Dataset Information

Lipid mediators of inflammation in BALF 3-11 days after infection with influenza

ABSTRACT: Bioactive lipid mediators play a crucial role in the induction and resolution of inflammation. To elucidate their involvement during influenza infection, liquid chromatography/mass spectrometry lipidomic profiling of 141 lipid species was performed on a mouse influenza model using two viruses of significantly different pathogenicity. Infection by the low-pathogenicity strain X31/H3N2 induced a proinflammatory response followed by a distinct anti-inflammatory response; infection by the high-pathogenicity strain PR8/H1N1 resulted in overlapping pro- and anti-inflammatory states. Integration of the large-scale lipid measurements with targeted gene expression data demonstrated that 5-lipoxygenase metabolites correlated with the pathogenic phase of the infection, whereas 12/15-lipoxygenase metabolites were associated with the resolution phase. Hydroxylated linoleic acid, specifically the ratio of 13- to 9-hydroxyoctadecadienoic acid, was identified as a potential biomarker for immune status during an active infection. Importantly, some of the findings from the animal model were recapitulated in studies of human nasopharyngeal lavages obtained during the 2009-2011 influenza seasons.

INSTRUMENT(S): API 4000 QTRAP (AB Sciex)

SUBMITTER: Peter Askovich

PROVIDER: MTBLS33 | MetaboLights | 2013-05-30

REPOSITORIES: MetaboLights

ACCESS DATA

Publications

Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation.

Tam Vincent C VC Quehenberger Oswald O Oshansky Christine M CM Suen Rosa R Armando Aaron M AM Treuting Piper M PM Thomas Paul G PG Dennis Edward A EA Aderem Alan A

Cell 20130701 1

Bioactive lipid mediators play a crucial role in the induction and resolution of inflammation. To elucidate their involvement during influenza infection, liquid chromatography/mass spectrometry lipidomic profiling of 141 lipid species was performed on a mouse influenza model using two viruses of significantly different pathogenicity. Infection by the low-pathogenicity strain X31/H3N2 induced a proinflammatory response followed by a distinct anti-inflammatory response; infection by the high-patho ...[more]

