Immune evasion, a critical strategy for rabies virus

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Immune evasion, a critical strategy for rabies
virus

• Monique Lafon
• Institut Pasteur Paris

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Rabies virus, a rare human disease with nearly
100 death
Strictly neuronotropic virus No viremia
Subversive strategy to avoid interruption of the
neuronal network which compromises the
infectious cycle
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Rabies a mouse model of CNS invasion
Acute rabies Challenge Virus Standard SHRBV
Fatal encephalo-myelitis Abortive rabies
Pasteur Virus strain CVS-F3, Abortive
rabies (myelitis) with paralytic sequelea

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Rabies virus triggers a strong immune response in
the periphery
Vuaillat et al, submitted
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Rabies specific immune response occurs in the
periphery (similar responses for pathogenic and
non pathogenic strains)
Total IgG Isotypes
Neutralizing
Roy A et al, J Virol 2007
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T cells are crucial factor in controlling
rabies virus neuroinvasiveness
Hippocampus
Spinal cord
Pathology
BALB/c abortive rabies
BALB/c nu/nu Fatal neuro invasive encephalitis
Galelli et al, 2000 J Neurovirol
Similar data with Rag1 and 2 mice Xiang et al,
1995, Hooper et al, 1998
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However, T cells do not control the highly
pathogenic rabies virus infection
Days post infection
Evasion of the T cell response
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Kinetic of migratory cells in the rabies virus
infected CNS
Acute rabies
Abortive rabies
Day post infection
Camelo et al, 2000, Baloul et al, 200
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Kinetic of migration and apoptosis (TUNEL) of
CD3 T cells in spinal cord sections of CVS
infected mice
Mean number of T cells per field
Baloul L et al, J neurovirol
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CVS-infected neurons rarely encounter apoptosis
Tunnel positive are T cells
Green Rabies virus antigen Red Tunel
Cerebellum
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How Rabies infected nervous system escape
imunosurveillance

• Stimulation of molecules decreasing T cell
  activity
• Calcitonin gene related peptide,
• (Dr E Weihe)
• FasL, HLA-G, B7-H1
• (Baloul et al, 2004, Lafon et al, 2005,
  2007)

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Fas-L expression in spinal cord of rabies virus
infected mice
Fas-L / Neu-N
Fas-L / NC-FITC
T cells
Fas
Acute
Abortive
Fas ligand
Baloul L et al, 2004 Lafon, 2005
Infected neurons
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Structure of FasL (mutation in gld mice)
(generalized proliferative disease )
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CVS encephalitis is reduced in FasL deficient
mice
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B7-H1 overexpression after rabies virus infection
in mouse NS
Lafon et al, submitted
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B7-H1 -/- mice are more resistant to acute
rabies than B7-H1/ mice
Lafon et al, submitted
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HLA-G, an immunosubversive molecule
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Lafon et al. , J Virol 2005, Mégret et al.,
Human Immunol , 2007
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Immunosubversive strategy of acute Rabies
Apoptosis of migratory T cells
also HLA-G, PD-L1
Infected neurons survive No control of infection
Rabies virus infection is neuroinvasive
Migratory T cells
express Fas
Passage through the BBB
Immune response in the periphery
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Immunosubversion may also hit B cells
Destruction of B cells or differential innate
immune responses ?
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Conclusions

• Rabies virus has adopted immunosubversive
  strategies to improve its survival and completion
  of the virus cycle
• It is a perequisite that post exposure treatment
  provide
• by stimulating a strong immune responses (B
  cells) without delay
• New therapeutic approaches by increasing T
  cell survival ?

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Rabies vaccination after exposure
Bite, entry of virus
Immunosubversion In the periphery and in the
nervous system
Efficacy of post exposure rabies virus vaccine
Take advantage of the short period of time
before immunoevasion has set up
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Pre-exposure rabies vaccination for children
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Enhancement of T cells activation in the CNS is
a survival factorfor acute rabies
EAE mice treated with myelin basic protein show
a better rabies (SHRBV) survival than non
treated
Maximal EAE Moderate EAE
Are MS patients less susceptible to rabies ?
Roy and Hooper, J Virol 2007
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Reduction of migratory cells into the CNS
infected with pathogenic strains
Roy et al, J Virol 2007
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Experimental immunosupression (DHEA) enhances
pathogenicity
Roy and Hooper , 2007
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Adoptive transfer of rabies virus sensitized
immune cells has no effect against infection
No transfer
Transfer 2h post infection
Roy et al, J Virol, 2007