MyD88 signaling by neurons induces chemokines that recruit protective leukocytes to the virus-infected CNS

During viral CNS infection, MyD88 signaling in infected neurons orchestrates recruitment of protective peripheral immune cells. Encephalitis protection Viral encephalitis is caused by infection of the CNS by neurotropic viruses and can result in long-term neurological complications or death. Ghita et al. studied the role of the innate immune signaling adapter myeloid differentiation primary response gene 88 (MyD88) in a vesicular stomatitis virus (VSV) murine model of CNS infection. MyD88 is a signaling adapter for TLR and IL-1 receptor signaling. Here, they observed that MyD88 was required for recruitment of leukocytes to the CNS, especially CD8 T cells, and it was critical for protection against death. MyD88 signaling in neurons was needed for chemokine production and leukocyte recruitment to the CNS, and together, these findings provide insight into innate immune mechanisms involved in protection against viral encephalitis. Viral encephalitis initiates a series of immunological events in the brain that can lead to brain damage and death. Astrocytes express IFN-β in response to neurotropic infection, whereas activated microglia produce proinflammatory cytokines and accumulate at sites of infection. Here, we observed that neurotropic vesicular stomatitis virus (VSV) infection causes recruitment of leukocytes into the central nervous system (CNS), which requires MyD88, an adaptor of Toll-like receptor and interleukin-1 receptor signaling. Infiltrating leukocytes, and in particular CD8+ T cells, protected against lethal VSV infection of the CNS. Reconstitution of MyD88, specifically in neurons, restored chemokine production in the olfactory bulb as well as leukocyte recruitment into the infected CNS and enhanced survival. Comparative analysis of the translatome of neurons and astrocytes verified neurons as the critical source of chemokines, which regulated leukocyte infiltration of the infected brain and affected survival.

[1]  D. Nayak,et al.  T cell engagement of cross-presenting microglia protects the brain from a nasal virus infection , 2020, Science Immunology.

[2]  P. Williamson,et al.  Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis , 2020, Science Advances.

[3]  S. Mirarab,et al.  Sequence Analysis , 2020, Encyclopedia of Bioinformatics and Computational Biology.

[4]  R. Klein,et al.  Astrocyte‐T cell crosstalk regulates region‐specific neuroinflammation , 2020, Glia.

[5]  Chiung-Ya Chen,et al.  Beyond defense: regulation of neuronal morphogenesis and brain functions via Toll-like receptors , 2019, Journal of Biomedical Science.

[6]  R. Klein,et al.  T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses , 2019, Nature Neuroscience.

[7]  Philippe A. Robert,et al.  IFN-γ Producing Th1 Cells Induce Different Transcriptional Profiles in Microglia and Astrocytes , 2018, Front. Cell. Neurosci..

[8]  M. Prinz,et al.  Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation during Viral Encephalitis , 2018, Cell Reports.

[9]  G. D. Liberto,et al.  Neurons under T Cell Attack Coordinate Phagocyte-Mediated Synaptic Stripping , 2018, Cell.

[10]  D. Gomez-Nicola,et al.  Neuroinflammation: Microglia and T Cells Get Ready to Tango , 2018, Front. Immunol..

[11]  R. Klein,et al.  Protective and Pathological Immunity during Central Nervous System Infections , 2017, Immunity.

[12]  Christopher M. Bland,et al.  Management of Viral Central Nervous System Infections: A Primer for Clinicians , 2017, Journal of central nervous system disease.

[13]  T. Korn,et al.  T cell responses in the central nervous system , 2017, Nature Reviews Immunology.

[14]  R. Klein,et al.  The Olfactory Bulb: An Immunosensory Effector Organ during Neurotropic Viral Infections. , 2016, ACS chemical neuroscience.

[15]  I. Bechmann,et al.  Central Nervous System Stromal Cells Control Local CD8+ T Cell Responses during Virus-Induced Neuroinflammation , 2016, Immunity.

[16]  A. Kröger,et al.  Type I Interferon response in olfactory bulb, the site of tick-borne flavivirus accumulation, is primarily regulated by IPS-1 , 2016, Journal of Neuroinflammation.

[17]  R. Klein,et al.  CCR5 limits cortical viral loads during West Nile virus infection of the central nervous system , 2015, Journal of Neuroinflammation.

[18]  H. Carabin,et al.  Global research priorities for infections that affect the nervous system , 2015, Nature.

[19]  R. Klein,et al.  Chemokines Referee Inflammation within the Central Nervous System during Infection and Disease , 2014, Advances in medicine.

[20]  Jun Xiao,et al.  Met-CCL5 represents an immunotherapy strategy to ameliorate rabies virus infection , 2014, Journal of Neuroinflammation.

[21]  D. Baker,et al.  Concomitant TLR/RLH Signaling of Radioresistant and Radiosensitive Cells Is Essential for Protection against Vesicular Stomatitis Virus Infection , 2014, The Journal of Immunology.

[22]  N. Sarvetnick,et al.  TLR signaling controls lethal encephalitis in WNV-infected brain , 2014, Brain Research.

[23]  N. Prow,et al.  Mechanism of West Nile Virus Neuroinvasion: A Critical Appraisal , 2014, Viruses.