PMID: 23827684

Similar Datasets

Project description:Leber2015 - Mucosal immunity and gut microbiome interaction during C. difficile infection This model is described in the article: Systems Modeling of Interactions between Mucosal Immunity and the Gut Microbiome during Clostridium difficile Infection. Leber A, Viladomiu M, Hontecillas R, Abedi V, Philipson C, Hoops S, Howard B, Bassaganya-Riera J. PLoS ONE 2015; 10(7): e0134849 Abstract: Clostridium difficile infections are associated with the use of broad-spectrum antibiotics and result in an exuberant inflammatory response, leading to nosocomial diarrhea, colitis and even death. To better understand the dynamics of mucosal immunity during C. difficile infection from initiation through expansion to resolution, we built a computational model of the mucosal immune response to the bacterium. The model was calibrated using data from a mouse model of C. difficile infection. The model demonstrates a crucial role of T helper 17 (Th17) effector responses in the colonic lamina propria and luminal commensal bacteria populations in the clearance of C. difficile and colonic pathology, whereas regulatory T (Treg) cells responses are associated with the recovery phase. In addition, the production of anti-microbial peptides by inflamed epithelial cells and activated neutrophils in response to C. difficile infection inhibit the re-growth of beneficial commensal bacterial species. Computational simulations suggest that the removal of neutrophil and epithelial cell derived anti-microbial inhibitions, separately and together, on commensal bacterial regrowth promote recovery and minimize colonic inflammatory pathology. Simulation results predict a decrease in colonic inflammatory markers, such as neutrophilic influx and Th17 cells in the colonic lamina propria, and length of infection with accelerated commensal bacteria re-growth through altered anti-microbial inhibition. Computational modeling provides novel insights on the therapeutic value of repopulating the colonic microbiome and inducing regulatory mucosal immune responses during C. difficile infection. Thus, modeling mucosal immunity-gut microbiota interactions has the potential to guide the development of targeted fecal transplantation therapies in the context of precision medicine interventions. This model is hosted on BioModels Database and identified by: BIOMD0000000583. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:While pandemic 2009 H1N1 influenza A viruses were responsible for numerous severe infections in humans, these viruses do not typically cause corresponding severe disease in mammalian models. However, the generation of a virulent 2009 H1N1 virus following serial lung passage in mice has allowed for the modeling of human lung pathology in this species. Genetic determinants of mouse-adapted 2009 H1N1 viral pathogenicity have been identified, but the molecular and signaling characteristics of the host response following infection with this adapted virus have not been described. Here, we compared the gene-expression response following infection of mice with A/CA/04/2009 (CA/04) or the virulent mouse-adapted strain (MA-CA/04). Microarray analysis revealed that increased pathogenicity of MA-CA/04 was associated with: (1) early and sustained inflammatory and interferon response that could be driven in part by interferon regulatory factors (IRFs) and increased NFM-oM-^AM-+B activation, as well as inhibition of the negative regulator TRIM24, (2) early and persistent infiltration of immune cells, including inflammatory macrophages, and (3) the absence of activation of lipid metabolism later in infection, that may be mediated by nuclear receptors inhibition, including PPARG, HNF1A and 4A, with pro-inflammatory consequences. Further investigation of these signatures in the host response to other H1N1 viruses of varied pathogenicity confirmed their general relevance for virulence of influenza virus and suggested that lung response to MA-CA/04 virus was similar to that following lethal H1N1 r1918 influenza virus. This study links for the first time differential activation of IRFs, nuclear receptors, and macrophage infiltration with influenza virulence in vivo. Six-to-eight-week-old female BALB/c mice were anesthetized and inoculated with 50 M-NM-<l of phosphate-buffered saline (PBS; Mock) or with 10^6 pfu of virus in a 50 M-NM-<l volume. Nine animals per condition group were used for tarray analysis, two or three animals per time point. There were seven condition groups: A/California/04/2009, MA1-A/California/04/2009, A/Mexico/4482/09, A/Brisbane/59/07, A/New Jersey/8/76, the reconstructed 1918 virus and timeM-bM-^@M-^Smatched mocks.

Project description:Systematic analyses of the temporal dynamics of transcriptomes and chromatin landscapes of macrophages during timecourse of TLR4-mediated inflammatory response. As a multifunctional effector cell, macrophages play pivotal roles in both the induction and resolution components of varied inflammatory processes. During the course of an inflammation response, macrophages engage in a homeostatic program characterized by tightly coordinated modulation of temporal outputs of both lipid metabolism and inflammation. We demonstrate inversely biphasic temporal dynamics of specific fatty acid metabolic and inflammatory gene expression profiles, associated with concordant temporal reprogramming of macrophage fatty acid profiles. In part, the late phase of the macrophage inflammatory response is characterized by tailoring of fatty acid related gene expressions, facilitating both significant induction of anti-inflammatory unsaturated fatty acid production and associated resolution of inflammation. We demonstrate the biphasic temporal dynamics of macrophage inflammation, specifically anti-inflammatory omega-3 and omega-9 unsaturated fatty acid levels, are transcriptionally driven genome-wide by an unexpected shift from an LXR to SREBP1-dominant regulatory program in the late phase inflammatory response. Collectively, our findings reveal a novel Srebp1-driven mechanism allowing the intimate inverse temporal relationship between the transcriptional regulation of inflammatory and fatty acid metabolic outputs; whereby modulation key transcriptional regulators (LXR, SREBP1 and NF-kB) of these pathways coordinate appropriate temporal tailoring of local enhancer associated reprogramming and eventual pathway regulatory interactions, during the course of TLR4-dependent inflammatory response in macrophages. This specific Srebp-driven, temporal reprogramming of macrophage fatty acid metabolism, characterized by late phase induction of anti-inflammatory unsaturated fatty acid production, is necessary for appropriate resolution of inflammation. Thus, this study suggests that selective reprogramming of macrophage lipid metabolism can serve as a viable therapeutic intervention aimed at ameliorating chronic inflammation and varied metabolic syndrome associated states.

