Altered Spatial and Temporal Gait Parameters in Mice Infected with Ross River Virus.

Eranga Abeyratne,Ali Zaid,Xiang Liu,Ronak Reshamwala,Adam Taylor,Todd Shelper,Suresh Mahalingam

doi:10.1128/msphere.00659-21

Abstract

ABSTRACTInfection with mosquito-borne arthritogenic alphaviruses, such as Ross River virus (RRV) and Barmah Forest virus (BFV), can lead to long-lasting rheumatic disease. Existing mouse models that recapitulate the disease signs and immunopathogenesis of acute RRV and BFV infection have consistently shown relevance to human disease. However, these mouse models, which chiefly model hindlimb dysfunction, may be prone to subjective interpretation when scoring disease. Assessment is therefore time-consuming and requires experienced users. The DigiGait system provides video-based measurements of movement, behavior, and gait dynamics in mice and small animals. Previous studies have shown DigiGait to be a reliable system to objectively quantify changes in gait in other models of pain and inflammation. Here, for the first time, we determine measurable differences in the gait of mice with infectious arthritis using the DigiGait system. Statistically significant differences in paw area and paw angle were detected during peak disease in RRV-infected mice. Significant differences in temporal gait parameters were also identified during the period of peak disease in RRV-infected mice. These trends were less obvious or absent in BFV-infected mice, which typically present with milder disease signs than RRV-infected mice. The DigiGait system therefore provides an objective model of variations in gait dynamics in mice acutely infected with RRV. DigiGait is likely to have further utility for murine models that develop severe forms of infectious arthritis resulting in hindlimb dysfunction like RRV.IMPORTANCE Mouse models that accurately replicate the immunopathogenesis and clinical disease of alphavirus infection are vital to the preclinical development of therapeutic strategies that target alphavirus infection and disease. Current models rely on subjective scoring made through experienced observation of infected mice. Here, we demonstrate how the DigiGait system, and interventions on mice to use this system, can make an efficient objective assessment of acute disease progression and changes in gait in alphavirus-infected mice. Our study highlights the importance of measuring gait parameters in the assessment of models of infectious arthritis.

Highlights

IMPORTANCE Mouse models that accurately replicate the immunopathogenesis and clinical disease of alphavirus infection are vital to the preclinical development of therapeutic strategies that target alphavirus infection and disease
Arthritogenic alphavirus-infected mice require intervention to run on the DigiGait apparatus during peak acute disease
The established murine models of acute River virus (RRV) and Barmah Forest virus (BFV) disease rely on the observable development of musculoskeletal pathology

Summary

Introduction

IMPORTANCE Mouse models that accurately replicate the immunopathogenesis and clinical disease of alphavirus infection are vital to the preclinical development of therapeutic strategies that target alphavirus infection and disease. Mouse models that recapitulate the disease signs and immunopathogenesis of RRV and BFV infection have been developed to dissect virus-induced inflammation [7] These models have consistently shown relevance to human disease, with significant overlap in both the soluble and cellular immune factors identified throughout the course of disease in infected humans and mice [8]. Multiple murine models of infectious arthritis, including the C57BL/6 models of RRV and BFV infection, monitor gait to some extent when determining clinical scores [17] These models, on the whole, rely heavily on subjective semiquantitative measures of gait, for example, the severity of lethargy, hindlimb weakness, or lameness. This type of analysis is open to individual interpretation and requires experienced users

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