A Transcriptomic Network Identified in Uninfected Macrophages Responding to Inflammation Controls Intracellular Pathogen Survival

Beattie, Lynette; Hermida, Micely D. R.; Moore, John W. J.; Maroof, Asher; Brown, Najmeeyah; Lagos, Dimitrios; Kaye, Paul M.

doi:10.1016/j.chom.2013.08.004

Cited by 40 publications

(52 citation statements)

References 47 publications

(58 reference statements)

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“…Indeed, gene expression profiling of liver-resident macrophages (Kuppfer cells) from mice infected with L . donovani identified a key transcriptomic network centered around the retinoid X receptor alpha, which was only active in bystander uninfected Kupffer cells exposed to the inflammatory factors in infected livers [19]. As observed for experimental VL [43], our study supports the view of compartmentalized responses, i.e., the dynamics of dominant pathways in specific cells of the spleen, liver, bone marrow and peripheral blood might be differentially associated with pro-inflammatory or regulatory processes during the course of the infection.…”

Section: Discussionmentioning

confidence: 99%

Blood Transcriptional Profiling Reveals Immunological Signatures of Distinct States of Infection of Humans with Leishmania infantum

et al. 2016

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Visceral leishmaniasis (VL) can be lethal if untreated; however, the majority of human infections with the etiological agents are asymptomatic. Using Illumina Bead Chip microarray technology, we investigated the patterns of gene expression in blood of active VL patients, asymptomatic infected individuals, patients under remission of VL and controls. Computational analyses based on differential gene expression, gene set enrichment, weighted gene co-expression networks and cell deconvolution generated data demonstrating discriminative transcriptional signatures. VL patients exhibited transcriptional profiles associated with pathways and gene modules reflecting activation of T lymphocytes via MHC class I and type I interferon signaling, as well as an overall down regulation of pathways and gene modules related to myeloid cells, mainly due to differences in the relative proportions of monocytes and neutrophils. Patients under remission of VL presented heterogeneous transcriptional profiles associated with activation of T lymphocytes via MHC class I, type I interferon signaling and cell cycle and, importantly, transcriptional activity correlated with activation of Notch signaling pathway and gene modules that reflected increased proportions of B cells after treatment of disease. Asymptomatic and uninfected individuals presented similar gene expression profiles, nevertheless, asymptomatic individuals exhibited particularities which suggest an efficient regulation of lymphocyte activation and a strong association with a type I interferon response. Of note, we validated a set of target genes by RT-qPCR and demonstrate the robustness of expression data acquired by microarray analysis. In conclusion, this study profiles the immune response during distinct states of infection of humans with Leishmania infantum with a novel strategy that indicates the molecular pathways that contribute to the progression of the disease, while also providing insights into transcriptional activity that can drive protective mechanisms.

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Section: Discussionmentioning

confidence: 99%

Blood Transcriptional Profiling Reveals Immunological Signatures of Distinct States of Infection of Humans with Leishmania infantum

et al. 2016

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“…A recent study suggested that RXRα is an important factor in the gene network involved in host defence against Leishmania donovani 43 . In addition to controlling host immune responses to bacterial and parasitic infections, we have shown here that RXRα overexpression or ligand activation increases host cell susceptibility to VSV, MHV68 and HSV-1 infection.…”

Section: Discussionmentioning

confidence: 99%

Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon

Liu

Razani

et al. 2014

Nat Commun

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The retinoid X receptor α (RXRα), a key nuclear receptor in metabolic processes, is down-regulated during host antiviral response. However, the roles of RXRα in host antiviral response are unknown. Here we show that RXRα overexpression or ligand activation increases host susceptibility to viral infections in vitro and in vivo, while Rxra −/− or antagonist treatment reduces infection by the same viruses. Consistent with these functional studies, ligand activation of RXR inhibits the expression of antiviral genes including type I interferon (IFN) and Rxra −/− macrophages produce more IFNβ than WT macrophages in response to polyI:C stimulation. Further results indicate that ligand activation of RXR suppresses the nuclear translocation of β-catenin, a co-activator of IFNβ enhanceosome. Thus, our studies have uncovered a novel RXR-dependent innate immune regulatory pathway, suggesting that the downregulation of RXR expression or RXR antagonist treatment benefits host antiviral response, whereas RXR agonist treatment may increase the risk of viral infections.

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“…Beattie et al described liver Kupffer cell shape changes as a read‐out of membrane activity upon infection with the live causative agent of a visceral form of Leishmaniasis, L. donovani . Upon phagocytosis, rapid activation of both infected and uninfected Kupffer cells in the vicinity is initiated, as measured by a decrease in membrane velocity . For the gram‐positive pathogen Listeria monocytogenes ( L. monocytogenes ), differential roles in the immune response induction could be shown for subcapsular red pulp (scDC) and myelomonocytic cells (MMC) in the spleen, which swarmed around non‐motile scDC forming foci from which blood flow was excluded, thus contributing to control of L. monocytogenes prior to development of T cell immunity .…”

Section: Initial Recognition and Innate Immune Responsementioning

confidence: 99%

From the Cradle to the Grave of an Infection: Host‐Pathogen Interaction Visualized by Intravital Microscopy

2019

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During infections, interactions between host immune cells and the pathogen occur in distinct anatomical locations and along defined time scales. This can best be assessed in the physiological context of an infection in the living tissue. Consequently, intravital imaging has enabled us to dissect the critical phases and events throughout an infection in real time in living tissues. Specifically, advances in visualizing specific cell types and individual pathogens permitted tracking the early events of tissue invasion of the pathogen, cellular interactions involved in the induction of the immune response as well the events implicated in clearance of the infection. In this respect, two vantage points have evolved since the initial employment of this technique in the field of infection biology. On the one hand, strategies acquired by the pathogen to establish within the host and circumvent or evade the immune defenses have been elucidated. On the other hand, analyzing infections from the immune system's perspective has led to insights into the dynamic cellular interactions that are involved in the initial recognition of the pathogen, immune induction as well as effector function delivery and immunopathology. Furthermore, an increasing interest in probing functional parameters in vivo has emerged, such as the analysis of pathogen reactivity to stress conditions imposed by the host organism in order to mediate clearance upon pathogen encounter. Here, we give an overview on recent intravital microscopy findings of hostpathogen interactions along the course of an infection, from both the immune system's and pathogen's perspectives. We also discuss recent developments and future perspectives in extracting intravital information beyond the localization of pathogens and their interaction with immune cells. Such reporter systems on the pathogen's physiological state and immune cell functions may prove useful in dissecting the functional dynamics of hostpathogen interactions.

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A Transcriptomic Network Identified in Uninfected Macrophages Responding to Inflammation Controls Intracellular Pathogen Survival

Cited by 40 publications

References 47 publications

Blood Transcriptional Profiling Reveals Immunological Signatures of Distinct States of Infection of Humans with Leishmania infantum

Blood Transcriptional Profiling Reveals Immunological Signatures of Distinct States of Infection of Humans with Leishmania infantum

Retinoid X receptor α attenuates host antiviral response by suppressing type I interferon

From the Cradle to the Grave of an Infection: Host‐Pathogen Interaction Visualized by Intravital Microscopy

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