scholarly journals Bacterial inhibition of CD8+ T-cells mediated cell death promotes neuroinvasion and within-host persistence

2020 ◽  
Author(s):  
Claire Maudet ◽  
Marouane Kheloufi ◽  
Sylvain Levallois ◽  
Julien Gaillard ◽  
Lei Huang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Cell Death ◽  
Nervous System ◽  
Virulence Gene ◽  
Cell Mediated Immunity ◽  
Dependent Manner ◽  
Central Nervous System Infections ◽  
Humanized Mouse Model ◽  
The Brain

AbstractCentral nervous system infections are amongst the most severe1,2, yet the mechanisms by which pathogens access the brain remain poorly understood. The model microorganism Listeria monocytogenes (Lm) is a major foodborne pathogen that causes neurolisteriosis, one of the deadliest central nervous system infections3,4. While immunosuppression is a well-established host risk factor for neurolisteriosis3,5, little is known regarding the bacterial factors underlying Lm neuroinvasion. We have developed a clinically-relevant experimental model of neurolisteriosis, using hypervirulent neuroinvasive strains6 inoculated in a humanized mouse model of infection7, and we show that the bacterial protein InlB protects infected monocytes from CD8+ T-cells Fas-mediated cell death, in a c-Met/PI3-kinase/FLIP-dependent manner. This blockade of anti-Lm specific cellular immune response lengthens infected monocytes lifespan, favoring Lm transfer from infected monocytes to the brain. The intracellular niche created by InlB-mediated cell-autonomous immunosuppression also promotes Lm fecal shedding, accounting for its selection as a Lm core virulence gene. Here, we have uncovered an unanticipated specific mechanism by which a bacterial pathogen confers to the cells it infects an increased lifespan by rendering them resistant to cell-mediated immunity. This promotes Lm within-host persistence and dissemination to the central nervous system, and transmission.

scholarly journals Bacterial inhibition of CD8+ T-cells mediated cell death promotes neuroinvasion and within-host persistence

2021 ◽  
Author(s):  
Marc Lecuit ◽  
Claire Maudet ◽  
Marouane Kheloufi ◽  
Sylvain Levallois ◽  
Julien Gaillard ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Cell Death ◽  
Nervous System ◽  
Cd8 T Cells ◽  
Cell Mediated Immunity ◽  
Dependent Manner ◽  
Central Nervous System Infections ◽  
Humanized Mouse Model ◽  
The Brain

Abstract Central nervous system infections are amongst the most severe, yet the mechanisms by which pathogens access the brain remain poorly understood. The model microorganism Listeria monocytogenes (Lm) is a major foodborne pathogen that causes neurolisteriosis, one of the deadliest central nervous system infections. While immunosuppression is a well-established host risk factor for neurolisteriosis, little is known regarding the bacterial factors underlying Lm neuroinvasion. We have developed a clinically-relevant experimental model of neurolisteriosis, using hypervirulent neuroinvasive strains inoculated in a humanized mouse model of infection, and we show that the bacterial protein InlB protects infected monocytes from CD8+ T-cells Fas-mediated cell death, in a c-Met/PI3-kinase/FLIP-dependent manner. This blockade of anti-Lm specific cellular immune response lengthens infected monocytes lifespan, favoring Lm transfer from infected monocytes to the brain. The intracellular niche created by InlB-mediated cell-autonomous immunosuppression also promotes Lm fecal shedding, accounting for its selection as a Lm core virulence gene. Here, we have uncovered an unanticipated specific mechanism by which a bacterial pathogen confers to the cells it infects an increased lifespan by rendering them resistant to cell-mediated immunity. This promotes Lm within-host persistence and dissemination to the central nervous system, and transmission.

scholarly journals A sart1 Zebrafish Mutant Results in Developmental Defects in the Central Nervous System

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2340
Author(s):  
Hannah E. Henson ◽  
Michael R. Taylor
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Developmental Defects ◽  
Whole Exome ◽  
The Central Nervous System ◽  
And Function ◽  
Upregulated Genes ◽  
The Brain

