Systems analysis reveals complex biological processes during virus infection fate decisions

The processes and mechanisms of virus infection fate decisions that are the result of a dynamic virus-immune system interaction with either an efficient effector response and virus elimination or an alleviated immune response and chronic infection are poorly understood. Here we characterized the host response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infections by gene coexpression network analysis of time-resolved splenic transcriptomes. We found first, an early attenuation of inflammatory monocyte/macrophage prior to the onset of T cell exhaustion and second, a critical role of the XCL1-XCR1 communication axis during the functional adaptation of the T cell response to the chronic infection state. These findings not only reveal an important feedback mechanism that couples T cell exhaustion with the maintenance of a lower level of effector T cell response but also suggest therapy options to better control virus levels during the chronic infection phase.info:eu-repo/semantics/publishedVersio

Computational Modeling-Based Discovery of Novel Classes of Anti-Inflammatory Drugs That Target Lanthionine Synthetase C-Like Protein 2

Background: Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the eukaryotic lanthionine synthetase component C-Like protein family involved in signal transduction and insulin sensitization. Recently, LANCL2 is a target for the binding and signaling of abscisic acid (ABA), a plant hormone with anti-diabetic and anti-inflammatory effects. Methodology/Principal Findings: The goal of this study was to determine the role of LANCL2 as a potential therapeutic target for developing novel drugs and nutraceuticals against inflammatory diseases. Previously, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of lanthionine synthetase component C-like protein 1 (LANCL1) as a template. Using this model, structure-based virtual screening was performed using compounds from NCI (National Cancer Institute) Diversity Set II, ChemBridge, ZINC natural products, and FDAapproved drugs databases. Several potential ligands were identified using molecular docking. In order to validate the antiinflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the lead compound, NSC61610, activated peroxisome proliferator-activated receptor gamma in a LANCL2- and adenylate cyclase/cAMP dependent manner in vitro and ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses

Immunoregulatory Mechanisms Underlying Prevention of Colitis-Associated Colorectal Cancer by Probiotic Bacteria

Background: Inflammatory bowel disease (IBD) increases the risk of colorectal cancer. Probiotic bacteria produce immunoregulatory metabolites in vitro such as conjugated linoleic acid (CLA), a polyunsaturated fatty acid with potent anticarcinogenic effects. This study aimed to investigate the cellular and molecular mechanisms underlying the efficacy of probiotic bacteria in mouse models of cancer. Methodology/Principal Findings: The immune modulatory mechanisms of VSL#3 probiotic bacteria and CLA were investigated in mouse models of inflammation-driven colorectal cancer. Colonic specimens were collected for histopathology, gene expression and flow cytometry analyses. Immune cell subsets in the mesenteric lymph nodes (MLN), spleen and colonic lamina propria lymphocytes (LPL) were phenotypically and functionally characterized. Mice treated with CLA or VSL#3 recovered faster from the acute inflammatory phase of disease and had lower disease severity in the chronic, tumor-bearing phase of disease. Adenoma and adenocarcinoma formation was also diminished by both treatments. VSL#3 increased the mRNA expression of TNF-a, angiostatin and PPAR c whereas CLA decreased COX-2 levels. Moreover, VSL#3-treated mice had increased IL-17 expression in MLN CD4+ T cells and accumulation of Treg LPL and memory CD4+ T cells. Conclusions/Significance: Both CLA and VSL#3 suppressed colon carcinogenesis, although VSL#3 showed greater anticarcinogeni

Probiotic Bacteria Produce Conjugated Linoleic Acid Locally in the Gut That Targets Macrophage PPAR γ to Suppress Colitis

Inflammatory bowel disease (IBD) therapies are modestly successful and associated with significant side effects. Thus, the investigation of novel approaches to prevent colitis is important. Probiotic bacteria can produce immunoregulatory metabolites in vitro such as conjugated linoleic acid (CLA), a polyunsaturated fatty acid with potent anti-inflammatory effects. This study aimed to investigate the cellular and molecular mechanisms underlying the anti-inflammatory efficacy of probiotic bacteria using a mouse model of colitis. The immune modulatory mechanisms of VSL#3 probiotic bacteria and CLA were investigated in a mouse model of DSS colitis. Colonic specimens were collected for histopathology, gene expression and flow cytometry analyses. Immune cell subsets in the mesenteric lymph nodes (MLN), spleen, blood and colonic lamina propria cells were phenotypically and functionally characterized. Fecal samples and colonic contents were collected to determine the effect of VSL#3 and CLA on gut microbial diversity and CLA production. CLA and VSL#3 treatment ameliorated colitis and decreased colonic bacterial diversity, a finding that correlated with decreased gut pathology. Colonic CLA concentrations were increased in response to probiotic bacterial treatment, but without systemic distribution in blood. VSL#3 and CLA decreased macrophage accumulation in the MLN of mice with DSS colitis. The loss of PPAR γ in myeloid cells abrogated the protective effect of probiotic bacteria and CLA in mice with DSS colitis. Probiotic bacteria modulate gut microbial diversity and favor local production of CLA in the colon that targets myeloid cell PPAR γ to suppress colitis

