The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity
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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.
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Deficiency in Mertk renders the CNS more susceptible to infection by neuroinvasive viruses such as La Crosse encephalitis virus and WNV.
“Deficiency in this receptor renders the CNS more susceptible to infection by neuroinvasive viruses such as La Crosse encephalitis virus and WNV.”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [152]
Detection of phosphatidylserine by the TAM receptor Mertk in CNS vascular endothelial cells results in barrier tightening because of synergy with type I interferon signaling.
“Detection of this ligand by the TAM receptor Mertk in CNS vascular endothelial cells results in barrier tightening because of synergy with type I interferon signaling (152).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [152]
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- Authors
- Miner, J. J., Daniels, B. P., Shrestha, B., Proenca-Modena, J. L., Lew, E. D., Lazear, H. M., Gorman, M. J., Lemke, G., Klein, R. S., & Diamond, M. S.
- Affiliations
- Washington University in St. Louis (US)
- Salk Institute for Biological Studies (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Diamond, Michael S
- Venue
- Nature Medicine
- Published
- 2015-11-02
- Volume
- 21
- Issue
- 12
- Pages
- 1464-1472
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4674389
- OpenAlex
- W1952498922
- Cited by
- 152
- References
- 50
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 25 · 2023: 11 · 2022: 8 · 2021: 15 · 2020: 12 · 2019: 15 · 2018: 10 · 2017: 23 · 2016: 16 · 2015: 1
- FWCI
- 8.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Americanae (AECID Library) (submittedVersion)
- UNC Libraries
- Funders
- National Science Foundation (1143954)
- Leukemia and Lymphoma Society
- Rheumatology Research Foundation
- NOMIS Stiftung
- National Institutes of Health (DGE-1143954, F31-NS07866, AI083019)
- National Cancer Institute (P30CA014195)
- National Institute of Allergy and Infectious Diseases (U19AI083019, R01AI101400)
- National Institute of Neurological Disorders and Stroke (R01NS085296, R01NS052632, F31-NS07866)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR007279)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- TAM receptors, MERTK, AXL, Tyro3, blood-brain barrier integrity, West Nile virus, La Crosse virus, encephalitis virus, phosphatidylserine, apoptotic mimicry, interferon-beta, cell junctions, brain microvascular endothelial cells, innate immunity
- MeSH terms
- c-Mer Tyrosine Kinase, Axl Receptor Tyrosine Kinase, Animals, Astrocytes, Blood-Brain Barrier, Encephalitis, California, Mice, Inbred C57BL, Permeability, Proto-Oncogene Proteins, Radiation Tolerance, West Nile Fever, West Nile virus, Signal Transduction, Survival Analysis, Interferon-beta, La Crosse virus, Mice, Knockout, Chemokines, Viral Load, Protective Agents, Receptor Protein-Tyrosine Kinases, Endothelial Cells, Microvessels, Adaptive Immunity
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