The spliceosome consists of accessory proteins and small nuclear ribonucleoproteins (snRNPs) that remove introns from RNA. As splicing defects are associated with degenerative conditions, a better understanding of spliceosome formation and function is essential. We provide insight into the role of a spliceosome protein U4/U6.U5 tri-snRNP-associated protein 1, or Squamous cell carcinoma antigen recognized by T-cells (Sart1). Sart1 recruits the U4.U6/U5 tri-snRNP complex to nuclear RNA. The complex then associates with U1 and U2 snRNPs to form the spliceosome. A forward genetic screen identifying defects in choroid plexus development and whole-exome sequencing (WES) identified a point mutation in exon 12 of sart1 in Danio rerio (zebrafish). This mutation caused an up-regulation of sart1. Using RNA-Seq analysis, we identified additional upregulated genes, including those involved in apoptosis. We also observed increased activated caspase 3 in the brain and eye and down-regulation of vision-related genes. Although splicing occurs in numerous cells types, sart1 expression in zebrafish was restricted to the brain. By identifying sart1 expression in the brain and cell death within the central nervous system (CNS), we provide additional insights into the role of sart1 in specific tissues. We also characterized sart1’s involvement in cell death and vision-related pathways.

scholarly journals Migration of CD8+T Cells into the Central Nervous System Gives Rise to Highly Potent Anti-HIV CD4dimCD8brightT Cells in a Wnt Signaling–Dependent Manner

2015 ◽  
Vol 196 (1) ◽  
pp. 317-327 ◽  
Author(s):  
Maureen H. Richards ◽  
Srinivas D. Narasipura ◽  
Melanie S. Seaton ◽  
Victoria Lutgen ◽  
Lena Al-Harthi
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Wnt Signaling ◽  
Cd8 T Cells ◽  
Dependent Manner ◽  
The Central Nervous System ◽  
Anti Hiv

Myeloid cells: The Trojan horse for T cell invasion into the brain

2019 ◽  
Vol 11 (520) ◽  
pp. eaaz9757
Author(s):  
Gilbert Gallardo
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Cell Invasion ◽  
Myeloid Cells ◽  
Autoimmune Encephalomyelitis ◽  
Lectin Receptors ◽  
The Central Nervous System ◽  
The Brain ◽  
Experimental Autoimmune

C-type lectin receptors on myeloid cells regulate the activation and infiltration of T cells into the central nervous system in experimental autoimmune encephalomyelitis.

scholarly journals Simian Immunodeficiency Virus-Infected Memory CD4+ T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Cheri A. Lee ◽  
Erin Beasley ◽  
Karthikeyan Sundar ◽  
Margery Smelkinson ◽  
Carol Vinton ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
B Cells ◽  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Neurological Complications ◽  
Immunodeficiency Virus ◽  
The Central Nervous System ◽  
The Brain

ABSTRACT Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not reflect the tempo of neuroAIDS progression in humans. Recently, we isolated a neuropathogenic clone, SIVsm804E-CL757 (CL757), obtained from an SIV-infected rhesus macaque (RM). CL757 causes a more protracted progression to disease, inducing SIVE in 50% of inoculated animals, with high cerebral spinal fluid viral loads, multinucleated giant cells (MNGCs), and perivascular lymphocytic cuffing in the central nervous system (CNS). This latter finding is reminiscent of human immunodeficiency virus (HIV) encephalitis in humans but not generally observed in rapid progressor animals with neuroAIDS. Here, we studied which subsets of cells within the CNS were targeted by CL757 in animals with neurological symptoms of SIVE. Immunohistochemistry of brain sections demonstrated infiltration of CD4+ T cells (CD4) and macrophages (MΦs) to the site of MNGCs. Moreover, an increase in mononuclear cells isolated from the brain tissues of RMs with SIVE correlated with increased cerebrospinal fluid (CSF) viral load. Subset analysis showed a specific increase in brain CD4+ memory T cells (Br-mCD4), brain-MΦs (Br-MΦs), and brain B cells (Br-B cells). Both Br-mCD4s and Br-MΦs harbored replication-competent viral DNA, as demonstrated by virus isolation by coculture. However, only in animals exhibiting SIVE/neuroAIDS was virus isolated from Br-MΦs. These findings support the use of CL757 to study the pathogenesis of AIDS viruses in the central nervous system and indicate a previously unanticipated role of CD4s cells as a potential reservoir in the brain. IMPORTANCE While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4+ T cells harbor replication-competent SIV DNA; however, only brain CD4+ T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.

