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


: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.


Nat Med


Nature medicine


Miner JJ,Daniels BP,Shrestha B,Proenca-Modena JL,Lew ED,Lazear HM,Gorman MJ,Lemke G,Klein RS,Diamond MS




Has Abstract


2015-12-01 00:00:00














  • Publisher Correction: Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency.

    abstract::In the version of this article originally published, there was an error in the legend for Extended Data Fig. 7. The legend for panel f was originally: "f, FACS analysis of IL7R-, CD62L- and CD45RA- expression on TRAC-1928ζ and TRAC-1XX CAR T cells at day 63 post CAR infusion (representative for at least n = 3 mice per...

    journal_title:Nature medicine

    pub_type: 已发布勘误


    authors: Feucht J,Sun J,Eyquem J,Ho YJ,Zhao Z,Leibold J,Dobrin A,Cabriolu A,Hamieh M,Sadelain M

    更新日期:2019-03-01 00:00:00

  • TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration.

    abstract::Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca(2+)-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H(2)O(2)) evoke...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Yamamoto S,Shimizu S,Kiyonaka S,Takahashi N,Wajima T,Hara Y,Negoro T,Hiroi T,Kiuchi Y,Okada T,Kaneko S,Lange I,Fleig A,Penner R,Nishi M,Takeshima H,Mori Y

    更新日期:2008-07-01 00:00:00

  • Novel role of human CD4 molecule identified in neurodegeneration.

    abstract::The human CD4 molecule (hCD4) is expressed on T lymphocytes and macrophages and acts as a key component of the cellular receptor for HIV. At baseline, hCD4 transgenic mice expressed hCD4 on microglia, the resident mononuclear phagocytes of the brain, and showed no neuronal damage. Activation of brain microglia by peri...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Buttini M,Westland CE,Masliah E,Yafeh AM,Wyss-Coray T,Mucke L

    更新日期:1998-04-01 00:00:00

  • Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression.

    abstract::Genetic variants of human and simian immunodeficiency virus (HIV and SIV) that evolve during the course of infection and progression to AIDS are phenotypically and antigenically distinct from their progenitor viruses present at early stages of infection. However, it has been unclear how these late variants, which are ...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Kimata JT,Kuller L,Anderson DB,Dailey P,Overbaugh J

    更新日期:1999-05-01 00:00:00

  • Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells.

    abstract::Despite a more than 20-year experience of therapeutic benefit, the relevant molecular and cellular targets of intravenous immunoglobulin (IVIg) in autoimmune disease remain unclear. Contrary to the prevailing theories of IVIg action in autoimmunity, we show that IVIg drives signaling through activating Fc gamma recept...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Siragam V,Crow AR,Brinc D,Song S,Freedman J,Lazarus AH

    更新日期:2006-06-01 00:00:00

  • Real-time quantitative RT-PCR after laser-assisted cell picking.

    abstract::The present study describes a technique for quantitation of mRNA in a few isotypic cells obtained from an intact organ structure by combining laser-assisted cell picking and real-time PCR. The microscopically controlled lasering of selected cells in stained tissue sections was applied to lung alveolar macrophages, whi...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Fink L,Seeger W,Ermert L,Hänze J,Stahl U,Grimminger F,Kummer W,Bohle RM

    更新日期:1998-11-01 00:00:00

  • A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis.

    abstract::Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAE...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Johnson DB,McDonnell WJ,Gonzalez-Ericsson PI,Al-Rohil RN,Mobley BC,Salem JE,Wang DY,Sanchez V,Wang Y,Chastain CA,Barker K,Liang Y,Warren S,Beechem JM,Menzies AM,Tio M,Long GV,Cohen JV,Guidon AC,O'Hare M,Chandra S

    更新日期:2019-08-01 00:00:00

  • Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria.

    abstract::Infection with Plasmodium falciparum during pregnancy leads to the accumulation of parasite-infected erythrocytes in the placenta, and is associated with excess perinatal mortality, premature delivery and intrauterine growth retardation in the infant, as well as increased maternal mortality and morbidity. P. falciparu...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Beeson JG,Rogerson SJ,Cooke BM,Reeder JC,Chai W,Lawson AM,Molyneux ME,Brown GV

    更新日期:2000-01-01 00:00:00

  • CD8+ T cell efficacy in vaccination and disease.

    abstract::Much effort has been devoted to the design of vaccines that induce adaptive cellular immunity, in particular CD8+ T cells, which have a central role in the host response to viral infections and cancers. To date, however, the development of effective T cell vaccines remains elusive. This is due, in part, to the lack of...

    journal_title:Nature medicine

    pub_type: 杂志文章,评审


    authors: Appay V,Douek DC,Price DA

    更新日期:2008-06-01 00:00:00

  • ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents.

