dependent cellular processes. In collaboration with virologist Dr. Gregory Moseley, we have shown that phosphoprotein-3 (P3) of the pathogenic Nishigahara rabies virus (Ni) binds to and causes MT bundling up to 300 nm wide. Furthermore, we determined a single mutation in pathogenic Ni-P3 (N226-H) inhibits this bundling effect comparable to an attenuated Ni strain Ni-CE. The presence of bundles correlates with an increased association of transcription factor STAT1 to MTs, antagonizing interferon-dependent antiviral responses that results in disease lethality.