Time-resolved systems analysis of virus infection fate regulation

The processes and mechanisms of virus infection fate decisions that are the result of a dynamic virus - immune system interaction with either an efficient effector response and virus elimination or an alleviated immune response and chronic infection are poorly understood. Here, we characterized the host response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infections by gene coexpression network analysis of time-resolved splenic transcriptomes. We found first, an early attenuation of inflammatory monocyte/macrophage prior to the onset of T cell exhaustion and second, a critical role of the XCL1-XCR1 communication axis during the functional adaptation of the T cell response to the chronic infection state. These findings not only reveal an important feedback mechanism that couples T cell exhaustion with the maintenance of a lower level of effector T cell response but also suggest therapy options to better control virus levels during the chronic infection phase.Encara són poc coneguts els processos i mecanismes resultants de la interacció dinàmica entre el virus i l’hoste que determinen que una infecció es resolgui favorablement gràcies a una resposta efectora eficient o que esdevingui crònica degut a l’atenuació de la resposta immunitària. En aquesta tesi, hem caracteritzat la resposta de l’hoste en front a una infecció aguda o crònica amb el virus de la coriomeningitis limfocítica (LCMV) mitjançant l’anàlisi de xarxes de coexpressió de gens derivades de transcriptomes de melsa. Els resultats obtinguts mostren, primer, una atenuació de monòcits/macròfags inflamatoris durant els primers dies després de la infecció i abans de que hi hagi esgotament de les cèl·lules T i, segon, un rol important de l’eix XCL1-XCR1 durant l’adaptació funcional de la resposta de cèl·lules T a la fase crònica de la infecció. Aquests descobriments, no només posen al descobert un mecanisme important de retroalimentació que uneix les cèl·lules T esgotades amb el manteniment d’un cert nivell de resposta efectora, sinó que també suggererixen noves opcions terapèutiques per intentar controlar la expansió del virus durant la fase crònica de la infecció

Time-resolved systems analysis of virus infection fate regulation

The processes and mechanisms of virus infection fate decisions that are the result of a dynamic virus - immune system interaction with either an efficient effector response and virus elimination or an alleviated immune response and chronic infection are poorly understood. Here, we characterized the host response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infections by gene coexpression network analysis of time-resolved splenic transcriptomes. We found first, an early attenuation of inflammatory monocyte/macrophage prior to the onset of T cell exhaustion and second, a critical role of the XCL1-XCR1 communication axis during the functional adaptation of the T cell response to the chronic infection state. These findings not only reveal an important feedback mechanism that couples T cell exhaustion with the maintenance of a lower level of effector T cell response but also suggest therapy options to better control virus levels during the chronic infection phase.Encara són poc coneguts els processos i mecanismes resultants de la interacció dinàmica entre el virus i l’hoste que determinen que una infecció es resolgui favorablement gràcies a una resposta efectora eficient o que esdevingui crònica degut a l’atenuació de la resposta immunitària. En aquesta tesi, hem caracteritzat la resposta de l’hoste en front a una infecció aguda o crònica amb el virus de la coriomeningitis limfocítica (LCMV) mitjançant l’anàlisi de xarxes de coexpressió de gens derivades de transcriptomes de melsa. Els resultats obtinguts mostren, primer, una atenuació de monòcits/macròfags inflamatoris durant els primers dies després de la infecció i abans de que hi hagi esgotament de les cèl·lules T i, segon, un rol important de l’eix XCL1-XCR1 durant l’adaptació funcional de la resposta de cèl·lules T a la fase crònica de la infecció. Aquests descobriments, no només posen al descobert un mecanisme important de retroalimentació que uneix les cèl·lules T esgotades amb el manteniment d’un cert nivell de resposta efectora, sinó que també suggererixen noves opcions terapèutiques per intentar controlar la expansió del virus durant la fase crònica de la infecció

Differential kinetics of splenic CD169+ macrophage death is one underlying cause of virus infection fate regulation