    abstract::The 55-kilodalton (kDa) protein from the E1B-region of adenovirus binds to and inactivates the p53 gene, which is mutated in half of human cancers. We have previously shown that the replication and cytopathogenicity of an E1B, 55-kDa gene-attenuated adenovirus, ONYX-015, is blocked by functional p53 in RKO and U20S ca...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Heise C,Sampson-Johannes A,Williams A,McCormick F,Von Hoff DD,Kirn DH

    更新日期:1997-06-01 00:00:00

  • Identification of oxadiazoles as new drug leads for the control of schistosomiasis.

    abstract::Treatment for schistosomiasis, which is responsible for more than 280,000 deaths annually, depends almost exclusively on praziquantel. Millions of people are treated annually with praziquantel, and drug-resistant parasites thus are likely to evolve. Phosphinic amides and oxadiazole 2-oxides, identified from a quantita...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Sayed AA,Simeonov A,Thomas CJ,Inglese J,Austin CP,Williams DL

    更新日期:2008-04-01 00:00:00

  • Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins.

    abstract::Mutations in genes encoding splicing factors (which we refer to as spliceosomal genes) are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition. Spl...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Lee SC,Dvinge H,Kim E,Cho H,Micol JB,Chung YR,Durham BH,Yoshimi A,Kim YJ,Thomas M,Lobry C,Chen CW,Pastore A,Taylor J,Wang X,Krivtsov A,Armstrong SA,Palacino J,Buonamici S,Smith PG,Bradley RK,Abdel-Wahab O

    更新日期:2016-06-01 00:00:00

  • Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes.

    abstract::Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wi...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Kim MS,Kwon HJ,Lee YM,Baek JH,Jang JE,Lee SW,Moon EJ,Kim HS,Lee SK,Chung HY,Kim CW,Kim KW

    更新日期:2001-04-01 00:00:00

  • Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy.

    abstract::Despite the central role of the liver in the regulation of glucose and lipid metabolism, there are currently no methods to directly assess hepatic oxidative metabolism in humans in vivo. By using a new (13)C-labeling strategy in combination with (13)C magnetic resonance spectroscopy, we show that rates of mitochondria...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Befroy DE,Perry RJ,Jain N,Dufour S,Cline GW,Trimmer JK,Brosnan J,Rothman DL,Petersen KF,Shulman GI

    更新日期:2014-01-01 00:00:00

  • Fighting tobacco dependence in Europe.

    abstract::The World Health Organization estimates that tobacco will become the largest single health problem by 2020, causing an estimated 8.4 million deaths annually. But the smoking burden will not be distributed evenly across the globe; deaths in developed nations are set to rise 50% to 2.4 million while those in Asia will s...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Raw M

    更新日期:2001-01-01 00:00:00

  • Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition.

    abstract::Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therape...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Johnson N,Li YC,Walton ZE,Cheng KA,Li D,Rodig SJ,Moreau LA,Unitt C,Bronson RT,Thomas HD,Newell DR,D'Andrea AD,Curtin NJ,Wong KK,Shapiro GI

    更新日期:2011-06-26 00:00:00

  • Endogenous antigen processing drives the primary CD4+ T cell response to influenza.

    abstract::By convention, CD4+ T lymphocytes recognize foreign and self peptides derived from internalized antigens in combination with major histocompatibility complex class II molecules. Alternative pathways of epitope production have been identified, but their contributions to host defense have not been established. We show h...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Miller MA,Ganesan AP,Luckashenak N,Mendonca M,Eisenlohr LC

    更新日期:2015-10-01 00:00:00

  • King of hearts: a splicing factor rules cardiac proteins.

    abstract::Alternative splicing ensures the expression of functionally diverse proteins from individual genes; however, aberrant mRNA splicing is associated with various conditions, including heart disease. A recent study provides new mechanistic insights into heart failure by showing that a human cardiomyopathy-linked mutation ...

    journal_title:Nature medicine

    pub_type: 评论,杂志文章


    authors: Linke WA,Bücker S

    更新日期:2012-05-04 00:00:00

  • Urinary bladder-urethral sphincter dysfunction in mice with targeted disruption of neuronal nitric oxide synthase models idiopathic voiding disorders in humans.

    abstract::Idiopathic voiding disorders affect up to 10-15% of men and women. We describe bladder abnormalities in mice with targeted deletion of the gene for neuronal nitric oxide synthase which model the clinical disorders. The mice possess hypertrophic dilated bladders and dysfunctional urinary outlets which do not relax in r...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Burnett AL,Calvin DC,Chamness SL,Liu JX,Nelson RJ,Klein SL,Dawson VL,Dawson TM,Snyder SH

