IlvY is an important regulator ofShigellainfectionin vitroandin vivo

AbstractShigellosis results from oral ingestion of the Gram-negative bacteriaShigella, and symptoms include severe diarrhea and dysentery. In the absence of vaccines, small molecule antibacterial drugs have provided treatment options for shigellosis. However,Shigelladrug resistance is rapidly emerging, andShigellastrains with resistance to both third-generation cephalosporins and azithromycin have been identified in Asia. A re-conceptualization is needed regarding the development of therapeutics that target bacterial pathogens in order to reduce resistance development and alteration of gut microbiota, which is depleted upon treatment with wide spectrum antibiotics, thereby increasing susceptibility to subsequent enteric infections. A more organism-specific approach is to develop agents targeting virulence factors such as toxins, adhesins, invasins, quorum sensing, and protein secretion systems. ForShigella, there is interest in targeting transcription factors essential forShigellainfectionin vivorather than specific effectors. Here we describe the importance of theShigellatranscription factor IlvY inShigellavirulencein vitroandin vivo. This work included the development of a novel, oral mouse model ofShigellainfection with wild-type adult mice. Unlike previous models, mice do not require antibiotic pretreatment or diet modifications. This mouse model was used to demonstrate the importance of IlvY forShigella in vivosurvival and that deletion ofilvYimpacts host responses to infection. These results illustrate that IlvY is a potential therapeutic target for the treatment of shigellosis. In addition, the novel mouse model provides an exciting new opportunity to investigate therapeutic efficacy againstShigellainfection and host responses to infection.