Extracellular HSP70, Neuroinflammation and Protection Against Viral Virulence

  • Michael OglesbeeEmail author
  • Mi Young Kim
  • Yaoling Shu
  • Sonia Longhi
Part of the Heat Shock Proteins book series (HESP, volume 16)


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.


70 kDa heat shock protein Exosome Hsp70 Interferon beta Neurovirulence Virus clearance 



Analysis of variance


Conserved helix-loop-helix ubiquitous ligase


Central nervous system


Cerebrospinal fluid


Damage-associated molecular pattern


Dulbecco’s Modified Eagle medium


Rodent brain adapted Ed-MeV


Edmonston measles virus


Enzyme-linked immunosorbent assay


Fetal calf serum


Mouse major histocompatibility complex


Heat shock factor


70 kDa heat shock protein




Type 1 interferon receptor


Intralumenal vesicle


Interferon regulatory factor 3


Viral polymerase protein


Lactate dehydrogenase




Mouse embryo fibroblasts


Measles virus


Major histocompatibility complex


Multivesicular body


Nucleocapsid protein


Mouse neuroblastoma cells that constitutively express hsp70


Vector transfected control mouse neuroblastoma cells


Nucleotide binding domain


Newcastle disease virus


Neuron specific enolase


Carboxyl terminus of the N protein


Pathogen-associated molecular pattern


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


Respiratory syncytial virus


Reverse transcription polymerase chain reaction


Substrate binding domain


Signal transducer and activator of transcription 1


Toll-like receptor


Toll-like receptor adapter molecule 2


TIR-domain-containing adapter-inducing interferon-β


Vesicular stomatitis virus



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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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Michael Oglesbee
    • 1
    Email author
  • Mi Young Kim
    • 2
  • Yaoling Shu
    • 3
  • Sonia Longhi
    • 4
  1. 1.Department of Veterinary BiosciencesThe Ohio State UniversityColumbusUSA
  2. 2.Pharmaceutical Safety Evaluation DivisionMinistry of Food and Drug SafetyCheongjuRepublic of Korea
  3. 3.Department of Neuroscience, Center for Brain and Spinal Cord RepairThe Ohio State UniversityColumbusUSA
  4. 4.CNRS, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMRAix-Marseille UnivMarseilleFrance

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