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1 Cytokine Expression in the Central Nervous System and Periphery during Infection with Rabies Virus Nicholas Johnson Rabies and Wildlife Zoonoses Group.

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Presentation on theme: "1 Cytokine Expression in the Central Nervous System and Periphery during Infection with Rabies Virus Nicholas Johnson Rabies and Wildlife Zoonoses Group."— Presentation transcript:

1 1 Cytokine Expression in the Central Nervous System and Periphery during Infection with Rabies Virus Nicholas Johnson Rabies and Wildlife Zoonoses Group WHO Collaborating Centre for the Characterization of Rabies and Rabies-Related Viruses

2 2 Interferon induction following infection with a fixed strain of Rabies virus (Challenge Virus Standard) RV nucleoprotein Interferon- Interferon – Interferon- 603bp x RV negative RV positive 310bp 603bp 310bp -actin TNF- Johnson et al., 2006 JGV 87, 2663

3 3 Objectives Measure inflammatory changes in response to infection with a non-fixed strain Observe inflammation within the Central Nervous System Identify possible mediators of inflammation (cytokines / chemokines) Compare the CNS to the periphery during infection

4 4 The Model InoculateAntibodiesSignsDeath Isolate RV 61 (UK human, ex-India) CD1 outbred mice Subdermal inoculation / hind footpad 11d course (sampled at 0, 5, 11) Brain / salivary glands: Transcript Spinal cord: Histopathology Blood: Cytokine / Antibody

5 5 Anti-RABV immunostaining in the Dorsal Root Ganglion & Spinal Cord Dorsal Root Ganglion (d11) Spinal cord (d11)

6 6 Inflammatory changes observed in the DRG and Spinal Cord DRG (Media only) DRG (RABV d11) Spinal cord (Media only) Spinal cord (RABV d11)

7 7 T- and B-Cell Lymphocyte Immunostaining CD45R/220 CD3 Dorsal Root GangliaSpinal cord

8 8 Inflammatory Cytokine Detection in the Brain CCL3 M RABV - RABV + Day ODay 5Day 11 GAPDH CCL2 CCL4 CCL5 Overt disease

9 9 Chemokine transcript response in the brain INF- CCL2 (MCP-1) CCL3 (MIP-1 ) CCL4 (MIP 1 ) CCL5 (Rantes)CXCL10 (IP10) Transcription fold increase Time post inoculation (days)

10 10 Peripheral Changes Salivary glands: No change in TLR-3 transcripts. Increases observed in levels of a number of inflammatory transcripts (IL-6, CCL5, CXCL10, 2-5 OAS1) Serum: Neutralising antibodies detected as early as day 5. No change in a range of cytokines (INF-, IL-2, IL-6, IL-10, TNF- )

11 11 Conclusions Inflammatory changes are observed in the CNS during neurovirulent infection with RABV. Infiltrating lymphocytes are predominantly CD3+ (but not observed in the brain) Interferons and chemokines are up-regulated in response to infection. Chemokine responses proceed detection of RABV in the brain. Chemokines that attract T cells show the greatest up-regulation. These changes are not reflected in the periphery.

12 12 Acknowledgements Co-authors Veterinary Laboratories Agency Anthony Fooks Sharon Brookes Karen Mansfield Derek Healy Daniel Hicks Alex Nunez University of Edinburgh John Fazakerley Clive McKimmie Funding Defra (UK): grant SE0524


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