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Henipavirus Mechanisms of Cell Entry and Spread Throughout the Human Host

Henipavirus Mechanisms of Cell Entry and Spread Throughout the Human Host. Tyler Kosowan MMIC 7050 Feb. 11 th , 2014. Overview. Introduction History Reservoir Host Transmission Routes Viral Cell Adhesion and Fusion Cell Entry Mechanisms Future Directions Summary. Introduction.

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Henipavirus Mechanisms of Cell Entry and Spread Throughout the Human Host

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  1. Henipavirus Mechanisms of Cell Entry and Spread Throughout the Human Host Tyler Kosowan MMIC 7050 Feb. 11th, 2014

  2. Overview • Introduction • History • Reservoir Host • Transmission Routes • Viral Cell Adhesion and Fusion • Cell Entry Mechanisms • Future Directions • Summary

  3. Introduction • Henipavirus is a genus of the viral family Paramyxoviridae • Species include Nipah Virus and Hendra Virus • Single-stranded, non-segmented, negative-stranded RNA genomes around 18 kilobases long

  4. Introduction • Symptoms - Fever and headache are common - Vasculitis around major organs ● Commonly brain and lungs ● Reduced level of consciousness or cough

  5. Introduction • Viral particles are encased in a lipid bilayer • 6 main genes encode for proteins: - Nucleocapsid (N), matrix (M), phosphoprotein (P), attachment glycoprotein (G), fusion glyocoprotein (F), and large (L) polymerase http://upload.wikimedia.org/wikipedia/commons/8/86/Henipavirus_structure.svg

  6. Introduction Hsu, V., 2007, Nipah and Hendra Viruses, Emerging Viruses in Human Populations, 16: 179–199

  7. History • Hendra virus first recorded Henipavirus infection of a human (Australia, 1994) • Since then, seven people have been infected ● 4 people have died ● Many more horses have been infected as well ● Some people infected treated with Ribavirin, but not all who received it survived

  8. History • Nipah virus first recorded infection of a human seen after Hendra virus (Malaysia, 1998)- 1999 outbreak in Singapore- Larger outbreaks in Bangladesh and eastern India (2001-2008) - Infection associated with swine contact- Ribavirin used in some cases and again, unreliable results seen

  9. Reservoir Host • Pteropus bats- Many species of this genus can carry the virus- Found to contain low titre of neutralizing antibodies ● Co-evolution?- Asymptomatic- Virus collected from various bat secretions and tissues ● urine, saliva, uterine fluid, fetal tissue

  10. Reservoir Host Luby, S., 2013, The pandemic potential of Nipah virus, Antiviral Research, 100: 38-43

  11. Reservoir Host Luby, S., 2013, The pandemic potential of Nipah virus, Antiviral Research, 100: 38-43

  12. Transmission Routes • 3 main routes for transmission of the virus- Bats feed from pots collecting date palm tree sap and infectious secretions left in sap- Bat secretions end up in livestock feed ● Infected animals can later infect humans - People who climb trees where bats roost shown to be more likely to get Henipavirus infection

  13. Transmission Routes • Human-to-human transmission seen with Nipah virus- considered possible with Hendra virus- Respiratory secretions common infection mechanism- Social norms can increase chance of transmission

  14. Viral Cell Adhesion and Fusion • 2 main viral surface proteins, G and F- G protein involved in attachment- F protein involved in fusion to get virus into cell http://upload.wikimedia.org/wikipedia/commons/8/86/Henipavirus_structure.svg

  15. Viral Cell Adhesion and Fusion • G Protein- Structure mimics human EphB receptor ● Class of tyrosine kinase receptors - Binds ephrinB2 and ephrinB3 ● ephrinB2-EphB interaction normally involved in vasculogenesis and axonal guidance - Nipah virus G protein has a stronger affinity for ephrinB than Hendra virus G protein

  16. Viral Cell Adhesion and Fusion • F Protein- Initially expressed as inactive trimer- Activation mechanism unknown ● Happens after G protein attaches to host- Once activated, pre-hairpin intermediate forms- Part of the active trimer is attracted to another to bend and bind the F protein ● Brings the viral and host membranes close

  17. Viral Cell Adhesion and Fusion Aguilar, H. and Iorio, R., 2012, Henipavirus Membrane Fusion and Viral Entry, Current Topics in Microbiology and Immunology, 359: 79–94