scholarly journals Priming of CD8+ T Cells during Central Nervous System Infection with a Murine Coronavirus Is Strain Dependent

2008 ◽  
Vol 82 (13) ◽  
pp. 6150-6160 ◽  
Author(s):  
Katherine C. MacNamara ◽  
Susan J. Bender ◽  
Ming Ming Chua ◽  
Richard Watson ◽  
Susan R. Weiss
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cns Infection ◽  
Cervical Lymph Nodes ◽  
T Cell Priming ◽  
The Brain

ABSTRACT Virus-specific CD8+ T cells are critical for protection against neurotropic coronaviruses; however, central nervous system (CNS) infection with the recombinant JHM (RJHM) strain of mouse hepatitis virus (MHV) elicits a weak CD8+ T-cell response in the brain and causes lethal encephalomyelitis. An adoptive transfer model was used to elucidate the kinetics of CD8+ T-cell priming during CNS infection with RJHM as well as with two MHV strains that induce a robust CD8+ T-cell response (RA59 and SJHM/RA59, a recombinant A59 virus expressing the JHM spike). While RA59 and SJHM/RA59 infections resulted in CD8+ T-cell priming within the first 2 days postinfection, RJHM infection did not lead to proliferation of naïve CD8+ T cells. While all three viruses replicated efficiently in the brain, only RA59 and SJHM/RA59 replicated to appreciable levels in the cervical lymph nodes (CLN), the site of T-cell priming during acute CNS infection. RJHM was unable to suppress the CD8+ T-cell response elicited by RA59 in mice simultaneously infected with both strains, suggesting that RJHM does not cause generalized immunosuppression. RJHM was also unable to elicit a secondary CD8+ T-cell response in the brain following peripheral immunization against a viral epitope. Notably, the weak CD8+ T-cell response elicited by RJHM was unique to CNS infection, since peripheral inoculation induced a robust CD8+ T-cell response in the spleen. These findings suggest that the failure of RJHM to prime a robust CD8+ T-cell response during CNS infection is likely due to its failure to replicate in the CLN.

scholarly journals CC Chemokines Mediate Leukocyte Trafficking into the Central Nervous System during Murine Neurocysticercosis: Role of γδ T Cells in Amplification of the Host Immune Response

2003 ◽  
Vol 71 (5) ◽  
pp. 2634-2642 ◽  
Author(s):  
Astrid E. Cardona ◽  
Paula A. Gonzalez ◽  
Judy M. Teale
Keyword(s):  
Central Nervous System ◽  
Immune Response ◽  
T Cells ◽  
Nervous System ◽  
T Cell ◽  
Γδ T Cells ◽  
Host Immune Response ◽  
Leukocyte Trafficking ◽  
Cellular Infiltration ◽  
The Brain

ABSTRACT According to a previous report, the degree of the host immune response highly correlates with severity of the disease in the murine model for neurocysticercosis. In wild-type mice, Mesocestoides corti infection induced a rapid and extensive accumulation of γδ T cells and macrophages in the brain. NK cells, dendritic cells, αβ T cells, and B cells were also recruited to the brain but at lower levels. In contrast, γδ T-cell-deficient mice exhibited decreased cellular infiltration and reduced central nervous system (CNS) pathology. To understand the mechanisms of leukocyte recruitment into the CNS, chemokine expression was analyzed in infected brains in the present study. MCP-1 (CCL2), MIP-1α (CCL3), and MIP-1β (CCL4) were up-regulated within 2 days after M. corti infection. Protein expression of RANTES (CCL5), eotaxin (CCL11), and MIP-2 was detected later, at 1 week postinfection. Correlating with the decreased cellular infiltration, delta chain T-cell receptor-deficient (TCRδ−/−) mice exhibited substantially reduced levels of most of the chemokines analyzed (with the exception of eotaxin). The results suggest that γδ T cells play an important role in the CNS immune response by producing chemokines such as MCP-1 and MIP-1α, enhancing leukocyte trafficking into the brain during murine neurocysticercosis.

