A mouse model of viral infection to understand postinfective fatigue syndrome

1
A mouse model of viral infection to understand
post-infective fatigue syndrome

• Suresh Mahalingam

2
Suresh
Development costs of 1 vaccine US 500-1000
m Market size required to recover investment
1-400 m people.
3
Ross River Virus

• Cause of Epidemic Polyarthritis in Australia and
  South Pacific.
• Mosquito borne
• Joint pain, Rash, and Myalgia with mild fever
• Inflammatory joint disease
• Mononuclear infiltrate observed in joint
  aspirates
• Viral antigen routinely found in afflicted joints
• Wrists, ankles, knee, and joints of hands and
  feet most commonly affected
• Symptoms are debilitating, though most cases
  resolve by 4 weeks post onset. Symptoms can
  persist for over 12 months.

4
Ross River Virus

• Mouse model (24 day old mice)
• macrophage mediated muscle disease and joint
  inflammation
• Severity differs between mouse strains
• Extremely severe in C57Bl/6
• joints
• Virus replication in bone/joint tissue
• Inflammation in joints

5
Ross River Virus Vectors
RRV (wild type)
RRV-gfp
24 day old mice s.c. with 103 pfu of RRV-GFP
6
Ross River virus in 24 and 28 day old mice
Mice were scored for development of hind limb
dysfunction
7
Ross River virus replication in 24 day old mice
MUSCLE
ANKLE
BRAIN
SERUM
8
Ross River Virus Vectors
RRV (wild type)
RRV-gfp (Double Promoter virus)
24 day old mice s.c. with 103 pfu of RRV-GFP
9
Synovial joint-Foot
Ankle joint
S
S
B
48 hr p.i.
P
Knee joint
Periosteum adjacent to knee
10
RRV Detected in Muscle
11
Ross River Virus-Induced Inflammation (Joints)
Infected
Uninfected
Bone
Bone
Muscle
5 days p.i.
Muscle
Periosteum
Periosteum
Infected
Uninfected
7 days p.i.
Synovial tissue
Synovial tissue
12
Ross River Virus-Induced Inflammation (muscle)
3 days p.i.
5 days p.i.
Uninfected
10 days p.i.
7 days p.i.
30 days p.i.
13
Ross River virus in 24 day old mice (mice do not
regain weight comparable to uninfected mice)
14
Periosteum 24 hr Synovial Space 72 hr
Muscle 72 hr
RRV infected (30 days p.i.)

Ross River virus detected in mice (30 days
post-infection)
15
Ross River virus persist in joint cells
1 day post-infection
12 days post-infection
26 days post-infection
16
Summary

• A mouse model of RRV infection has been
  established that mimics clinical human RRV
  disease (arthritis, arthralgia).
• The mouse model of RRV infection can be used to
  investigate PIFS.

17
Acknowledgements
University of Canberra Dr Brett Lidbury Dr
Michael Frese Dr Cristina Musso Dr Ruben
Ramirez Dr Jasjit Johal Nestor Rulli
University of North Carolina Mark Heise Tem
Morrison Reed Shabmann
University of New South Wales Andrew Lloyd
Queensland Institute of Medical Research Andreas
Suhrbier
Purdue University Richard Kuhn
Funding NHMRC ARC University of Canberra
Research Office