A Mouse Model for Studying Post-Acute Arthritis of Chikungunya

Abstract

Chikungunya virus (CHIKV) was introduced to the Americas in 2013, causing two million infections across over thirty countries. CHIKV causes a chronic debilitating arthritis in one fourth of infected individuals and currently evidence-based targeted therapies for the treatment of CHIKV arthritis are lacking. Multiple mouse models of chikungunya have been developed to study acute CHIKV infection. In humans, post-CHIKV arthritis may persist for months to years after viremia from a CHIKV infection has resolved. Therefore, the development of a mouse model of post-acute arthritis of chikungunya may facilitate the study of potential novel therapeutics for this arthritis. In this article we describe the development of a wild-type immunocompetent C57BL/6 mouse model for post-acute arthritis of chikungunya, including a histologic inflammation scoring system, as well as suggestions for how this mouse model may be used to examine the efficacy of novel therapies for CHIKV arthritis.

Keywords: arthritis; arthritis therapy; bone erosion; chikungunya; mouse model; myositis; synovitis.

Figure 1

Chikungunya viremia in PFU/mL per mouse by days post infection (DPI). This graphical representation shows viremia in PFU/mL per infected mouse (black lines) and per uninfected control mice (red lines), as well as the average curve for infected mice (blue lines).

Figure 2

Foot swelling in inoculated foot (arrow) 7 days post inoculation. Note swelling appreciated in the left foot without swelling in the non-inoculated right foot.

Figure 3

Tarsal joint measurements per mouse by days post infection (DPI). Scatter plots showing the differences from baseline tarsal joint measurements for each day post-CHIKV infection. Mice were injected with approximately 25 μL intradermal of CHIKV inoculum (A,B) or PBS (C,D) in the left footpad on Day 0. Tarsal joint measurements were baselined by subtracting Day 0 pre-infection measurements for each mouse from the post-infection measurements. Horizontal solid lines represent the mean difference from baseline for each DPI.

Figure 4

Non-infected mouse with normal joint. Photomicrograph of a normal joint with opposing normal articular cartilage with subchondral bone. There is no evidence of inflammation or erosion. A small amount of synovium (shown with arrow) is present, which appears normal. The joint capsule shows normal connective tissue.

Figure 5

Histologic Evidence of Inflammation by 7 days post-infection (DPI) (a–e). (a) The section shows a lympho-histiocytic synovitis (denoted by a cross) with articular cartilage scalloping and articular cartilage erosion (denoted by a triangle) with extension to cortical bone erosion. The lympho-histiocytic inflammatory response overlies the articular cartilage and cortical bone. There are no neutrophils, no vasculitis and no fibrinoid necrosis. (b) The section shows an active periostitis with cortical bone erosion (denoted with a triangle) consisting of inflammatory mononuclear cells and osteoclastic giant cells. There is no evidence of neutrophilic infiltration. Adjacent to the cortical bone erosion is an active mononuclear periostitis. (c) Section shows cortical bone with active periostitis, cortical bone erosions and reparative new bone formation (thin arrow). (d) Sections demonstrate a mononuclear lympho-histiocytic active myositis with myofiber degeneration and minimal regenerative activity; there is no evidence of healing or fibrosis. (e) The section shows interosseous inflammation (denoted with a circle) of soft tissue that is predominantly mononuclear without evidence of granuloma or suppuration. Bone is denoted with a cross. A periostitis is present on cortical bone surface (thin arrow).

Figure 6

Histologic evidence of inflammation by 21 days post-infection (DPI) (a–c). (a) The histopathology reveals an active myositis with myofiber degenerative change. The lympho-histiocytic inflammatory infiltrate permeates the skeletal muscle (thin arrow) and extends to cortical bone, causing a periostitis with mild cortical bone erosion (thick arrow). (b) Section of joint active arthritis with an erosive lympho-histiocytic synovitis with articular cartilage scalloping and articular cartilage erosion with extension to cortical bone erosion (thin arrow). There is joint capsule inflammation, which extends into soft tissue. (c) Section of joint arthritis demonstrates an active lympho-histiocytic synovitis (thin arrow) with cartilage damage and erosion. The active joint inflammation shows extensive involvement and erosion of articular cartilage (thick arrow) with inflammatory extension of the joint capsule.