[24]  M. Regner,et al.  Cytolytic effector pathways and IFN‐γ help protect against Japanese encephalitis , 2013, European journal of immunology.

[25]  K. Pfeffer,et al.  Cutting edge: Divergent cell-specific functions of MyD88 for inflammatory responses and organ injury in septic peritonitis. , 2012, Journal of immunology.

[26]  I. Bechmann,et al.  Host strategies against virus entry via the olfactory system , 2011, Virulence.

[27]  Songbin Fu,et al.  A Novel Toll-like Receptor That Recognizes Vesicular Stomatitis Virus* , 2010, The Journal of Biological Chemistry.

[28]  B. Heimrich,et al.  Fusion-active glycoprotein G mediates the cytotoxicity of vesicular stomatitis virus M mutants lacking host shut-off activity. , 2010, The Journal of general virology.

[29]  M. Diamond,et al.  The Innate Immune Adaptor Molecule MyD88 Restricts West Nile Virus Replication and Spread in Neurons of the Central Nervous System , 2010, Journal of Virology.

[30]  T. Lane,et al.  The Role of Chemokines during Viral Infection of the CNS , 2010, PLoS pathogens.

[31]  S. Akira,et al.  The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors , 2010, Nature Immunology.

[32]  S. Akira,et al.  Pattern Recognition Receptors and Inflammation , 2010, Cell.

[33]  R. Palmiter,et al.  Cell-type-specific isolation of ribosome-associated mRNA from complex tissues , 2009, Proceedings of the National Academy of Sciences.

[34]  I. Bechmann,et al.  Local Type I IFN Receptor Signaling Protects against Virus Spread within the Central Nervous System1 , 2009, The Journal of Immunology.

[35]  B. Mishra,et al.  Expression and distribution of Toll-like receptors 11–13 in the brain during murine neurocysticercosis , 2008, Journal of Neuroinflammation.

[36]  Michael Gale,et al.  Toll-Like Receptor 3 Has a Protective Role against West Nile Virus Infection , 2008, Journal of Virology.

[37]  M. Diamond,et al.  CXCR3 Mediates Region-Specific Antiviral T Cell Trafficking within the Central Nervous System during West Nile Virus Encephalitis1 , 2008, The Journal of Immunology.

[38]  H. Boddeke,et al.  Neuronal Chemokines: Versatile Messengers In Central Nervous System Cell Interaction , 2007, Molecular Neurobiology.

[39]  B. Becher,et al.  Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. , 2006, The Journal of clinical investigation.

[40]  M. Diamond,et al.  CD8+ T Cells Require Perforin To Clear West Nile Virus from Infected Neurons , 2006, Journal of Virology.

[41]  R. Cholera,et al.  Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection , 2005, The Journal of experimental medicine.

[42]  F. Mégret,et al.  Virus Infection Switches TLR-3-Positive Human Neurons To Become Strong Producers of Beta Interferon , 2005, Journal of Virology.

[43]  M. Diamond,et al.  Neuronal CXCL10 Directs CD8+ T-Cell Recruitment and Control of West Nile Virus Encephalitis , 2005, Journal of Virology.

[44]  E. Fikrig,et al.  Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis , 2004, Nature Medicine.

[45]  Akiko Iwasaki,et al.  Recognition of single-stranded RNA viruses by Toll-like receptor 7. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[46]  P. Kennedy.  Neurological infection , 2004, The Lancet Neurology.

[47]  Jiahuai Han,et al.  Identification of Lps2 as a key transducer of MyD88-independent TIR signalling , 2003, Nature.

[48]  S. Akira,et al.  Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway , 2003, Science.

[49]  D. Gutmann,et al.  Astrocyte-Specific Inactivation of the Neurofibromatosis 1 Gene (NF1) Is Insufficient for Astrocytoma Formation , 2002, Molecular and Cellular Biology.

[50]  J. Marth,et al.  Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. , 2001, Genes & development.

[51]  O. Kretz,et al.  Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety , 1999, Nature Genetics.

[52]  C. Janeway,et al.  MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. , 1998, Molecular cell.

[53]  S. Akira,et al.  Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. , 1998, Immunity.

[54]  P. Feng,et al.  IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. , 1997, Science.

[55]  C. Aoki,et al.  Central neuropathogenesis of vesicular stomatitis virus infection of immunodeficient mice , 1993, Journal of virology.

[56]  R. Zinkernagel,et al.  Functional analysis of T lymphocyte subsets in antiviral host defense. , 1987, Journal of immunology.

[57]  B. Dietzschold,et al.  The role of toll-like receptors in the induction of immune responses during rabies virus infection. , 2011, Advances in virus research.

[58]  R. Zinkernagel,et al.  Neutralizing antiviral B cell responses. , 1997, Annual review of immunology.

[59]  A. Gupta,et al.  Two-way cross-protection between West Nile and Japanese encephalitis viruses in bonnet macaques. , 1992, Acta virologica.

[60]  G. Casey,et al.  Experimental oral and nasal transmission of rabies virus in mice. , 1979, Canadian journal of comparative medicine : Revue canadienne de medecine comparee.