Antiviral macrophage responses in flavivirus encephalitis Ashhurst, Thomas Myles; Vreden, Caryn van; Munoz-Erazo, Luis ...
Indian journal of medical research (New Delhi, India : 1994),
11/2013, Letnik:
138, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Mosquito-borne flaviviruses are a major current and emerging threat, affecting millions of people worldwide. Global climate change, combined with increasing proximity of humans to animals and ...mosquito vectors by expansion into natural habitats, coupled with the increase in international travel, have resulted in significant spread and concomitant increase in the incidence of infection and severe disease. Although neuroinvasive disease has been well described for some viral infections such as Japanese Encephalitis virus (JEV) and West Nile virus (WNV), others such as dengue virus (DENV) have recently displayed an emerging pattern of neuroinvasive disease, distinct from the previously observed, systemically-induced encephalomyelopathy. In this setting, the immune response is a crucial component of host defence, in preventing viral dissemination and invasion of the central nervous system (CNS). However, subversion of the anti-viral activities of macrophages by flaviviruses can facilitate viral replication and spread, enhancing the intensity of immune responses, leading to severe immune-mediated disease which may be further exacerbated during the subsequent infection with some flaviviruses. Furthermore, in the CNS myeloid cells may be responsible for inducing specific inflammatory changes, which can lead to significant pathological damage during encephalitis. The interaction of virus and cells of the myeloid lineage is complex, and this interaction is likely responsible at least in part, for crucial differences between viral clearance and pathology. Recent studies on the role of myeloid cells in innate immunity and viral control, and the mechanisms of evasion and subversion used by flaviviruses are rapidly advancing our understanding of the immunopathological mechanisms involved in flavivirus encephalitis and will lead to the development of therapeutic strategies previously not considered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IRF8 (interferon-regulatory factor-8) plays a critical role in regulating myeloid cell differentiation. However, the role of this transcription factor in the development of Ly6C+ inflammatory ...monocytes and their migration to the infected brain has not been examined. We have previously shown that West Nile virus (WNV) infection of wild-type (WT) mice triggers a significant increase in numbers of Ly6C+ monocytes in the bone marrow. These cells traffic via the blood to the infected brain, where they give rise to proinflammatory macrophages. Here, we show that WNV-infected IRF8-deficient (IRF8-/-) mice had significantly reduced numbers of Ly6C+ monocytes in the periphery, with few of these cells found in the blood. Furthermore, low numbers of inflammatory monocyte-derived macrophages were observed in the brains of IRF8-/- mice throughout infection. Adoptive transfer of IRF8-/- Ly6C+ monocytes demonstrated that these cells were intrinsically unable to traffic to the inflamed brain. Low expression of the chemokine receptor CCR2 and integrin VLA-4 by IRF8-/- monocytes likely contributed to this defect, as the interactions between these proteins and their ligands are critical for monocyte egress and migration to inflammatory foci. These data highlight a critical role for IRF8 in inflammatory monocyte differentiation and migration during WNV infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
In adult cancer, immune signatures such as the T cell-inflamed gene expression profile (GEP) have been developed to predict which patients are likely to respond to immune checkpoint ...inhibitors (ICIs) beyond high tumor mutation burden (TMB) and PD-L1 expression. The GEP infers T cell infiltration and activation in the tumor microenvironment (TME) from transcriptomic data. However, it is not known whether tools such as GEP are applicable in pediatric cancer, as the TME in childhood cancers is largely unexplored and response to ICIs are rare. We have undertaken an integrated analysis of the pediatric TME using RNA-sequencing (RNA-seq) and immunohistochemistry (IHC). Our goal is to identify patients with T cell-inflamed or “hot” tumors who may benefit from ICIs. Through Australia's ZERO childhood cancer precision medicine program we performed RNA-seq on 347 high-risk pediatric cancers (estimated <30% chance of survival) and performed IHC for CD4, CD8, CD45 and PD-L1 on 112 matching samples. Using both informatic assessments and IHC as