The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity

Jonathan J. Miner, Brian P. Daniels, Bimmi Shrestha, Jose L. Proenca-Modena, Erin D. Lew, Helen M. Lazear, Matthew J. Gorman, Greg Lemke, Robyn S. Klein, Michael S. Diamond

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.

Original languageEnglish (US)
Pages (from-to)1464-1472
Number of pages9
JournalNature medicine
Volume21
Issue number12
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Fingerprint

Virus Diseases
Blood-Brain Barrier
Viruses
Phosphatidylserines
Antiviral Agents
La Crosse virus
Encephalitis Viruses
Virus Internalization
Intercellular Junctions
Protein S
Brain
Innate Immunity
Interferons
Chemical activation
Permeability
Down-Regulation
Endothelial Cells
Ligands
Endothelial cells
Phenotype

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Miner, J. J., Daniels, B. P., Shrestha, B., Proenca-Modena, J. L., Lew, E. D., Lazear, H. M., ... Diamond, M. S. (2015). The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity. Nature medicine, 21(12), 1464-1472. https://doi.org/10.1038/nm.3974
Miner, Jonathan J. ; Daniels, Brian P. ; Shrestha, Bimmi ; Proenca-Modena, Jose L. ; Lew, Erin D. ; Lazear, Helen M. ; Gorman, Matthew J. ; Lemke, Greg ; Klein, Robyn S. ; Diamond, Michael S. / The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity. In: Nature medicine. 2015 ; Vol. 21, No. 12. pp. 1464-1472.
@article{b8fe4f0b9d1249f69abc075abda547cc,
title = "The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity",
abstract = "The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.",
author = "Miner, {Jonathan J.} and Daniels, {Brian P.} and Bimmi Shrestha and Proenca-Modena, {Jose L.} and Lew, {Erin D.} and Lazear, {Helen M.} and Gorman, {Matthew J.} and Greg Lemke and Klein, {Robyn S.} and Diamond, {Michael S.}",
year = "2015",
month = "12",
day = "1",
doi = "https://doi.org/10.1038/nm.3974",
language = "English (US)",
volume = "21",
pages = "1464--1472",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "12",

}

Miner, JJ, Daniels, BP, Shrestha, B, Proenca-Modena, JL, Lew, ED, Lazear, HM, Gorman, MJ, Lemke, G, Klein, RS & Diamond, MS 2015, 'The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity', Nature medicine, vol. 21, no. 12, pp. 1464-1472. https://doi.org/10.1038/nm.3974

The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity. / Miner, Jonathan J.; Daniels, Brian P.; Shrestha, Bimmi; Proenca-Modena, Jose L.; Lew, Erin D.; Lazear, Helen M.; Gorman, Matthew J.; Lemke, Greg; Klein, Robyn S.; Diamond, Michael S.

In: Nature medicine, Vol. 21, No. 12, 01.12.2015, p. 1464-1472.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity

AU - Miner, Jonathan J.

AU - Daniels, Brian P.

AU - Shrestha, Bimmi

AU - Proenca-Modena, Jose L.

AU - Lew, Erin D.

AU - Lazear, Helen M.

AU - Gorman, Matthew J.

AU - Lemke, Greg

AU - Klein, Robyn S.

AU - Diamond, Michael S.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.

AB - The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.

UR - http://www.scopus.com/inward/record.url?scp=84946956225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946956225&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/nm.3974

DO - https://doi.org/10.1038/nm.3974

M3 - Article

C2 - 26523970

VL - 21

SP - 1464

EP - 1472

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 12

ER -