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Chaperokine Activity of Heat Shock Proteins pp 23–55Cite as

Extracellular HSP70, Neuroinflammation and Protection Against Viral Virulence

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Part of the book series: Heat Shock Proteins ((HESP,volume 16))

Abstract

The major inducible 70 kDa heat shock protein (hsp70) is induced by and supports intracellular replication of viruses belonging to diverse families. Paradoxically, this virus-hsp70 interaction is protective in mouse models of viral neurovirulence, enhancing T cell mediated immune clearance in an interferon β (IFN-β)-dependent manner. Protection reflects early release of hsp70 from viable infected neurons and induction of strong innate immune responses in uninfected brain macrophages, including the induction of IFN-β through Toll-like receptor 4. Potency of the response is inherent in the fact that hsp70 is released at a time when pathogen-associated molecular patterns (PAMPs) are in low abundance, and that the innate response is driven by uninfected cells, free from viral interference. Release of hsp70 from viable cells is primarily exosomal, and infection enhances total exosome release and hsp70 content on the surface of exosomes. Exosome content of hsp70 reflects levels of hsp70 in the infected cell. Findings have broad virological relevance and support a protective role for fever, a potent stimulus for hsp70 induction. While protective in the context of microbial infection, recent findings support potential untoward effects of inappropriate extracellular hsp70 release in non-infectious neuroinflammatory conditions.

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Abbreviations

ANOVA:

Analysis of variance

CHUK:

Conserved helix-loop-helix ubiquitous ligase

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DAMP:

Damage-associated molecular pattern

DMEM:

Dulbecco’s Modified Eagle medium

Ed CAM/RB:

Rodent brain adapted Ed-MeV

Ed-MeV:

Edmonston measles virus

ELISA:

Enzyme-linked immunosorbent assay

FCS:

Fetal calf serum

H-2:

Mouse major histocompatibility complex

HSF:

Heat shock factor

hsp70:

70 kDa heat shock protein

IFN:

Interferon

IFNAR:

Type 1 interferon receptor

ILV:

Intralumenal vesicle

IRF3:

Interferon regulatory factor 3

L:

Viral polymerase protein

LDH:

Lactate dehydrogenase

LPS:

Lipopolysaccharide

MEF:

Mouse embryo fibroblasts

MeV:

Measles virus

MHC:

Major histocompatibility complex

MVB:

Multivesicular body

N:

Nucleocapsid protein

N2a-HSP:

Mouse neuroblastoma cells that constitutively express hsp70

N2a-V:

Vector transfected control mouse neuroblastoma cells

NBD:

Nucleotide binding domain

NDV:

Newcastle disease virus

NSE:

Neuron specific enolase

NTAIL :

Carboxyl terminus of the N protein

PAMP:

Pathogen-associated molecular pattern

PBD:

Peptide binding domain (also known as the substrate binding domain, SBD)

RSV:

Respiratory syncytial virus

RT-PCR:

Reverse transcription polymerase chain reaction

SBD:

Substrate binding domain

STAT-1:

Signal transducer and activator of transcription 1

TLR:

Toll-like receptor

TRAM:

Toll-like receptor adapter molecule 2

TRIF:

TIR-domain-containing adapter-inducing interferon-β

VSV:

Vesicular stomatitis virus

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Acknowledgements

This work was supported in part by funds from the National Institute of Neurological Disorders and Stroke (R01NS31693). We thank Dr. Mamuka Kvaratskhelia (The Ohio State University) for assistance in the proteome analysis of exosomes and Dr. Prosper Boyaka (The Ohio State University) for suggestions in preparing the manuscript.

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Authors and Affiliations

  1. Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA

    Michael Oglesbee

  2. Pharmaceutical Safety Evaluation Division, Ministry of Food and Drug Safety, Cheongju, Republic of Korea

    Mi Young Kim

  3. Department of Neuroscience, Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA

    Yaoling Shu

  4. CNRS, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR, Aix-Marseille Univ, Marseille, France

    Sonia Longhi

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  1. Michael Oglesbee
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  2. Mi Young Kim
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  3. Yaoling Shu
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  4. Sonia Longhi
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Correspondence to Michael Oglesbee .

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Editors and Affiliations

  1. Department of Medicine and Director, Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer Center, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Punit Kaur

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Oglesbee, M., Kim, M.Y., Shu, Y., Longhi, S. (2019). Extracellular HSP70, Neuroinflammation and Protection Against Viral Virulence. In: Asea, A., Kaur, P. (eds) Chaperokine Activity of Heat Shock Proteins . Heat Shock Proteins, vol 16. Springer, Cham. https://doi.org/10.1007/978-3-030-02254-9_2

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