Matrix metalloproteinase 14 regulates HSV-1 infection in neuroblastoma cells

Patricia Llorente,Víctor Mejías,Isabel Sastre,María Recuero,Jesús Aldudo,Maria J Bullido

doi:10.1016/j.antiviral.2021.105116

Abstract

Growing evidence supports that chronic or latent infection of the central nervous system might be implicated in Alzheimer's disease (AD). Among them, Herpes simplex virus type 1 (HSV-1) has emerged as a major factor in the etiology of the disease. Our group is devoted to the study of the relationship among HSV-1, oxidative stress (OS) and neurodegeneration. We have found that HSV-1 induces the main neuropathological hallmarks of AD, including the accumulation of intracellular amyloid beta (Aβ), hyperphosphorylated tau protein and autophagic vesicles, that OS exacerbates these effects, and that matrix metalloproteinase 14 (MMP-14) participates in the alterations induced by OS.In this work, we focused on the role of MMP-14 in the degenerative markers raised by HSV-1 infection. Interestingly, we found that MMP-14 blockage is a potent inhibitor of HSV-1 infection efficiency, that also reduces the degeneration markers, accumulation of Aβ and hyperphosphorylated tau, induced by the virus. Our results point to MMP-14 as a potent antiviral target to control HSV-1 infection and its associated neurodegenerative effects.

Highlights

We focused on the role of matrix metalloproteinase 14 (MMP-14) in the degenerative markers raised by Herpes simplex virus type 1 (HSV-1) infection
Taking this relation among matrix metalloproteinase family (MMPs) and viral infections into account, we decided to explore the role of MMP-14 in HSV-1 infection and the Alz heimer’s disease (AD)-like phenotype in cell models of neurodegeneration induced by the virus (Santana et al, 2012a, b, 2013)
SK-N-MC cells were treated with the inhibitor for 24 h before the infection, or the inhibitor was added after viral adsorption

Summary

Introduction

Growing evidence indicates that chronic or latent infection of the central nervous system might be implicated in the etiology of Alz heimer’s disease (AD) (see recent reviews (Fulop et al, 2018; Haas and Lathe 2018; Harris and Harris 2015; Itzhaki 2016)). Evidence from epidemiological studies postulate that, in synergy with the possession of the APOE-ε4 allele, HSV-1 infection represents a risk factor for AD (Itzhaki et al, 1997). A big epidemiological survey in the Taiwanese population raised the striking observation that the risk of senile dementia was much greater in HSV-seropositive subjects and that antiviral treatment caused a dramatic decrease in the development of dementia (Tzeng et al, 2018). These findings have refueled the field leading some researchers to claim for a change in the current paradigms relating the causes and mechanisms of AD (Fulop et al, 2018; Haas and Lathe 2018)

Role of MMPs in viral infections

Cell lines

Cell treatments

Cell analysis

MMP-14 inhibition or deficiency reduces HSV-1 infection

MMP-14 inhibition affects HSV-1 infection at early stages of the viral cycle