Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons.

Andy Yanez,Heather Sriranganathan,Telvin Harrell,Angela Ives,Andrea Bertke

doi:10.3390/pathogens6010005

Andy Yanez, Heather Sriranganathan + Show 3 more

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https://doi.org/10.3390/pathogens6010005

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Abstract

Herpes simplex viruses (HSV1 and HSV2) establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF) maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs). Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG) and sympathetic superior cervical ganglia (SCG) after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF) deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN) and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons.

Highlights

Following infection and replication in the epithelium, herpes simplex viruses 1 and 2 (HSV1 and HSV2) gain entry into sensory and autonomic neurons innervating the site of infection [1,2,3,4]
Previous studies showed that nerve growth factor (NGF) deprivation efficiently induced HSV1 reactivation from cultured sympathetic neurons derived from embryonic mouse superior cervical ganglia (SCG) [22,24]
We sought to determine if NGF deprivation induced reactivation of HSV1 and HSV2 in cultured mouse sympathetic neurons derived from adult mice

Summary

Introduction

Following infection and replication in the epithelium, herpes simplex viruses 1 and 2 (HSV1 and HSV2) gain entry into sensory and autonomic neurons innervating the site of infection [1,2,3,4]. In other types of neurons, the viruses do not replicate and instead establish latency, from which they can periodically reactivate to cause recurrent disease. Half of HSV1 latent sites are detected in a population of sensory neurons identified as Fe-A5+ neurons, but few latent sites are detected in neurons recognized by the monoclonal antibody KH10 (KH10+) or isolectin GS-IB4 (IB4+), due to selective HSV1 replication in KH10/IB4+ neurons, which kills them [5,7]. HSV2 preferentially establishes latency in KH10/IB4+ neurons and selectively replicates in Fe-A5+ neurons, resulting in Fe-A5+ neuronal cell death and minimal latent sites detectable in Fe-A5+ neurons [6,8]

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