TLR2/MyD88 pathway-dependent regulation of dendritic cells by dengue virus promotes antibody-dependent enhancement via Th2-biased immunity.

Junu Aleyas George,Ajit Mahadev Patil,Seong Kug Eo,Ferdaus Mohd Altaf Hossain,Erdenebelig Uyangaa,Sang-Youel Park,Jin Hur,John-Hwa Lee,Jin Young Choi,Koanhoi Kim,Seong Bum Kim

doi:10.18632/oncotarget.22525

Junu Aleyas George, Ajit Mahadev Patil + Show 9 more

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https://doi.org/10.18632/oncotarget.22525

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Abstract

Possible risk mediators in primary dengue virus (DenV) infection that favor secondary DenV infection to life-threatening dengue hemorrhagic fever (DHF) and shock syndrome (DSS) via antibody-dependent enhancement (ADE) have not yet been described. Here, DenV infection enhanced the expression of inflammatory mediators and activation molecules in dendritic cells (DCs) through TLR2/MyD88 pathway. TLR2 appeared to facilitate DenV infection in DCs that were less permissive than macrophages for viral replication. In experiments using separate evaluations of DenV-infected and uninfected bystander DCs, infected DCs showed impaired maturation accompanied with TLR2-dependent production of inflammatory cytokines, by which uninfected bystander DCs showed increased expression of co-stimulatory molecules. Differential phosphorylation of MAPK and STAT3 was also detected between DenV-infected and uninfected DCs. Furthermore, DenV infection stimulated Th2-polarized humoral and cellular immunity against foreign and DenV Ag via TLR2/MyD88 pathway, and DenV-infected DCs were revealed to facilitate Th2-biased immune responses in TLR2-dependent manner. TLR2/MyD88-mediated Th2-biased Ab responses to primary DenV infection increased the infectivity of secondary homotypic or heterotypic DenV via ADE. Collectively, these results indicate that TLR2/MyD88 pathway in DC-priming receptors can drive Th2-biased immune responses during primary DenV infection, which could favor secondary DenV infection to DHF/DSS via ADE.

Highlights

Dengue virus (DenV) is an enveloped, singlestranded, and positive-polarity RNA virus of the Flaviviridae family
It is well accepted that antibody-dependent enhancement (ADE) can exacerbate disease severity in dengue virus (DenV) infection, possible www.impactjournals.com/oncotarget risk factors in primary infection that favor secondary infection to severe form by ADE have not yet been fully demonstrated
In order to address the impact of TLR signaling on innate responses of dendritic cells (DCs) upon primary DenV infection, we assessed the impact of each TLR molecule on primary DenV infection using BM-derived DC (BMDC) derived from mice lacking a TLR such as TLR2, TLR3, TLR4, or TLR9

Summary

Introduction

Dengue virus (DenV) is an enveloped, singlestranded, and positive-polarity RNA virus of the Flaviviridae family. It is estimated that as many as 390 million people per year are exposed to DenV infection. There is a continuous increase in incidence and severity of DenV infection due to geographic expansion of its vector, the Aedes aegypti mosquito [1,2,3]. DenV infection induces diseases of varying degrees of severity in humans, from dengue fever (DF), which is usually self-limiting, to lifethreatening dengue hemorrhagic fever (DHF) or dengue www.impactjournals.com/oncotarget shock syndrome (DSS) [4]. 500,000 cases of DHF and 12,000 deaths, in infants, occur in about 50-100 million cases of DF every year worldwide [5]

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