independent measures of immune infiltration, we mapped the immune landscape of the TME across a broad range of high-risk pediatric cancers. As RNA-seq is increasingly used in the analysis of patient tumors, we investigated numerous molecular correlates of immune infiltration, tailored specifically to pediatric patients. RNA-seq was used to generate the GEP and map expression profiles of immune checkpoint genes, and deconvolution algorithms were used to extract the immune cell composition for every tumor. The correlation analysis between IHC, deconvolution of cell mixture composition and GEP were assessed, including PD-L1 protein and mRNA expression. We observed significant correlation between PD-L1 protein and mRNA expression and a weak correlation of CD8+ T cells with GEP. Deconvoluted TME estimates were most tightly correlated with the presence of T cell infiltrates (CD4 and CD8) with IHC. TMB and tumor purity estimates were derived from whole genome sequencing for each case. No correlation was observed between TMB and immune infiltration, however, tumor purity was negatively correlated with immune infiltration. Using IHC as an independent marker of a T cell-inflamed TME, we have identified a novel pediatric immune signature that includes markers of CD4 and CD8 T cells, T cell cytotoxicity, T and NK cell recruitment and activation, MHC Class II molecules and immune checkpoints. This is the first study to comprehensively analyze the pediatric TME in a cohort of this size and diversity, with matching IHC for orthogonal validation. Through the combination of RNA-seq and IHC, we have devised a novel immune signature specific to pediatrics and these techniques have identified a subset of patients that are immune “hot” and may potentially respond to ICIs. Conversely, we also highlight the potential of identifying immune “cold” patients who may need immunomodulatory combination strategies to maximize immune response.
Citation Format: Chelsea Mayoh, Rachael L. Terry, Marie Wong, Loretta M. Lau, Dong Anh Khuong-Quang, Marion K. Mateos, Vanessa Tyrrell, Michelle Haber, David S. Ziegler, Mark J. Cowley, Joseph A. Trapani, Paul J. Neeson, Paul G. Ekert. The unexplored immune landscape of high-risk pediatric cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3044.
Abstract
Type I IFN (α/β) signaling is crucial in the antiviral response and is mediated by STAT1, STAT2 and IRF9 while type II IFN (γ) uses STAT1. We studied the role of STAT1, STAT2 and IRF9 in the ...host response to systemic infection with lymphocytic choriomeningitis virus (LCMV). In wild type (WT), STAT2 KO and IRF9 KO mice, infection was non-lethal and virus was either cleared (WT) or established persistence (STAT2 and IRF9 KO). In contrast, in STAT1 KO mice, infection was lethal with severe immune pathology with T-cells, macrophages and granulocytes and elevated expression of various cytokines, particularly IFN-γ, present in various organs. However, lethality was unaltered in LCMV-infected STAT1 KO mice that lacked the IFN-γ receptor. While clearance of LCMV in WT mice is mediated by CD8+ T-cells, depletion of these cells in LCMV-infected STAT1 KO mice did not affect lethality. However, depletion of CD4+ T-cells prevented lethality in LCMV-infected STAT1 KO mice with a considerable reduction in tissue immune pathology. In vitro stimulation assays revealed a skewing of the T-cell response to the Th17 phenotype in LCMV-infected STAT1 KO but not WT mice. These findings indicated that STAT1 has a major protective function in LCMV infection, not only being crucial for limiting viral replication and spread, but also preventing the emergence of a lethal CD4+ T-cell response possibly mediated by Th17 cells. Support : NHMRC grant 512407.
This is the most comprehensive and current reference resource on climate change available today. It features forty-nine individual chapters by some of the world's leading climate scientists. Its five ...sections address climate change in five dimensions: ecological impacts, policy analysis, international considerations, United States considerations, and mitigation options to reduce carbon emissions. In many ways, this volume supersedes the Fourth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC). Many important developments too recent to be treated in the 2007 IPCC documents are covered here. Overall, Climate Change Science and Policy paints a direr picture of the effects of climate change than do the IPCC reports. It reveals that climate change has progressed faster than the IPCC reports anticipated and that the outlook for the future is bleaker than the IPCC reported.
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