Lung Macrophage Memory Development and Responses in Secondary Pneumonia and Sepsis

Information

  • Research Project
  • 10317455
  • ApplicationId
    10317455
  • Core Project Number
    R01AI164721
  • Full Project Number
    1R01AI164721-01
  • Serial Number
    164721
  • FOA Number
    PA-20-185
  • Sub Project Id
  • Project Start Date
    8/27/2021 - 3 years ago
  • Project End Date
    7/31/2025 - 7 months from now
  • Program Officer Name
    LANE, MARY CHELSEA
  • Budget Start Date
    8/27/2021 - 3 years ago
  • Budget End Date
    7/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    01
  • Suffix
  • Award Notice Date
    8/26/2021 - 3 years ago

Lung Macrophage Memory Development and Responses in Secondary Pneumonia and Sepsis

Project Summary Increased susceptibility to secondary bacterial pneumonia is a significant clinical complication of pulmonary viral infections. The characterization of molecular players that leave immunological scars/memory for sustained periods after clinical recovery from viral infections is vital for preventing secondary pneumonic infections. Our current knowledge in this regard is vastly limited, and the studies so far have mainly focused on ?immunologically tolerized? dendritic cells and macrophages developing as a result of immunosuppressive microenvironment established upon resolution of primary infection. In this application, based on our strong supportive data (communicated to Nature Immunology) showing that IFN? produced during pulmonary influenza infection imprints an immunological memory in alveolar macrophages (AMs) that drive a pathologic innate memory response to a subsequent bacterial pathogen, we propose to identify the novel mechanism of transcriptional reprogramming in these immunologically trained AMs. In this regard, pausing of RNA polymerase II (Pol II) at the transcriptional start site of most mammalian genes and its release onto the gene body for rapid transcription upon cellular activation is a key step in determination of transcriptional activation. By using state-of-the art genome-wide techniques, we have found that IFN? responsive genes in macrophages acquire Pol II enrichment at the promotor-proximal regions during their transcriptional induction phase that controls simultaneous elongation and subsequent gene expression. We termed this novel mechanism Acquired Promoter-proximal Pol II enrichment (APPe), and propose that APPe is responsible for IFN-induced memory phenotype in influenza infection. Further, we found that chromatin modifier Protein Arginine Methyltransferase 8 (PRMT8) is involved in IFN-induced memory response by establishing APPe early in trained-macrophages. Based on these data, we will determine: (Aim 1) how PRMT8 controls IFN-induced memory transcriptional reprogramming responsible for an earlier and greater transcription of IFN-responsive genes in these trained AMs upon reactivation during secondary bacterial infection, and whether PRMT8 deficiency ameliorates pathology and reinstates an appropriate immune response to secondary bacterial infection by both Gram-negative (Klebsiella pneumoniae) and Gram-positive bacteria (Staphylococcus aureus, and Streptococcus pneumoniae/ pneumococcus); (Aim 2) how transcriptional memory outcomes in AMs during secondary bacterial pneumonia are regulated through the rate-liming step of APPe via PRMT8 mediated APPe occurrence for an early, uncontrolled transcription of target genes that are involved in cytokine storm and later severe sepsis. The successful completion of proposed work will address a major gap in our knowledge of mechanisms dictating macrophage functions during influenza and subsequent bacterial infections, which will have implications for future therapeutic measures.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    1
  • Direct Cost Amount
    456665
  • Indirect Cost Amount
    154203
  • Total Cost
    610868
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
    SCHOOLS OF ARTS AND SCIENCES
  • Funding ICs
    NIAID:610868\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    UNIVERSITY OF NORTH DAKOTA
  • Organization Department
    PSYCHOLOGY
  • Organization DUNS
    102280781
  • Organization City
    GRAND FORKS
  • Organization State
    ND
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    582027306
  • Organization District
    UNITED STATES