Journal
CELL HOST & MICROBE
Volume 28, Issue 3, Pages 402-+Publisher
CELL PRESS
DOI: 10.1016/j.chom.2020.05.012
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Funding
- United States National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) [R01AI145879]
- Intramural Program of the NIAID, NIH
- Intramural Program of the National Heart Lung and Blood Institute, NIH
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZICHL005907, ZICHL006228] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001030] Funding Source: NIH RePORTER
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Bacteria and their toxins are associated with significant human morbidity and mortality. While a few bacterial toxins are well characterized, the mechanism of action for most toxins has not been elucidated, thereby limiting therapeutic advances. One such example is the highly potent pore-forming toxin, hemolysin BL (HBL), produced by the gram-positive pathogen Bacillus cereus. However, how HBL exerts its effects and whether it requires any host factors is unknown. Here, we describe an unbiased genome-wide CRISPRCas9 knockout screen that identified LPS-induced TNF-alpha factor (LITAF) as the HBL receptor. Using LITAF-deficient cells, a second, subsequent whole-genome CRISPR-Cas9 screen identified the LITAF-like protein CDIP1 as a second, alternative receptor. We generated LITAF-deficient mice, which exhibit marked resistance to lethal HBL challenges. This work outlines and validates an approach to use iterative genome-wide CRISPR-Cas9 screens to identify the complement of host factors exploited by bacterial toxins to exert their myriad biological effects.
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