Acute infection and chronic infection are the two most common fates of pathogenic virus infections. While several factors that contribute to these fates are described, the critical control points and the mechanisms that underlie infection fate regulation are incompletely understood. Using the acute and chronic lymphocytic choriomeningitis virus (LCMV) infection model of mice, we find that the early dynamic pattern of the IFN-I response is a differentiating trait between both infection fates. Acute-infected mice generate a 2-wave IFN-I response while chronic-infected mice generate only a 1-wave response. The underlying cause is a temporal difference in CD8 T cell-mediated killing of splenic marginal zone CD169+ macrophages. It occurs later in acute infection and thus enables CD169+ marginal zone macrophages to produce the 2nd IFN-I wave. This is required for subsequent immune events including induction of inflammatory macrophages, generation of effector CD8+ T cells and virus clearance. Importantly, these benefits come at a cost for the host in the form of spleen fibrosis. Due to an earlier marginal zone destruction, these ordered immune events are deregulated in chronic infection. Our findings demonstrate the critical importance of kinetically wellcoordinated sequential immune events for acute infection control and highlights that it may come at a cost for the host organism.We thank the Flow Cytometry and Genomic Core Facilities (Universitat Pompeu Fabra) and the Advanced Light Microscopy Unit (ALMU-CRG) for excellent technical support, Monica Perez (CReSA-IRTA-UAB) for helping with the histology samples and Hector Huerga Encabo (Immunology Unit, Universitat Pompeu Fabra) for fruitful discussions and ideas. We further thank Dr. Kenji Kohno and Dr. Masato Tanaka for allowing us to use their CD169-DTR transgenic mice which we obtained through Dr. Andres Hidalgo. The graphical abstract was created using BioRender.com platform. This work was supported by grants from the Spanish Ministry of Science and Innovation grant No. PID2019-106323RB-I00 AEI//10.13039/501100011033 and PID2022-141395OB-I00, the “Unidad de Excelencia María de Maeztu”, funded by the AEI (CEX2018-000792-M), the Russian Science Foundation grant No. 23-11-00116 and the AEC funded by ISCIII /MINECO (PT17/0009/0019) and co-funded by FEDER.info:eu-repo/semantics/publishedVersio

Differential kinetics of splenic CD169+ macrophage death is one underlying cause of virus infection fate regulation

Acute infection and chronic infection are the two most common fates of pathogenic virus infections. While several factors that contribute to these fates are described, the critical control points and the mechanisms that underlie infection fate regulation are incompletely understood. Using the acute and chronic lymphocytic choriomeningitis virus (LCMV) infection model of mice, we find that the early dynamic pattern of the IFN-I response is a differentiating trait between both infection fates. Acute-infected mice generate a 2-wave IFN-I response while chronic-infected mice generate only a 1-wave response. The underlying cause is a temporal difference in CD8 T cell-mediated killing of splenic marginal zone CD169+ macrophages. It occurs later in acute infection and thus enables CD169+ marginal zone macrophages to produce the 2nd IFN-I wave. This is required for subsequent immune events including induction of inflammatory macrophages, generation of effector CD8+ T cells and virus clearance. Importantly, these benefits come at a cost for the host in the form of spleen fibrosis. Due to an earlier marginal zone destruction, these ordered immune events are deregulated in chronic infection. Our findings demonstrate the critical importance of kinetically well-coordinated sequential immune events for acute infection control and highlights that it may come at a cost for the host organism

Effect of the CLA and VSL#3 treatment on colon histopathology on experimental <i>Helicobacter typhlonius</i>-induced colorectal cancer.

<p>Bacterial-free 129/SvEv and IL-10 gene deficient (IL-10−/−) 129/SvEv mice in a 129/SvEv background (n = 60) were treated with the VSL#3 probiotic (n = 20), CLA-supplemented (1 g/100 g) (n = 20) or control diets (n = 20) for 32 days and then were infected with <i>H. typhlonius</i> in order to develop experimental colorectal cancer associated with colitis. After the necropsy, all specimens underwent blinded histological examination and were scored 1–4 on mucosal wall thickening (A), leukocyte infiltration (B), adenomas (C) and adenocarcinomas (D). Data are represented as mean ± standard error. Points with an asterisk are significantly different when compared to the control group (<i>P</i><0.05).</p

Effect of VSL#3 and dietary conjugated linoleic acid (CLA) supplementation on experimental <i>Helicobacter typhlonius</i>-induced colorectal cancer.

<p>Bacterial-free 129/SvEv and IL-10 gene deficient (IL-10−/−) 129/SvEv mice in a 129/SvEv background (n = 60) were treated with the VSL#3 probiotic (n = 20), CLA-supplemented (1 g/100 g) (n = 20) or control diets (n = 20) for 32 days and then were infected with <i>H. typhlonius</i> in order to develop experimental colorectal cancer associated with colitis. The disease activity index, a composite score reflecting clinical signs of the disease, was assessed daily for mice undergoing the DSS challenge (A). Colon, spleen and mesenteric lymph nodes (MLN) (B–D) were macroscopically scored for inflammation. Data are represented as mean ± standard error. Points with an asterisk are significantly different when compared to the control group (<i>P</i><0.05).</p