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Interferon γ inhibits Ebola Virus Infection
Siddhesh Uday SapreRoll No. : 17
M.Sc. Virology (Part-I)National Institute of Virology, Pune
Rhein BA, Powers LS, Rogers K, Anantpadma M, Singh BK, Sakurai Y, et al. (2015)PLoS Pathog 11(11): e1005263. doi:10.1371/journal. ppat.1005263
Image credits: Visual Science
Virus taxonomy • EBOV: ssRNA (-ve sense), large, pleomorphic, filamentous ≈ 1400 nm• Family- Filoviridae (filus= thread like)• Genus- Ebolavirus• Species- Bundibugyo EBOV Sudan EBOV Zaire EBOV Reston EBOV Taї forest EBOV (formerly called Côte d’Ivoire)
Ebov Structure• Shape: enveloped, filamentous (long tube with many
branches and turns); number 6 curvature• Size : 80 nm (diameter)• 800-1000 nm (length)• RNA ≈ 1% of the total mass of the virus!!!
Cell Tropism of EBOV• EBOLA Virus (EBOV) is Pantropic• Infects all the cells of the body except
Lymphocytes• MΦs & DCs= Early targets
Nature Reviews Immunology 7, 556-567 (July 2007) | doi:10.1038/nri2098
Image Credits: False colour electron micrograph (NIH)
M1 Phenotype Proinflammatory cytokines IL-6, TNF-α, CXCL-10
Image credits: Molecular mechanisms of Ebola virus pathogenesis doi:10.1038/cdd.2015.67
Aims & Objectives:Basic purpose: To investigate if IFN γ can be used as a prophylactic and/ or therapeutic treatment option in case of EBOV
infection (i) time period for a maximum dose response ?
(ii) downstream effects
(iii) molecular level of IFN γ inhibition/ control
(iv) optimal dose of IFN γ
Materials and methods used • Preparation of Virus Stock & Concentration• Primary cell isolation & cytokine stimulations• EBOV & EBOV GP/rVSV infection of MΦs• Mouse cell RNA isolation & qRT- PCR• Human MΦ RNA extraction & microarray analysis• ISG Inhibition studies• IRF1 siRNA knockdown of EBOV GP/rVSV infection by exosome delivery
NOTE :Animal studies- BALB/c mice, C57BL/6 , IFN-γR deficient mice were used
Fig 1. IFNγ-treated macrophages are resistant to EBOV infection.
Rhein BA, Powers LS, Rogers K, Anantpadma M, Singh BK, et al. (2015) Interferon-γ Inhibits Ebola Virus Infection. PLoS Pathog 11(11): e1005263. doi:10.1371/journal.ppat.1005263
Fig 2. IFNγ blocks EBOV GP/rVSV and EBOV RNA synthesis.
Rhein BA, Powers LS, Rogers K, Anantpadma M, Singh BK, et al. (2015) Interferon-γ Inhibits Ebola Virus Infection. PLoS Pathog 11(11): e1005263. doi:10.1371/journal.ppat.1005263
Fig 3. Human MDM gene expression is altered by 24 hours of IFNγ treatment.
Rhein BA, Powers LS, Rogers K, Anantpadma M, Singh BK, et al. (2015) Interferon-γ Inhibits Ebola Virus Infection. PLoS Pathog 11(11): e1005263. doi:10.1371/journal.ppat.1005263
Fig 4. Identification of IFNγ-stimulated genes that inhibit EBOV infection.
Rhein BA, Powers LS, Rogers K, Anantpadma M, Singh BK, et al. (2015) Interferon-γ Inhibits Ebola Virus Infection. PLoS Pathog 11(11): e1005263. doi:10.1371/journal.ppat.1005263
Fig 5. IFNγ reduces EBOV-GP/rVSV morbidity and mortality.
Rhein BA, Powers LS, Rogers K, Anantpadma M, Singh BK, et al. (2015) Interferon-γ Inhibits Ebola Virus Infection. PLoS Pathog 11(11): e1005263. doi:10.1371/journal.ppat.1005263
Fig 6. IFNγ protects mice from EBOV morbidity and mortality.
Rhein BA, Powers LS, Rogers K, Anantpadma M, Singh BK, et al. (2015) Interferon-γ Inhibits Ebola Virus Infection. PLoS Pathog 11(11): e1005263. doi:10.1371/journal.ppat.1005263
ConclusionsThe researchers carried out the studies in murine models using the actual EBOV, MA-EBOV, and EBOV GP/rVSV in both, BSL-4 & BSL-2 B2 conditions, which lead them to the following conclusions:
1.IFN-γ -novel & effective therapeutic option
2. >160 ISGs ≈ 3 novel IFN-γ stimulated factors GBP5, RARRES3 & VAMP5
3. BSL-2 model = safer and cost effective alternative
References
• Molecular mechanisms of Ebola virus pathogenesis doi:10.138/cdd.2015.67
• Pathogenesis of the Viral Haemorrhagic Fevers doi: 10.1146/annurev-pathol-020712-164041
• How Ebola and Marburg viruses battle the immune system doi: 10.1038/nri2098
• Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus doi: 10.1038/nrmicro3524
• How Ebola Virus Infects Cells (N ENG J MED 352;25)
• Biological Agents: Viral Haemorrhagic Fevers (Pacific EMPRINTS), University of Hawaii (http://cdc.train.org/)
• How Ebola Virus Counters the Interferon System doi: 10.1111/j.1863-2378.2012.01454.x
• Immunology of protection from Ebola virus infection (Vaccine perspectives; Science Translational Medicine)
• Immunopathology of highly virulent pathogens: insights from Ebola virus doi: 10.1038/ni1519
Thank You!!!
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