Project description:Occasional transmission of highly pathogenic avian H5N1 influenza viruses to humans causes severe pneumonia with high mortality. To better understand the mechanisms via which H5N1 viruses induce severe disease in humans, we infected cynomolgus macaques with six different H5N1 strains isolated from human patients and compared their pathogenicity and the global host responses to the virus infection. Although all H5N1 viruses replicated in the respiratory tract, there was substantial heterogeneity in their replicative ability and in the disease severity induced, which ranged from asymptomatic to fatal. A comparison of global gene expression between severe and mild disease cases indicated that interferon-induced up-regulation of genes related to innate immunity, apoptosis, and antigen processing/presentation in the early phase of infection was limited in severe disease cases, although interferon expression was up-regulated in both severe and mild cases. Furthermore, co-expression analysis of microarray data, which reveals the dynamics of host responses during the infection, demonstrated that the limited expression of these genes early in infection led to a failure to suppress virus replication and to the hyperinduction of genes related to immunity, inflammation, coagulation, and homeostasis in the late phase of infection, resulting in a more severe disease. Our data suggest that the attenuated interferon-induced activation of innate immunity, apoptosis, and antigen presentation in the early phase of H5N1 virus infection leads to subsequent severe disease outcome. Bronchial brushes for microarray studies were obtained from female cynomolgus macaques infected with influenza viruses. Three animals per group were inoculated with one of three H5N1 influenza viruses (VN3028II, VN30259 or VN3040). The early phase of infection refers to timepoints Pre (prior to infection), 1, and 3 days post-infection. The late phase of infection refers to days 5 and 7 post-infection. Samples collected prior to infection (labeled as Pre) served as control data for each infection group.

Project description:Background: Pandemic H1N1 influenza A is a newly emerging strain of human influenza that is easily transmitted between people and has spread globally to over 116 countries. Human infection leads to symptoms ranging from mild to severe with lower respiratory complications observed in a small but significant number of infected individuals. Little is currently known about host immunity and Pandemic H1N1 influenza infections. Methods: We examined the pathogenic potential of the pandemic influenza A vaccine strain, A/California/07/2009 (H1N1), in ferrets, and characterized the host immune responses using microarray analysis. Gene expression profiles in lung tissue were compared with those from ferrets infected with A/Brisbane/59/2007. Results: Chemokines CCL2, CCL8, CXCL7 and CXCL10 along with the majority of ISGs were expressed early, correlated to lung pathology, and abruptly decreased expression in 5 days. Interestingly, the drop in innate immune gene expression was replaced by a significant increase in the expression of the adaptive immune genes for granzymes and immunoglobulins. Serum anti-pandemic influenza H1N1 antibodies were also observed on day 7, commensurate with the elimination of viral load. Conclusions: We propose that the innate phase of host immunity causes lung pathology and a delay or failure to effectively switch to the adaptive phase contributes to morbidity and mortality during severe human pandemic H1N1 influenza A infections. Keywords: influenza, immune response, cytokines, chemokines, lung infection, time course In the experiment with influenza A/California/07/2009 (H1N1),15 ferrets were randomly allocated to 5 groups: Day 0 (before infection), and Day 3, 5, 7 and 14 (post infection) with 3 biological replicates for each group. Likewise, a second experiment with A/Brisbane/59/2007 (H1N1) was carried out using the same experimental groups, except for a group in Day 2, instead Day 3. Ferrets were euthanized and lung tissue was excised for RNA purification on the scheduled date. The subsequent gene expression analysis was performed with Affymetrix GeneChip Canine Genome 2.0 Array. Day 0 groups were used as control.

Dataset Information

Lipid mediators of inflammation in BALF 3-11 days after infection with influenza

Publications

Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure