Viruses disguised as apoptotic debris hijack the host apoptotic clearance machinery

1. VIRALAPOPTOTIC MIMICRY
Deepak Praveen Raj S
P-2076
PhD Scholar
Major Credit Seminar
on

2. Overview

3.  It is defined by the exposure of Phosphatidylserine (PS) - a
marker for apoptosis - on the pathogen surface - for entry into the
host cell
 It was first proposed by Vanlandschoot and Leroux-Roels in 2003
 Molecular mimicry may arise via divergent or convergent
evolution
(Amara and Mercer, 2015)
Introduction
Classic apoptotic mimicry Non-classic apoptotic mimicry

4. (Benedict et al., 2002)
Apoptosis

5. Virus evade apoptosis
p53
Death receptors
Antiapoptotic
protein Bcl-2
Blinding sensors
SV40 large T antigen
Human Papillomavirus E6 protein
Adenovirus E1B, E4orf6 protein
Hepatitis B virus pX protein
Mimicking Bcl-2
Adenovirus E1B-19K
Intrinsic pathway
p53 (Bak)
Inhibit apoptosis
TNF (Bax)
Extrinsic pathway
CMV UL37 gene
(Benedict et al., 2002)

6. Caspase regulationModulation of TNFR signaling
Contd…
(Benedict et al., 2002)

7.  PS is most enriched in the inner leaflet of the plasma membrane
 vesicular trafficking
(Leventis and Grinstein, 2010)
Importance of PS in viral apoptotic
mimicry

8. (Soares et al, 2009)
Contd…
Herpesviruses , HCV , HIV-1
Rises in intracellular Ca2+
Activating PS exporters and inhibiting PS
import by translocases
ATP11C and
CDC50A
Caspase
recognition sites
Apoptotic PS
exposure

9. Contd…
PC
PS
Flippase Floppase Scramblase

10.  PS may incorporated viral envelopes during budding for promotion of
favorable membrane curvature (Segawa et al., 2014)
PS acquisition by virions
Phosphatidylser
ine acquisition
from ER sheets
Budding from
lipid rafts
Budding
from the
ER lumen
CME
Macropino
cytosis
virus entry

11.  Tim-1, Tim-3 and Tim-4 genes
 Epithelial cells, mast cells, B cells,
and activated CD4+ T cells
 Directly bind to TIM and CD300
 Filoviruses infection
 TIM-4 has additional PS binding
residues outside of the pocket
(Jemielity et al., 2013)
PS Receptors

12.  TYRO3 - Brain and Dendritic cells
 AXL - Dendritic cells , organs , epithelial,
mesenchymal, and haematopoietic origin
 Mer - Monocytes and Bone marrow
(i) Degradation of IκB
(ii) Activate the SOCS
(iii) Prevent the ubiquitilation of the TRAF-6
(Hafizi and Dahlback, 2006 &
Tank and Maury, 2015 )
Indirect PSR

13. Contd…
(Hafizi and Dahlback, 2009)

14.  Vaccinia virus has an affinity for lipids
 MVs reached the cell body
 Formation of blebs along the cell body
 Bleb retraction and cortical actin
reassembly coincided with virus entry
 PAK1 an essential factor for MV
infection
(Morizono and Chen, 2014)
Classic apoptotic mimicry

15.  Infectivity was inhibited by 90%
 Binding MVs with 0.5% Nonidet-
P40
 Only PS-reconstituted viruses
exhibited restore infectivity and
plaque formation
 Delipidated MVs were highly
attenuated for Rac1 activation
 Ps relipidated MVs restored Rac1
activation
Contd…
(Mercer and Helenius, 2008)

16. (Gyamfi et al, 2015)
Contd…
VP40 dimerize
Align its C-terminal domains
Lysine residues
Linear hexameric assembly
Continuous filaments
Multilayered matrix
N-terminal
domain
C-terminal
domain
1 195 326

17.  TIM1 overexpression does not enhance filovirus entry in cells
lacking the cognate entry receptor for these viruses
 Interactions with both PSR and virus-specific entry receptors
 PSR act as a scaffold
 New World Arenaviruses cells receptor is transferrin receptor 1
(Tank and Maury, 2015 )
Contd…

