A novel approach for deep phenotyping the CD4 T cell response to Mycobacterium Tuberculosis

Information

  • Research Project
  • 10109987
  • ApplicationId
    10109987
  • Core Project Number
    R21AI149311
  • Full Project Number
    5R21AI149311-02
  • Serial Number
    149311
  • FOA Number
    PA-19-053
  • Sub Project Id
  • Project Start Date
    2/18/2020 - 4 years ago
  • Project End Date
    1/31/2022 - 2 years ago
  • Program Officer Name
    EICHELBERG, KATRIN
  • Budget Start Date
    2/1/2021 - 3 years ago
  • Budget End Date
    1/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    02
  • Suffix
  • Award Notice Date
    1/13/2021 - 3 years ago

A novel approach for deep phenotyping the CD4 T cell response to Mycobacterium Tuberculosis

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) caused 1.3 million global deaths in 2017, yet an effective vaccine remains elusive. A major challenge in the field has been selecting which Mtb antigens (from among >4000 proteins) to include in a vaccine, and what T cell functions it should aim to elicit. Previous attempts to define protective immunity against Mtb have shown mixed success and have focused on diversity in one dimension at a time ? eg using proteins / lyates to identify diverse CD4 T cell states (eg cytokine polyfunctionality), or defining cytokine production in response to diverse peptides predicted to bind human leukocyte antigens (HLAs). We hypothesize that deep, simultaneous analysis of both T cell specificity and phenotype will: (i) reveal an interdependence between these 2 dimensions of the anti-Mtb response that is not currently well-understood, and (ii) enable, in future studies, improved correlates of protection against disease that can empower vaccine studies and inform treatment strategies. To achieve this new `deep-2D' view of the response, we propose to integrate 2 novel technologies: (i) a platform we recently developed for experimentally screening the Mtb proteome for peptides that bind diverse HLA class II proteins (`PepSeq'), and (ii) single cell sequencing, enabling linked analysis of transcriptome and peptide:HLA binding within thousands of T cells. If successful, this project would establish a rationale and toolkit for `deep-2D' analysis of the T cell response to Mtb that we could subsequently apply to larger cohorts designed to reveal correlates of disease protection in both natural history and vaccine settings. The approach would also be directly applicable to other complex pathogens.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R21
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
    160197
  • Indirect Cost Amount
    120078
  • Total Cost
    280275
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
  • Funding ICs
    NIAID:280275\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    CMIA
  • Study Section Name
    Cellular and Molecular Immunology - A Study Section
  • Organization Name
    TRANSLATIONAL GENOMICS RESEARCH INST
  • Organization Department
  • Organization DUNS
    118069611
  • Organization City
    PHOENIX
  • Organization State
    AZ
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    850042274
  • Organization District
    UNITED STATES