    更新日期:1997-05-01 00:00:00

  • Nociceptor sensitization in pain pathogenesis.

    abstract::The incidence of chronic pain is estimated to be 20-25% worldwide. Few patients with chronic pain obtain complete relief from the drugs that are currently available, and more than half report inadequate relief. Underlying the challenge of developing better drugs to manage chronic pain is incomplete understanding of th...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Gold MS,Gebhart GF

    更新日期:2010-11-01 00:00:00

  • A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity.

    abstract::Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that is initiated when self-reactive T cells enter the brain and become locally activated after encountering their specific nervous antigens. When and where the disease-relevant antigen encounters occur is unclear. Here we combined fluores...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Lodygin D,Odoardi F,Schläger C,Körner H,Kitz A,Nosov M,van den Brandt J,Reichardt HM,Haberl M,Flügel A

    更新日期:2013-06-01 00:00:00

  • Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis.

    abstract::We previously demonstrated that low biosynthesis of ω-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet-fed mice. These findings prompted a more direct study of the therapeutic potential...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: White PJ,St-Pierre P,Charbonneau A,Mitchell PL,St-Amand E,Marcotte B,Marette A

    更新日期:2014-06-01 00:00:00

  • Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

    abstract::Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs)...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Cañadas I,Thummalapalli R,Kim JW,Kitajima S,Jenkins RW,Christensen CL,Campisi M,Kuang Y,Zhang Y,Gjini E,Zhang G,Tian T,Sen DR,Miao D,Imamura Y,Thai T,Piel B,Terai H,Aref AR,Hagan T,Koyama S,Watanabe M,Baba H,

    更新日期:2018-08-01 00:00:00

  • Inhibition of gastric inhibitory polypeptide signaling prevents obesity.

    abstract::Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with ins...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Miyawaki K,Yamada Y,Ban N,Ihara Y,Tsukiyama K,Zhou H,Fujimoto S,Oku A,Tsuda K,Toyokuni S,Hiai H,Mizunoya W,Fushiki T,Holst JJ,Makino M,Tashita A,Kobara Y,Tsubamoto Y,Jinnouchi T,Jomori T,Seino Y

    更新日期:2002-07-01 00:00:00

  • Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough.

    abstract::Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is u...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Fox AJ,Lalloo UG,Belvisi MG,Bernareggi M,Chung KF,Barnes PJ

    更新日期:1996-07-01 00:00:00

  • Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120.

    abstract::Diabetes, a disease in which the body does not produce or use insulin properly, is a serious global health problem. Gut polypeptides secreted in response to food intake, such as glucagon-like peptide-1 (GLP-1), are potent incretin hormones that enhance the glucose-dependent secretion of insulin from pancreatic beta ce...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Hirasawa A,Tsumaya K,Awaji T,Katsuma S,Adachi T,Yamada M,Sugimoto Y,Miyazaki S,Tsujimoto G

    更新日期:2005-01-01 00:00:00

  • Detecting opioid overdoses with smartphones.

    abstract:: ...

    journal_title:Nature medicine

    pub_type: 评论,杂志文章


    authors: Stower H

    更新日期:2019-02-01 00:00:00

  • Active movement of T cells away from a chemokine.

    abstract::Movement towards or away from a given stimulus guides the directional migration of prokaryotes, simple eukaryotes and neurons. As bi-directional cues may influence entry and exit of immune effector cells from tissue sites, we evaluated the migratory responses of T-cell subsets to varying concentrations of the chemokin...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Poznansky MC,Olszak IT,Foxall R,Evans RH,Luster AD,Scadden DT

    更新日期:2000-05-01 00:00:00

  • Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.

    abstract::One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Bard F,Cannon C,Barbour R,Burke RL,Games D,Grajeda H,Guido T,Hu K,Huang J,Johnson-Wood K,Khan K,Kholodenko D,Lee M,Lieberburg I,Motter R,Nguyen M,Soriano F,Vasquez N,Weiss K,Welch B,Seubert P,Schenk D,Yednock

    更新日期:2000-08-01 00:00:00

  • In vivo imaging of glucose uptake and metabolism in tumors.

    abstract::Tumors have a greater reliance on anaerobic glycolysis for energy production than normal tissues. We developed a noninvasive method for imaging glucose uptake in vivo that is based on magnetic resonance imaging and allows the uptake of unlabeled glucose to be measured through the chemical exchange of protons between h...

    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Walker-Samuel S,Ramasawmy R,Torrealdea F,Rega M,Rajkumar V,Johnson SP,Richardson S,Gonçalves M,Parkes HG,Arstad E,Thomas DL,Pedley RB,Lythgoe MF,Golay X

    更新日期:2013-08-01 00:00:00