scholarly journals GENOMIC INSTABILITY IN THE BRAIN: ETIOLOGY, PATHOGENESIS AND NEW BIOLOGICAL MARKERS OF PSYCHIATRIC DISORDERS

2012 ◽  
Vol 67 (9) ◽  
pp. 45-53 ◽  
Author(s):  
A. S. Tiganov ◽  
Yu. B. Yurov ◽  
S. G. Vorsanova ◽  
I.Y Yu. Yurov
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Psychiatric Disorders ◽  
Genomic Instability ◽  
Genome Analysis ◽  
Biological Marker ◽  
Molecular Medicine ◽  
Therapeutic Practice ◽  
The Brain

The latest advances in molecular medicine, medical genetics and neurobiology have provided for a new look at processes occurring in cells of the brain and have allowed to discover previously unknown phenomena associated with mental traits and to propose new biomedical direction which include genomics, psychiatry and neurobiology ― brain genomics. The application of modern molecular and cellular technologies of genome analysis in the brain in common psychiatric disorders (autism, schizophrenia and Alzheimer’s disease) has shown that genomic instability is a phathogenetic mechanism of central nervous system abnormalities and plays a role in the brain development. Genomic disbalance alters neural homeostasis leads to cell death and is an important biological marker of psychiatric disorders which determine genomic pathways. These alterations lead to synaptic disfunction and neurodegeneration. In the present review, the main advances of brain genomics and potential application in diagnostic, clinical and therapeutic practice. 

scholarly journals High Frequency of Virus-Specific CD8+ T Cells in the Central Nervous System of Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251

2003 ◽  
Vol 77 (22) ◽  
pp. 12346-12351 ◽  
Author(s):  
Marcin Moniuszko ◽  
Charlie Brown ◽  
Ranajit Pal ◽  
Elzbieta Tryniszewska ◽  
Wen-Po Tsai ◽  
...  
Keyword(s):  
Central Nervous System ◽  
T Cells ◽  
Nervous System ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Specific Response ◽  
Immunodeficiency Virus ◽  
The Central Nervous System ◽  
The Brain

ABSTRACT Infection with human immunodeficiency virus or simian immunodeficiency virus (SIV) induces virus-specific CD8+ T cells that traffic to lymphoid and nonlymphoid tissues. In this study, we used Gag-specific tetramer staining to investigate the frequency of CD8+ T cells in peripheral blood and the central nervous system of Mamu-A*01-positive SIV-infected rhesus macaques. Most of these infected macaques were vaccinated prior to SIVmac251 exposure. The frequency of Gag181-189 CM9 tetramer-positive cells was consistently higher in the cerebrospinal fluid and the brain than in the blood of all animals studied and did not correlate with either plasma viremia or CD4+-T-cell level. Little or no infection in the brain was documented for most animals by nucleic acid sequence-based amplification or in situ hybridization. These data suggest that this Gag-specific response may contribute to the containment of viral replication in this locale.

Central Nervous System Infections

2012 ◽  
Author(s):  
John W. Wilson ◽  
Lynn L. Estes
Keyword(s):  
Magnetic Resonance Imaging ◽  
Central Nervous System ◽  
Nervous System ◽  
Magnetic Resonance ◽  
Antimicrobial Therapy ◽  
Immunocompromised Patients ◽  
Resonance Imaging ◽  
Central Nervous System Infections ◽  
Neck Stiffness ◽  
The Brain

•Clinical: The diagnosis of meningitis is suggested by the constellation of headache, fever, and neck stiffness. Some patients may also experience changes in mental status.•Radiology: Computed tomograms or magnetic resonance imaging of the brain may be indicated for immunocompromised patients and patients with papilledema or focal neurologic deficits. However, neuroimaging should not delay initiation of antimicrobial therapy....

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