18.  SV40 cellular receptor ganglioside GM1
 VP1 mimic Gas6
 Basis of the homology between VP1 and
the ligand Gas6
 Axl extracellular domain fits nicely into
an accessible groove
 VP1 pentamer-Axl interaction using
PatchDock - known structures of VP1
and Axl
(Drayman et al., 2013)
Non-classic apoptotic mimicry

19.  Budding into cellular organelle (MVB)
 PS enhance exosome like particle bind to TIM-1 on target cells
(Feng et al., 2013)
Contd…

20.  PS vesicles provide greater infection efficiency for viruses
(Chen et al., 2015)
Contd…
Selective
advantages
Genetic
pool
PS
scavenging
cells

21. Virus genus PS function in virus life cycle PS receptors A.M Type
Alphavirus Binding , endocytosis, infection AXL, CD300a, TIM1 and
TIM 4
Classic
Arenavirus Binding , endocytosis, infection AXL, TIM1 and TYRO3 Classic
Alfabaculovirus Binding , endocytosis, infection AXL, TIM1 Classic
Ebolavirus and
marburgvirus
Binding , endocytosis, infection and
immune evasion
AXL, TIM1 , TIM3, TIM4
and TYRO3
Classic
Flavivirus Binding , endocytosis, infection and
immune evasion
AXL, TIM1 , TIM3, TIM4
and TYRO3
Classic
Orthopoxvirus Signalling, endocytosis and infection AXL Classic
Vesiculovirus Binding , endocytosis, infection AXL and TIM1 Classic
Enterovirus Infection Unknown Non-classic
Hepatitisvirus Unknown TIM1 Non-classic
Polyomavirus Binding , endocytosis, infection AXL Non-classic

22.  Apoptotic clearance is intimately linked with a dampening of
inflammatory responses
 Tripartite complex with PS and GAS6, TAM receptors
Viral immune evasion
(Amara and Mercer, 2015)

23.  CD300a is a direct PSR expressed mainly on myeloid and
mast cells
 Binding of PS to CD300a, the cytoplasmic ITIM recruits the
phosphatase SHP1 , which blocks the release of inflammatory
cytokines and chemokines
 CD300a modulates the inflammatory and innate immune
responses of the host
(Oda et al., 2012)
Contd…

24. (Vanlandschoot and Roels, 2003)
HBV Immune Evasion Strategy
HBsAg
complement
factors
Phagocytosis
of complex
Proinflammatory
cytokine
DCs
stimulation of
Ag-driven T-
cell
Peripheral
tolerance
Depletion of T and B cells
Increased secretion of IL-10
HBsAg
TNF-α (LPS)
GM-CSF
INF-α (VSV)

25.  Bavituximab prepared by,
Mouse (3G4) VH and Vκ
domains
Human IgG1κ constant domains
 Ab binding to PS is dependent on
plasma protein β2GP1
 3G4 enhances binding of β2GP1 to
PS
 β2GP1 is complement control protein
(Luster et al., 2006 & Thomas and Thorpe., 2017)
Targeting PS as a antiviral strategy

26. 1) Opsonization and clearance of infectious virus from the
bloodstream
2) Induces ADCC of virus infected cells
 PGN632- human mab
1) Bavituximab is chimeric and could induce ab against
mouse determinants
2) Avoids possible depletion of β2GP1 in patients
 PGN632 induced β-chemokine production which blocked the
CCR5 coreceptor
(Dowall et al., 2016)
Contd…

27.  Viruses disguised as apoptotic debris hijack the apoptotic
clearance machinery
 Extension the cell type specificity of the virus
 Binding of PS to its PSR alters the cytokine expression
 Restriction to viral treatment e.g: Synagis, Ribavirin
 PS may hold promise as an effective antiviral strategy
 Drug resistance could be less of a problem for PS targeted
antivirals
Conclusion

28. Door has to be Open
1
• Detailed mechanism of acquisition of PS
has to be explore
2
• BAI1 , RAGE do not mediate virus entry
3
• Adaptive immune response
4
• The in vivo relevance of viral apoptotic
mimicry needs to be explored

29. Thank you