interferon γ inhibits ebola virus infection compat

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!!!