Genome-wide RNAi screen in IFN-γ-treated human macrophages identifies genes mediating resistance to the intracellular pathogen Francisella tularensis.

PloS One
Hongwei ZhouLester Kobzik

Abstract

Interferon-gamma (IFN-γ) inhibits intracellular replication of Francisella tularensis in human monocyte-derived macrophages (HMDM) and in mice, but the mechanisms of this protective effect are poorly characterized. We used genome-wide RNA interference (RNAi) screening in the human macrophage cell line THP-1 to identify genes that mediate the beneficial effects of IFN-γ on F. tularensis infection. A primary screen identified ∼200 replicated candidate genes. These were prioritized according to mRNA expression in IFN-γ-primed and F. tularensis-challenged macrophages. A panel of 20 top hits was further assessed by re-testing using individual shRNAs or siRNAs in THP-1 cells, HMDMs and primary human lung macrophages. Six of eight validated genes tested were also found to confer resistance to Listeria monocytogenes infection, suggesting a broadly shared host gene program for intracellular pathogens. The F. tularensis-validated hits included 'druggable' targets such as TNFRSF9, which encodes CD137. Treating HMDM with a blocking antibody to CD137 confirmed a beneficial role of CD137 in macrophage clearance of F. tularensis. These studies reveal a number of important mediators of IFN-γ activated host defense against intracellular pathoge...Continue Reading

References

Sep 1, 1991·Infection and Immunity·L D AnthonyF E Nano
Sep 1, 1966·Journal of Bacteriology·J E Nutter, Q N Myrvik
Dec 9, 1998·Proceedings of the National Academy of Sciences of the United States of America·D DiSepioS Nagpal
Jun 25, 1999·Journal of Leukocyte Biology·J Langstein, H Schwarz
Jun 21, 2001·JAMA : the Journal of the American Medical Association·D T DennisUNKNOWN Working Group on Civilian Biodefense
Oct 9, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Eric GhigoJean-Louis Mege
Mar 22, 2003·Trends in Microbiology·Richard W TitballMats Forsman
May 1, 1961·Archives of Internal Medicine·S SASLAWS CARHART
May 1, 1961·Archives of Internal Medicine·S SASLAWS CARHART
Oct 4, 2003·Nature Reviews. Drug Discovery·Mark A Lindsay
Nov 13, 2004·Nature·Jürgen SoutschekHans-Peter Vornlocher
Nov 20, 2004·Nature Reviews. Microbiology·Petra C F OystonRichard W Titball
Dec 25, 2004·Journal of Leukocyte Biology·Herbert Schwarz
Aug 23, 2005·Infection and Immunity·Daniel L ClemensMarcus A Horwitz
Mar 23, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anatoly L MayburdJames L Mulshine
Sep 5, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Dongsheng JiangHerbert Schwarz
Nov 26, 2008·Autophagy·Thomas J CremerJonathan P Butchar
Mar 31, 2010·Nature Immunology·Teresa Fernandes-AlnemriEmad S Alnemri
May 12, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jonathan W JonesDenise M Monack
Nov 16, 2010·Seminars in Oncology·Paolo A AsciertoIgnacio Melero
Jun 21, 2011·Frontiers in Microbiology·Jonathan Wiley JonesDenise M Monack

❮ Previous
Next ❯

Citations

Apr 19, 2016·Scientific Reports·Bidisha BhattacharyaIgor Kramnik
Nov 28, 2013·Pharmaceuticals·Olivia PerwitasariRalph A Tripp
Apr 27, 2021·Frontiers in Cellular and Infection Microbiology·Virtu Solano-ColladoStefania Spanò

❮ Previous
Next ❯

Methods Mentioned

BETA
PCR
fluorescence
flow cytometry
fluorescence microscopy
PMA
FACS
nucleotide exchange
transfection
gene knockdown
bronchoalveolar

Software Mentioned

MATLAB®
Prism
Eisen Lab Cluster Analysis and Visualization
Ingenuity
BLAT
GraphPad
Sequencer

Related Concepts

Related Feeds

CRISPR & Staphylococcus

CRISPR-Cas system enables the editing of genes to create or correct mutations. Staphylococci are associated with life-threatening infections in hospitals, as well as the community. Here is the latest research on how CRISPR-Cas system can be used for treatment of Staphylococcal infections.

Aminoglycosides (ASM)

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.

Aminoglycosides

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.