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Viral induction of central nervous system innate immune responses.

ABSTRACT: The ability of the central nervous system (CNS) to generate innate immune responses was investigated in an in vitro model of CNS infection. Cultures containing CNS cells were infected with mouse hepatitis virus-JHM, which causes fatal encephalitis in mice. Immunostaining indicated that viral infection had a limited effect on culture characteristics, overall cell survival, or cell morphology at the early postinfection times studied. Results from Affymetrix gene array analysis, assessed on RNA isolated from virally and sham-infected cultures, were compared with parallel protein assays for cytokine, chemokine, and cell surface markers. Of the 126 transcripts found to be differentially expressed between viral and sham infections, the majority were related to immunological responses. Virally induced increases in interleukin-6 and tumor necrosis factor alpha mRNA and protein expression correlated with the genomic induction of acute-phase proteins. Genomic and protein analysis indicated that viral infection resulted in prominent expression of neutrophil and macrophage chemotactic proteins. In addition, mRNA expression of nonclassical class I molecules H2-T10, -T17, -M2, and -Q10, were enhanced three- to fivefold in virus-infected cells compared to sham-infected cells. Thus, upon infection, resident brain cells induced a breadth of innate immune responses that could be vital in directing the outcome of the infection and, in vivo, would provide signals which would summon the peripheral immune system to respond to the infection. Further understanding of how these innate responses participate in immune protection or immunopathology in the CNS will be critical in efforts to intervene in severe encephalitis.

SUBMITTER: Rempel JD

PROVIDER: S-EPMC1061546 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature

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Viral induction of central nervous system innate immune responses.

Rempel J D JD Quina L A LA Blakely-Gonzales P K PK Buchmeier M J MJ Gruol D L DL

Journal of virology 20050401 7

The ability of the central nervous system (CNS) to generate innate immune responses was investigated in an in vitro model of CNS infection. Cultures containing CNS cells were infected with mouse hepatitis virus-JHM, which causes fatal encephalitis in mice. Immunostaining indicated that viral infection had a limited effect on culture characteristics, overall cell survival, or cell morphology at the early postinfection times studied. Results from Affymetrix gene array analysis, assessed on RNA iso ...[more]

PMID: 15767437

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Project description:The role of innate immunity in the pathogenesis of cryptococcal meningitis is unclear. We hypothesized that natural killer (NK) cell and monocyte responses show central nervous system (CNS) compartment-specific profiles, and are altered by antifungal therapy and combination antiretroviral therapy (cART) during cryptococcal meningitis/HIV coinfection.Substudy of a prospective cohort study of adults with cryptococcal meningitis/HIV coinfection in Durban, South Africa.We used multiparametric flow cytometry to study compartmentalization of subsets, CD69 (a marker of activation), CXCR3 and CX3CR1 expression, and cytokine secretion of NK cells and monocytes in freshly collected blood and cerebrospinal fluid (CSF) at diagnosis (n = 23), completion of antifungal therapy induction (n = 19), and after a further 4 weeks of cART (n = 9).Relative to blood, CSF was enriched with CD56(bright) (immunoregulatory) NK cells (P = 0.0004). At enrolment, CXCR3 expression was more frequent among blood CD56(bright) than either blood CD56(dim) (P < 0.0001) or CSF CD56(bright) (P = 0.0002) NK cells. Antifungal therapy diminished blood (P < 0.05), but not CSF CXCR3(pos) NK-cell proportions nor CX3CR1(pos) NK-cell proportions. CD56(bright) and CD56(dim) NK cells were more activated in CSF than blood (P < 0.0001). Antifungal therapy induction reduced CD56(dim) NK-cell activation in CSF (P = 0.02). Activation of blood CD56(bright) and CD56(dim) NK cells was diminished following cART commencement (P < 0.0001, P = 0.03). Immunoregulatory NK cells in CSF tended to secrete higher levels of CXCL10 (P = 0.06) and lower levels of tumor necrosis factor ? (P = 0.06) than blood immunoregulatory NK cells. CSF was enriched with nonclassical monocytes (P = 0.001), but antifungal therapy restored proportions of classical monocytes (P = 0.007).These results highlight CNS activation, trafficking, and function of NK cells and monocytes in cryptococcal meningitis/HIV and implicate immunoregulatory NK cells and proinflammatory monocytes as potential modulators of cryptococcal meningitis pathogenesis during HIV coinfection.

