High-throughput CRISPR screens to dissect macrophage-Shigella interactions

BioRxiv : the Preprint Server for Biology
Y. LaiTimothy K. Lu

Abstract

Shigellosis, the primary cause of diarrheal deaths worldwide, particularly affects children living in low and middle-income countries. The causative agent, Shigella spp., invades and replicates in the epithelium of the large intestine, eliciting an intense inflammatory response and tissue destruction. However, how Shigella rewires macrophages prior to epithelial cell invasion is poorly understood. Here we show that Shigella flexneri induces the production of pro-inflammatory cytokines and chemokines and triggers host pyruvate catabolism for energy acquisition before rapidly killing macrophages. To identify host factors modulated by S. flexneri, we performed genome-wide and focused secondary CRISPR knockout and CRISPRi screens in human monocytic THP-1 cells infected with S. flexneri and evaluated host cell survival. Knockdown of key components of the Toll-like receptor 1/2 signaling pathway significantly reduced pro-inflammatory cytokine and chemokine production, enhanced host cell survival, and controlled intracellular pathogen growth. Knockdown of the enzymatic component of the mitochondrial pyruvate dehydrogenase complex also enhanced THP-1 cell survival. Small molecule inhibitors, which selectively inhibit key components of ...Continue Reading

Related Concepts

Dengue Fever
Fetal Development Aspects
Antivirals, topical
Pathogenic Organism
DNA-Directed RNA Polymerase
SH2D4A protein, human
Virus Replication
Human leukocyte interferon
Sofosbuvir
Flaviviridae

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Related Papers

PLoS Neglected Tropical Diseases
Caroline de FreitasThiago Souza
BioRxiv : the Preprint Server for Biology
Carolina de FreitasThiago Souza
International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases
Sandra E Reznik, Charles R Ashby
© 2020 Meta ULC. All rights reserved