  18. Viral Cell Adhesion and Fusion • F Protein (continued)- Initially synthesized as F0 form- Cleavage only happens once the virus is in the host cell, not activated outside ● Cleavage by cathepsin (protease)-Cleaved into F1 and F2 ● F1 stays on viral particle ready to be activated ● F2 is discarded

  19. Viral Cell Adhesion and Fusion Diederich, S., Thiel, L., and Maisner, A., 2008, Role of endocytosis and cathepsin-mediated activation in Nipah virus entry, Virology, 375: 391–400

  20. Cell Entry Mechanisms • EphB normally acts on ephrinB2 which initiates a signal cascade which leads to macropincytosis and internalization of the pair - Signal cascade usually involves vasculogenesis • Macropinocytosis samples a larger volume of the external environment outside the cell than micropinocytosis • Viral mimicry of EphB still activates this cascade leading to fillopodia formation

  21. Cell Entry Mechanisms Pernet, O. et al., 2009, Nipah virus entry can occur by macropinocytosis, Virology, 395: 298–311

  22. Cell Entry Mechanisms • Infection of polarized cells- Viral M protein collects at apical surface of cell ● Collects viral components for viral progeny budding and release- Some G and F proteins collect around other sides of the cell leading to fusion of the cell with adjacent, healthy cells ● This leads to formation of multi-nucleated cells

  23. Cell Entry Mechanisms • Infection of polarized cells (continued)- Multi-nucleated cell state disrupts polar orientation- M protein then collects at all cell surfaces ● Viral budding in all directions ● Late stage infection properties of virus- This helps dissemination through host and in immediate release back to external environment

  24. Cell Entry Mechanisms Lamp, B. et al., 2013, Nipah Virus Entry and Egress from Polarized Epithelial Cells, Journal of Virology, 87(6): 3143–3154

  25. Future Directions • Current treatments for Henipavirus is Ribavirin or combination therapy with Chloroquine-Results poor, but still seem to affect the virus • Best trials for new therapy seem to be pointing at targeting G and F viral surface proteins- Best candidate to date is m102.4 ● Great results in animal models

  26. Summary • Since its discovery in 1994, Henipavirus has already shown ability to spread • Pteropus bats are reservoir host • Infection involves virus recognizing conserved gene product (ephrinB2) on cell surface to force access via endosome compartment • Viral fusion protein used to get virus into cytoplasm via activation from host and viral factors • Polarized cells initially release mature virions from apical surface- Multi-nucleation disrupts this and virus can spread in all directions including the bloodstream to become systemic • Best candidate for effective treatment is m102.4

  27. References • Ksiazek, T., Rot, P., and Rollin, P., 2011, A review of Nipah and Hendra viruses with an historical aside, Virus Research, 162: 173-183 • Luby, S. et al., 2009, Transmission of Human Infection with Nipah Virus, Emerging Infections, 49:1743–1748 • Hsu, V., 2007, Nipah and Hendra Viruses, Emerging Viruses in Human Populations, 16: 179–199 • Luby, S., 2013, The pandemic potential of Nipah virus, Antiviral Research, 100: 38-43 • Halpin, K. et al., 2011, Pteropid Bats are Confirmed as the Reservoir Hosts of Henipaviruses: A Comprehensive Experimental Study of Virus Transmission, American Society of Tropical Medicine and Hygiene, 85(5):946-951 • Negrete, O. et al., 2005, EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus, Nature, 436: 401-405 • Aguilar, H. and Iorio, R., 2012, Henipavirus Membrane Fusion and Viral Entry, Current Topics in Microbiology and Immunology, 359: 79–94 • Diederich, S., Thiel, L., and Maisner, A., 2008, Role of endocytosis and cathepsin-mediated activation in Nipah virus entry, Virology, 375: 391–400 • Pernet, O. et al., 2009, Nipah virus entry can occur by macropinocytosis, Virology, 395: 298–311 • Norbury, C., 2006, Drinking a lot is good for dendritic cells, Immunology, 117(4): 443–451 • Lamp, B. et al., 2013, Nipah Virus Entry and Egress from Polarized Epithelial Cells, Journal of Virology, 87(6): 3143–3154 • Rockx, B. et al., 2010, A Novel Model of Lethal Hendra Virus Infection in African Green Monkeys and the Effectiveness of Ribavirin Treatment, Journal of Virology, 84(19): 9831–9839 • Broder, C. et al., 2013, A treatment for and vaccine against the deadly Hendra and Nipah viruses, Antiviral Research, 100: 8-13

  28. Questions? http://video.adultswim.com/rick-and-morty/anatomy-park.html

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