Dual TLR2/9 Recognition of Herpes Simplex Virus Infection Is Required for Recruitment and Activation of Monocytes and NK Cells and Restriction of Viral Dissemination to the Central Nervous System.

Erdenebileg Uyangaa,Bumseok Kim,Jin Young Choi,Ferdaus Mohd Altaf Hossain,Koanhoi Kim,Ajit Mahadev Patil,Sung Ok Park,Seong Kug Eo

doi:10.3389/fimmu.2018.00905

Erdenebileg Uyangaa, Bumseok Kim + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2018.00905

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Abstract

The importance of TLR2 and TLR9 in the recognition of infection with herpes simplex virus (HSV) and HSV-caused diseases has been described, but some discrepancies remain concerning the benefits of these responses. Moreover, the impact of TLR2/9 on innate and adaptive immune responses within relevant mucosal tissues has not been elucidated using natural mucosal infection model of HSV. Here, we demonstrate that dual TLR2/9 recognition is essential to provide resistance against mucosal infection with HSV via an intravaginal route. Dual TLR2/9 ablation resulted in the highly enhanced mortality with exacerbated symptoms of encephalitis compared with TLR2 or TLR9 deficiency alone, coinciding with highly increased viral load in central nervous system tissues. TLR2 appeared to play a minor role in providing resistance against mucosal infection with HSV, since TLR2-ablated mice showed higher survival rate compared with TLR9-ablated mice. Also, the high mortality in dual TLR2/9-ablated mice was closely associated with the reduction in early monocyte and NK cell infiltration in the vaginal tract (VT), which was likely to correlate with low expression of cytokines and CCR2 ligands (CCL2 and CCL7). More interestingly, our data revealed that dual TLR2/9 recognition of HSV infection plays an important role in the functional maturation of TNF-α and iNOS-producing dendritic cells (Tip-DCs) from monocytes as well as NK cell activation in VT. TLR2/9-dependent maturation of Tip-DCs from monocytes appeared to specifically present cognate Ag, which effectively provided functional effector CD4+ and CD8+ T cells specific for HSV Ag in VT and its draining lymph nodes. TLR2/9 expressed in monocytes was likely to directly facilitate Tip-DC-like features after HSV infection. Also, dual TLR2/9 recognition of HSV infection directly activated NK cells without the aid of dendritic cells through activation of p38 MAPK pathway. Taken together, these results indicate that dual TLR2/9 recognition plays a critical role in providing resistance against mucosal infection with HSV, which may involve a direct regulation of Tip-DCs and NK cells in VT. Therefore, our data provide a more detailed understanding of TLR2/9 role in conferring antiviral immunity within relevant mucosal tissues after mucosal infection with HSV.

Highlights

Herpes simplex viruses including type 1 (HSV-1) and type 2 (HSV-2) are ubiquitous, host-adapted pathogens with a prevalence rate of around 90% worldwide [1, 2]
To clarify the role of TLR2 and TLR9 in inflamed tissues after mucosal herpes simplex virus (HSV) infection, we assessed the survival of WT, TLR2 KO, TLR9 KO, and TLR2/9 double knock-out (DKO) mice following vaginal infection with different doses of the HSV-1 McKrae strain (1 × 106, 1 × 107, and 5 × 107 pfu/mouse)
TLR2 KO mice showed modest mortality with 30, 30, and 40%, while TLR9 KO mice exhibited apparently enhanced mortality with 55, 60, and 70%, depending on the infection dose. These results indicate that both TLR2 and TLR9 are essential to provide the resistance to mucosal infection with HSV-1, and TLR9 appears to play a more important role in providing resistance to mucosal HSV-1 infection compared with the TLR2

Summary

Introduction

Herpes simplex viruses including type 1 (HSV-1) and type 2 (HSV-2) are ubiquitous, host-adapted pathogens with a prevalence rate of around 90% worldwide [1, 2]. The ablation of TLR2 and, to a lesser extent, TLR9 results in significantly diminished lesions in stromal keratitis caused by HSV-1 infection [14] By contrast with these findings, TLR2 appears to play a role in reducing viral load in the trigeminal ganglia or brain after intravaginal (i.vag.) infection with HSV-2, and such control of viral replication requires TLR9 for maximal synergy [15]. The ablation of TLR9 and TLR2/9 results in highly increased susceptibility to HSV-caused encephalitis after intranasal inoculation with HSV-1 [16], which suggests that TLR2/9 are required for preventing HSV dissemination into central nervous system (CNS) tissues These various results on the role of TLR2/9 in HSV-caused diseases indicate the need for detailed analysis in a more relevant infection model for a clear understanding. The impact of TLR2/9 on early innate immune

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