Project description:UnlabelledViral cellular immune surveillance is a dynamic and fluid system that is driven by finely regulated cellular processes including cytokines and other factors locally in the microenvironment and systemically throughout the body. It is questionable as to what extent the central nervous system (CNS) is an immune-privileged organ protected by the blood-brain barrier (BBB). Recent evidence suggests converging pathways through which viral infection, and its associated immune surveillance processes, may alter the integrity of the blood-brain barrier, and lead to inflammation, swelling of the brain parenchyma and associated neurological syndromes. Here, we expand upon the recent "gateway theory", by which viral infection and other immune activation states may disrupt the specialized tight junctions of the BBB endothelium making it permeable to immune cells and factors. The model we outline here builds upon the proposition that this process may actually be initiated by cytokines of the IL-17 family, and recognizing the intimate balance between TH17 and TH9 cytokine profiles systemically. We argue that immune surveillance events, in response to viruses such as the Human Immunodeficiency Virus (HIV), cause a TH17/TH9 induced gateway through blood brain barrier, and thus lead to characteristic neuroimmune pathology. It is possible and even probable that the novel TH17/TH9 induced gateway, which we describe here, opens as a consequence of any state of immune activation and sustained chronic inflammation, whether associated with viral infection or any other cause of peripheral or central neuroinflammation. This view could lead to new, timely and critical patient-centered therapies for patients with neuroimmune pathologies across a variety of etiologies.AbbreviationsBBB - blood brain barrier, BDV - Borna disease virus, CARD - caspase activation and recruitment domains, CD - clusters of differentiation, CNS - central nervous system, DAMP - damage-associated molecular patterns, DENV - Dengue virus, EBOV - Ebola virus, ESCRT - endosomal sorting complex required for transport-I, HepC - Hepatitis C virus, HIV - human immunodeficiency virus, IFN - interferon, ILn - interleukin-n, IRF-n - interferon regulatory factor-n, MAVS - mitochondrial antiviral-signaling, MBGV - Marburg virus, M-CSF - macrophage colony-stimulating factor, MCP-1 - monocyte chemotactic protein 1 (aka CCL2), MHC - major histocompatibility complex, MIP-α β - macrophage inflammatory protein-1 α β (aka CCL3 & CCL4), MIF - macrophage migration inhibitory factor, NVE - Nipah virus encephalitis, NK - natural killer cell, NLR - NLR, NOD - like receptor, NOD - nucleotide oligomerization domain, PAMP - pathogen-associated molecular patterns, PtdIns - phosphoinositides, PV - Poliovirus, RIG-I - retinoic acid-inducible gene I, RIP - Receptor-interacting protein (RIP) kinase, RLR - RIG-I-like receptor, sICAM1 - soluble intracellular adhesion molecule 1, STAT-3 - signal tranducer and activator of transcription-3, sVCAM1 - soluble vascular cell adhesion molecule 1, TANK - TRAF family member-associated NF- . B activator, TBK1 - TANK-binding kinase 1, TLR - Toll-like receptor, TNF - tumor necrosis factor, TNFR - TNF receptor, TNFRSF21 - tumor necrosis factor receptor superfamily member 21, TRADD TNFR-SF1A - associated via death domain, TRAF TNFR - associated factor, Tregs - regulatory T cellsubpopulation (CD4/8+CD25+FoxP3+), VHF - viral hemorrhagic fever.

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Viral induction of central nervous system innate immune responses.

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Viral induction of central nervous system innate immune responses.

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