Innate lymphotoxin receptor mediated signaling promotes HSV-1 associated neuroinflammation and viral replication

Yong Liang; Kaiting Yang; Jingya Guo; Joanna Wroblewska; Yang-Xin Fu; Hua Peng

doi:10.1038/srep10406

Innate lymphotoxin receptor mediated signaling promotes HSV-1 associated neuroinflammation and viral replication

Sci Rep. 2015 May 20:5:10406. doi: 10.1038/srep10406.

Authors

Yong Liang¹, Kaiting Yang¹, Jingya Guo², Joanna Wroblewska³, Yang-Xin Fu³, Hua Peng²

Affiliations

¹ 1] Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [2] University of Chinese Academy of Sciences, Beijing 100049, China.
² Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
³ Department of Pathology and Committee on Immunology, University of Chicago, Chicago, Illinois 60637, USA.

Abstract

Host anti-viral innate immunity plays important roles in the defense against HSV-1 infection. In this study, we find an unexpected role for innate LT/LIGHT signaling in promoting HSV-1 replication and virus induced inflammation in immunocompromised mice. Using a model of footpad HSV-1 infection in Rag1(-/-) mice, we observed that blocking LT/LIGHT signaling with LTβR-Ig could significantly delay disease progression and extend the survival of infected mice. LTβR-Ig treatment reduced late proinflammatory cytokine release in the serum and nervous tissue, and inhibited chemokine expression and inflammatory cells infiltration in the dorsal root ganglia (DRG). Intriguingly, LTβR-Ig treatment restricted HSV-1 replication in the DRG but not the footpad. These findings demonstrate a critical role for LT/LIGHT signaling in modulating innate inflammation and promoting HSV-1 replication in the nervous system, and suggest a new target for treatment of virus-induced adverse immune response and control of severe HSV-1 infection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chemokines / genetics
Chemokines / metabolism
Cytokines / genetics
Cytokines / metabolism
Ganglia, Spinal / cytology
Ganglia, Spinal / metabolism
Ganglia, Spinal / virology
Herpes Simplex / metabolism
Herpes Simplex / mortality
Herpes Simplex / pathology
Herpesvirus 1, Human / physiology*
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Immunity, Innate
Inflammation*
Lymphotoxin beta Receptor / chemistry
Lymphotoxin beta Receptor / metabolism*
Lymphotoxin-alpha / antagonists & inhibitors
Lymphotoxin-alpha / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophil Infiltration
Protein Binding
Real-Time Polymerase Chain Reaction
Signal Transduction
Spinal Cord / metabolism
Spinal Cord / virology
Survival Rate
Tumor Necrosis Factor Ligand Superfamily Member 14 / antagonists & inhibitors
Tumor Necrosis Factor Ligand Superfamily Member 14 / genetics
Tumor Necrosis Factor Ligand Superfamily Member 14 / metabolism
Virus Replication

Substances

Chemokines
Cytokines
Homeodomain Proteins
Lymphotoxin beta Receptor
Lymphotoxin-alpha
Tumor Necrosis Factor Ligand Superfamily Member 14
RAG-1 protein