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Principal Investigator: Vincent Tam
Organization: TEMPLE UNIV OF THE COMMONWEALTH
Fiscal Year: 2024
Award: $395,008
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Secondary bacterial infection following influenza (super-infection) can lead to cytokine storm (an overexuberant
immune response) that often leads to pneumonia and death in patients. Our work focuses on the molecular
mechanisms by which the immune system returns to homeostasis after microbial infections. Taking a holistic,
systems approach, we investigated the inflammatory responses during a single (influenza or Staphylococcus
aureus) and super-infection (influenza/S. aureus). We conducted transcriptional and lipidomic analyses in
samples from a mouse super-infection model. Our lipidomic analysis was focused on eicosanoids because they
play critical roles in inducing and resolving inflammation. When compared to single infections, we discovered an
overproduction of a subset of eicosanoids during super-infection. These lipids (anti-inflammatory CYP450 lipid
mediators, primarily DHET) can activate the nuclear receptors and transcription factors PPARa and PPARg.
During influenza single infection, moderate induction of CYP lipids (primarily EET) during the resolution phase
allows for appropriate anti-inflammatory responses to promote the return to homeostasis. We hypothesize that
while EET promotes the physiological resolution of inflammation after microbial infections, DHET produced at
an aberrant level during super-infection leads to the alteration in macrophage polarization and inhibition of
bacterial clearance. The failure to control the bacterial pathogen amplifies the immune signals to recruit additional
immune cells which eventually cause irreversible tissue damage. We will take the following approaches during
single and super-infection to investigate the effects of the eicosanoid-PPAR axis on the inflammatory response.
First, we will determine the effects of perturbing the eicosanoid-PPAR axis on the resolution or amplification of
inflammation during single and super-infection. We will use chemical inhibitors in combination with genetic
models to determine whether the animals will be protected from or succumb to disease during single and super-
infection. We will determine the lipidomic profiles to assess the specific effects of the inhibitors have on the
eicosanoid metabolism networks. We will also determine the bacterial/viral loads, cellularity, pathohistology, and
targeted transcriptional profiling of macrophages. Second, we will determine the mechanism by which
eicosanoid-activated PPARα/γ modulates immune signaling, macrophage polarization and immune metabolism
in vitro. Macrophage polarization (classically or alternative activated) can amplify or resolve inflammatory
responses. We will determine the potency of different CYP450 metabolites to activate PPARα/γ within mouse
and primary human macrophages. We will determine how eicosanoids (CYP450 metabolites) affect the immune
signaling, macrophage polarization, and lipid metabolism. Interestingly, While the induction of inflammation has
been the subject of active investigation, the mechanisms underlying the resolution of inflammation have been
elusive. By gaining insights into the resolution of inflammation during single and super-infection, we will develop
novel therapeutic targets for infection- and immune-related human diseases.
Terms: <Affect><Alveolar Macrophages><Animals><Anti-Bacterial Agents><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Autoregulation><Bacterial Infections><Basal Transcription Factor><Basal transcription factor genes><Blood Serum><Body Tissues><COVID-19 infection><COVID-19 virus infection><COVID19 infection><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellularity><Cessation of life><Chemicals><Clinical><Complication><Death><Disease><Disease Outcome><Disorder><Eicosanoids><Electrospray Ionization><Failure><Fatty Acid Metabolism Pathway><Fatty Acids><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Models><Genetic Transcription><Goals><Grippe><Homeostasis><Human><Immune><Immune response><Immune signaling><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunomodulation><Immunotherapeutic agent><In Vitro><Infection><Inflammation><Inflammatory><Inflammatory Response><Influenza><Intermediary Metabolism><Intracellular Communication and Signaling><Investigation><KO mice><Knock-out Mice><Knockout Mice><Lipids><Lung><Lung Respiratory System><Macrophage><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microbial Superinvasion><Modeling><Modern Man><Molecular><Murine><Mus><Mφ><Nuclear Receptors><Null Mouse><PPAR><PPAR alpha><PPAR gamma><PPAR-g><PPAR-α><PPAR-γ><PPARalpha><PPARgamma><PPARα><PPARγ><Patients><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor α><Peroxisome Proliferator-Activated Receptor γ><Peroxisome Proliferator-Activated Receptors><Phase><Physiologic><Physiological><Physiological Homeostasis><Play><Pneumonia><Process><Production><Pulmonary Macrophages><RNA Expression><Research><Resolution><Role><S aureus><S. aureus><S. aureus infection><SARS-CoV-2 infection><SARS-CoV2 infection><Sampling><Serum><Severe acute respiratory syndrome coronavirus 2 infection><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Spatial Distribution><Staph aureus><Staph aureus infection><Staphylococcus aureus><Staphylococcus aureus infection><Subcellular Process><System><Systems Biology><Thiazolidinedione Receptor><Time><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virus Diseases><Work><analyze gene expression><anti-bacterial><arachidonic metabolism><bacteria infection><bacteria pathogen><bacterial disease><bacterial pathogen><biological signal transduction><clinical relevance><clinically relevant><coronavirus disease 2019 infection><cytokine release syndrome><cytokine storm><eicosanoid metabolism><fat metabolism><fatty acid metabolism><flu infection><flu virus infection><gene expression analysis><gene expression assay><host response><human disease><imaging mass spectrometry><immune drugs><immune modulation><immune regulation><immune system response><immune-based therapeutics><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapeutics><immunotherapy agent><improved><infected with COVID-19><infected with COVID19><infected with S. aureus><infected with SARS-CoV-2><infected with SARS-CoV2><infected with Staph aureus><infected with Staphylococcus aureus><infected with coronavirus disease 2019><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><infected with severe acute respiratory syndrome coronavirus 2><influenza infection><influenza virus infection><inhibitor><insight><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lipid mediator><lipid metabolism><lipidomics><mass spectrometric imaging><microbial><mouse model><murine model><nano-string><nanostring><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><pathogen><pathogenic bacteria><pulmonary><recruit><resolutions><response><secondary infection><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><super infection><superinfection><transcription factor><transcriptional profiling><viral infection><virus infection><virus-induced disease>