This document summarizes immune evasion strategies used by flaviviruses. It discusses how flaviviruses evade innate immune responses such as type I interferon responses and complement system activation. It also describes adaptive immune evasion mechanisms, including antigenic variation, antibody-dependent enhancement of infection, and inhibition of antigen presentation. The document provides diagrams illustrating key concepts and cites related studies on flavivirus immune evasion and modulation of host inflammatory responses.

1. Immune evasion strategies of flaviviruses
Vaccine
Jing Yea,b, Bibo Zhua,b, Zhen F. Fua,b,c, Huanchun Chena,b, Shengbo Caoa,b
November 13 , 2012
a State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University,
Wuhan, Hubei 430070, PR China
b Laboratory of Animal Virology, College of Veterinary Medicine, Huazhong Agricultural
University, Wuhan, Hubei 430070, PR China
c Department of Pathology, University of Georgia, Athens, GA 30602, USA
Presented by:
Siddhesh Uday Sapre,
Roll No. 17
National Institute of Virology, INDIA

2. Genome & life-cycle of flaviviruses
• Flaviviruses: env, ss +ve- sense RNA, 10.5-11 kb genome
• Monocistronic RNA single polyprotein cleaved by
host+ viral proteases
• Host cells: Monocyte, MΦ & DCs Entry: RME
• Site of Viral RNA replication: rER & VPs(derived from
Golgi)
• Assembly: ER immature particles displaying prM
transport through trans- golgi network furin
mediated cleavage (prM to M) exocytosis
Picture credits: ViralZone.expasy.org
(2015)

3. Adapted from: Michael S Diamond, Evasion of innate and
adaptive immunity by flaviviruses, Immunology and Cell
Biology 81, 196–206 (2003)
Fig. Flavivirus infection and immune response Fig. Arboviral Infection & Host inflammatory response
Adapted from: Marieke Pingen et al., Host Inflammatory
Response to Mosquito Bites Enhances the Severity of
Arbovirus Infection, Immunity, 44, 1455-1469 (2016)

4. Simplified depiction of the putative process of flavivirus infection from
entry of the virus via the skin to clearance and/or immunopathology
Adapted from: Nicholas JC King and Alison M Kesson, Interaction of flaviviruses with cells of the vertebrate host and decoy of
the immune response Immunology and Cell Biology 81, 207–216 (2003)

5. Innate immune evasion:
1. Type I IFN response
i. Delay in PRR detection
ii. Inhibition of IFN gene transcription
iii. Suppression of IFN signalling
iv. Impairing functions of antiviral ISGs
v. sfRNAs as immunoevasins
2. Complement system evasion
3. NK cell immunity

6. Type I IFN signal pathway and evasion strategy of flaviviruses
Adapted from: Jing Yea et al. Immune evasion strategies of flaviviruses, Vaccine 31: 461-471 (2013)

7. Type I IFN signal pathway and evasion strategy of flaviviruses
Adapted from: Jing Yea et al. Immune evasion strategies of flaviviruses, Vaccine 31: 461-471 (2013)

8. Strategies used by flaviviruses to modulate complement pathway
Adapted from: Jing Yea et al. Immune evasion strategies of flaviviruses, Vaccine 31: 461-471 (2013)

9. Potential mechanism for flavivirus escape from NK cell detection

10. Adaptive immune evasion:
1. Humoral immune response
i. Ag’ic variation
ii. Ab-dependent enhancement (ADE) of infection
iii. Partial maturation
2. Cellular immune response
i. Inhibition of Ag presentation
ii. Ag’ic variation

11. Selection of flavivirus variants that escape recognition by neutralizing antibodies

12. Strategies used by flaviviruses to evade adaptive immune responses
Adapted from: Jing Yea et al. Immune evasion strategies of flaviviruses, Vaccine 31: 461-471 (2013)

13. Unexplored areas:
1. Detailed mechanisms involved in RNA-based strategies for immune
evasion
2. Quality of adaptive immune response affected by modulation of
innate immune responses
3. If flaviviruses interfere with the expression of various molecules like
integrins, chemokines and relative receptors involved in rolling and
migration of various immune cells

14. Related studies
1. Ali Zohaib et al. The Role of Ubiquitination in Regulation of Innate Immune Signaling,
Curr. Issues Mol. Biol. 18: 1-10 (2016)
2. RongJiang et al. Roles of TLR3 and RIG-I in Mediating the Inflammatory Response in
Mouse Microglia following Japanese Encephalitis Virus Infection, Journal of Immunology
Research, 2014: 1-11 (2014)
3. Rui Jin et al. Japanese Encephalitis Virus Activates Autophagy as a Viral Immune Evasion
Strategy, PLoS One, 8: 1-11 (2013)
4. Mehul S. Suthar et al. Innate Immune Sensing of Flaviviruses, PLoS Pathogens 9: 1-4
(2013)
5. Daniel Ruzek et al. Breakdown of the Blood-Brain Barrier during Tick-Borne Encephalitis
in Mice Is Not Dependent on CD8+ T-Cells, 6 (5): 1-9 (2011)

15. References
1. Michael S Diamond, Evasion of innate and adaptive immunity by flaviviruses, Nature
Immunology and Cell Biology 81: 196–206 (2003)
2. Nicholas JC King and Alison M Kesson, Interaction of flaviviruses with cells of the
vertebrate host and decoy of the immune response Nature Immunology and Cell
Biology 81: 207–216 (2003)
3. John S Mackenzie, Duane J Gubler & Lyle R Petersen Emerging flaviviruses: the spread
and resurgence of Japanese encephalitis, West Nile and dengue viruses Nature
Medicine 10: 98-109 (2004)
4. Nicholas JC King et al. Immunopathology of flavivirus infections, Nature Immunology
and Cell Biology 85: 33–42 (2007)
5. Katherine R. Spindler et al. Viral disruption of the blood-brain barrier, Trends
Microbiol. 20 (6): 282-290 (2012)