Early activation of MyD88-mediated autophagy sustains HSV-1 replication in human monocytic THP-1 cells.

Gabriel Siracusano,Maria Teresa Sciortino,Audrey Esclatine,Assunta Venuti,Antonio Mastino,Daniele Lombardo

doi:10.1038/srep31302

Abstract

Autophagy is a cellular degradation pathway that exerts numerous functions in vital biological processes. Among these, it contributes to both innate and adaptive immunity. On the other hand, pathogens have evolved strategies to manipulate autophagy for their own advantage. By monitoring autophagic markers, we showed that HSV-1 transiently induced autophagosome formation during early times of the infection of monocytic THP-1 cells and human monocytes. Autophagy is induced in THP-1 cells by a mechanism independent of viral gene expression or viral DNA accumulation. We found that the MyD88 signaling pathway is required for HSV-1-mediated autophagy, and it is linked to the toll-like receptor 2 (TLR2). Interestingly, autophagy inhibition by pharmacological modulators or siRNA knockdown impaired viral replication in both THP-1 cells and human monocytes, suggest that the virus exploits the autophagic machinery to its own benefit in these cells. Taken together, these findings indicate that the early autophagic response induced by HSV-1 exerts a proviral role, improving viral production in a semi-permissive model such as THP-1 cells and human monocytes.

Highlights

Macroautophagy is an evolutionary conserved degradation pathway in which cytoplasmic components are sequestered into double membraned structures, known as autophagosomes
We showed that HSV-1 transiently induced autophagy in human monocytic THP-1 cells, independently of the presence of viral DNA or of viral protein synthesis
We found that HSV-1 induces autophagy during the early times of its infection in human undifferentiated monocytes as well

Summary

Introduction

Macroautophagy ( referred to as autophagy) is an evolutionary conserved degradation pathway in which cytoplasmic components are sequestered into double membraned structures, known as autophagosomes. Autophagosomes fuse with lysosomes to form autolysosomes where the content is degraded by lysosomal enzymes It is a highly regulated process, in which Beclin[1] protein plays a key role in both autophagosome formation and maturation. In addition to its role in development and maintaining cellular homeostasis, autophagy is involved in the innate and adaptive immune responses against pathogens, including viruses, and is considered to be an important antiviral defence mechanism. TLRs are transmembrane proteins located either at the plasma membrane or in endosomes They signal via myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β(TRIF)-dependent pathways, two adaptor proteins recruited to TIR domains upon TLRs stimulation[8]. Autophagy stimulation appears to be essential for viral replication in THP-1 cells, suggesting that autophagy plays a proviral role during HSV-1 infection of these cells. Some of the key experiments performed on human monocytes confirm the early activation of autophagy upon HSV-1 infection and its proviral role

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Conclusion