The Solute Carrier Transporter SLC15A3 Participates in Antiviral Innate Immune Responses against Herpes Simplex Virus-1.

Longzhen He,Yuanyuan Li,Peiling Li,Leqing Zhu,Baocheng Wang,Lianghua Bin,Feiyan Zou

doi:10.1155/2018/5214187

Abstract

The innate immune response is the first line defense against viral infections. Novel genes involved in this system are continuing to emerge. SLC15A3, a proton-coupled histidine and di-tripeptide transporter that was previously found in lysosomes, has been reported to inhibit chikungunya viral replication in host cells. In this study, we found that SLC15A3 was significantly induced by DNA virus herpes simplex virus-1(HSV-1) in monocytes from human peripheral blood mononuclear cells. Aside from monocytes, it can also be induced by HSV-1 in 293T, HeLa cells, and HaCaT cells. Overexpression of SLC15A3 in 293T cells inhibits HSV-1 replication and enhances type I and type III interferon (IFN) responses, while silencing SLC15A3 leads to enhanced HSV-1 replication with reduced IFN production. Moreover, we found that SLC15A3 interacted with MAVS and STING and potentiated MAVS- and STING-mediated IFN production. These results demonstrate that SLC15A3 participates in anti-HSV-1 innate immune responses by regulating MAVS- and STING-mediated signaling pathways.

Highlights

The innate immune response against viral infection is initiated by pattern recognition receptors (PRR) that recognize virally derived pathogen-associated molecular patterns (PAMPs)
In order to identify novel genes that are involved in the innate immune response against herpes simplex virus-1 (HSV-1), we analyzed the transcriptomes of HSV-1-stimulated human PBMCs in comparison to PBMCs without HSV-1 stimulation using a previously published data set (GSE60481) [21]
These experiments identified a group of solute carrier (SLC) transporters which were significantly upregulated in HSV-1-stimulated PBMCs as compared to PBMCs without stimulation (Table S3)

Summary

Introduction

The innate immune response against viral infection is initiated by pattern recognition receptors (PRR) that recognize virally derived pathogen-associated molecular patterns (PAMPs). Viral nucleic acids, including DNA and RNA, are classic PAMPs that activate signaling pathways leading to induction of type I/type III interferons and proinflammatory cytokines. These cytokines subsequently induce a wide range of genes to restrict and kill invading viruses, mediate inflammatory responses, and regulate adaptive immune responses [1,2,3]. Cytosolic RNA sensors and DNA receptors have been identified to recognize virus-derived double-stranded RNA and DNA in host cells, respectively. Two DExD/H-box RNA helicases, retinoic acid-inducible gene 1 (RIG-1) and melanoma differentiation-associated gene 5 (MDA5), recognize double-stranded RNA and activate downstream signaling cascades through adaptor MAVS (VISA) [4,5,6]. STING (MITA) is the adaptor for cGAS to activate IFN responses [12,13,14]

Methods

Results

Conclusion