Macrophages are essential in the early immune response against many pathogens. Besides killing pathogens they can also initiate the adaptive immune response by presenting antigens to T cells. Interferon gamma (IFNy) and tumor necrosis factor (TNF) are essential cytokines for successful clearance of many infectious agents. Activation of macrophages by synergistic effects of these cytokines leads to upregulation of many effector molecules that can kill pathogens or inhibit their growth. To devise strategies to improve the early defense against a variety of pathogens it is important to understand individual genetic variation in the response to pathogens. Our hypothesis is that many genetic differences in disease resistance are due to differences in the macrophage response to pathogens and/or to the effects of IFNy+TNF. Our goal is therefore to identify the genes mediating the variation in the macrophage response to IFNy+TNF and to infection with bioterrorism agents. To do this we will measure the transcriptome of IFNy+TNF-stimulated or infected macrophages from recombinant inbred mice derived from crosses between pathogen susceptible and resistant mice. We will then identify mouse genomic regions that affect transcription levels of individual genes using quantitative trait locus (QTL) analysis. Naive or IFNy+TNF-stimulated macrophages will also be infected with various pathogens and assayed for ability to inhibit the pathogen's growth. Genomic regions affecting the macrophage response will be compared to previously identified genomic regions affecting disease resistance. The identification of a common chromosomal location for both expression QTLs and disease trait QTLs will be used to nominate genes in the disease susceptibility locus. These will be tested in an in vitro killing assay by knocking down the gene using RNAi and measuring the effect on the macrophage's ability to kill the pathogen. We will use Toxoplasma gondii and Francisella tularensis, NIAID category B and A bioterrorism agents that replicate in a parasitophorous vacuole vs the cytoplasm, respectively. We expect to gain a deeper understanding of the molecular basis for genetic variation in the host response to pathogens with a distinct intracellular lifestyle.

Public Health Relevance

;Killing of pathogens by macrophages is an important first defense mechanism. We will identify genes that underlie differences in the macrophage response to pathogens and to IFNy and TNF, which are important cytokines that activate macrophages to kill pathogens. It is expected that a detailed understanding of the molecular basis for genetic variation in the host response to pathogens will reveal novel therapeutic targets.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DDS-M (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
United States
Zip Code
Clark, Margaret J; Miduturu, Chandra; Schmidt, Aaron G et al. (2016) GNF-2 Inhibits Dengue Virus by Targeting Abl Kinases and the Viral E Protein. Cell Chem Biol 23:443-52
Russo, Brian C; Stamm, Luisa M; Raaben, Matthijs et al. (2016) Intermediate filaments enable pathogen docking to trigger type 3 effector translocation. Nat Microbiol 1:16025
Kirienko, Daniel R; Revtovich, Alexey V; Kirienko, Natalia V (2016) A High-Content, Phenotypic Screen Identifies Fluorouridine as an Inhibitor of Pyoverdine Biosynthesis and Pseudomonas aeruginosa Virulence. mSphere 1:
Taylor, Travis J; Diaz, Fernando; Colgrove, Robert C et al. (2016) Production of immunogenic West Nile virus-like particles using a herpes simplex virus 1 recombinant vector. Virology 496:186-93
Chou, Yi-ying; Cuevas, Christian; Carocci, Margot et al. (2016) Identification and Characterization of a Novel Broad-Spectrum Virus Entry Inhibitor. J Virol 90:4494-510
Mellata, Melha; Mitchell, Natalie M; Schödel, Florian et al. (2016) Novel vaccine antigen combinations elicit protective immune responses against Escherichia coli sepsis. Vaccine 34:656-62
Helenius, Iiro Taneli; Nair, Aisha; Bittar, Humberto E Trejo et al. (2016) Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression. J Biomol Screen 21:363-71
Stone, Laura K; Baym, Michael; Lieberman, Tami D et al. (2016) Compounds that select against the tetracycline-resistance efflux pump. Nat Chem Biol 12:902-904
Balasubramanian, Anuradha; Manzano, Mark; Teramoto, Tadahisa et al. (2016) High-throughput screening for the identification of small-molecule inhibitors of the flaviviral protease. Antiviral Res 134:6-16
Vrentas, Catherine E; Moayeri, Mahtab; Keefer, Andrea B et al. (2016) A Diverse Set of Single-domain Antibodies (VHHs) against the Anthrax Toxin Lethal and Edema Factors Provides a Basis for Construction of a Bispecific Agent That Protects against Anthrax Infection. J Biol Chem 291:21596-21606

Showing the most recent 10 out of 401 publications