Immune evasion strategies of flaviviruses

VaccineJing 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. 17National Institute of Virology, INDIA

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)

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)

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)

Innate immune evasion:

1. Type I IFN responsei. Delay in PRR detectionii. Inhibition of IFN gene transcriptioniii. Suppression of IFN signallingiv. Impairing functions of antiviral ISGsv. sfRNAs as immunoevasins

2. Complement system evasion

3. NK cell immunity

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)

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)

Strategies used by flaviviruses to modulate complement pathway

Adapted from: Jing Yea et al. Immune evasion strategies of flaviviruses, Vaccine 31: 461-471 (2013)

Potential mechanism for flavivirus escape from NK cell detection

Adaptive immune evasion:1. Humoral immune responsei. Ag’ic variationii. Ab-dependent enhancement (ADE) of infection

iii. Partial maturation2. Cellular immune responsei. Inhibition of Ag presentationii. Ag’ic variation

Selection of flavivirus variants that escape recognition by neutralizing antibodies

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)

Unexplored areas:1. Detailed mechanisms involved in RNA-based strategies for immune

evasion2. Quality of adaptive immune response affected by modulation of

innate immune responses3. If flaviviruses interfere with the expression of various molecules like

integrins, chemokines and relative receptors involved in rolling and migration of various immune cells

Related studies1. 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)

References1. 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)