Yeast Functional Genomic Screens Lead to Identification of a Role for a Bacterial Effector in Innate Immunity Regulation

PLoS Pathogens

Cammie F Lesser¹  Monica F Morrison¹  Keri A Siggers¹  Ngozi A Eze¹  Roger W Kramer¹  Naomi L Slagowski¹  Michael N Starnbach²  Kara S Giddings² 

[1] Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America;Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts, United States of America

关键词: Shigellosis;    MAPK signaling cascades;    Saccharomyces cerevisiae;    Yeast infections;    Ontologies;    Yeast;    Shigella;    Gene expression;   

DOI  :  10.1371/journal.ppat.0030021

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Numerous bacterial pathogens manipulate host cell processes to promote infection and ultimately cause disease through the action of proteins that they directly inject into host cells. Identification of the targets and molecular mechanisms of action used by these bacterial effector proteins is critical to understanding pathogenesis. We have developed a systems biological approach using the yeast Saccharomyces cerevisiae that can expedite the identification of cellular processes targeted by bacterial effector proteins. We systematically screened the viable yeast haploid deletion strain collection for mutants hypersensitive to expression of the Shigella type III effector OspF. Statistical data mining of the results identified several cellular processes, including cell wall biogenesis, which when impaired by a deletion caused yeast to be hypersensitive to OspF expression. Microarray experiments revealed that OspF expression resulted in reversed regulation of genes regulated by the yeast cell wall integrity pathway. The yeast cell wall integrity pathway is a highly conserved mitogen-activated protein kinase (MAPK) signaling pathway, normally activated in response to cell wall perturbations. Together these results led us to hypothesize and subsequently demonstrate that OspF inhibited both yeast and mammalian MAPK signaling cascades. Furthermore, inhibition of MAPK signaling by OspF is associated with attenuation of the host innate immune response to Shigella infection in a mouse model. These studies demonstrate how yeast systems biology can facilitate functional characterization of pathogenic bacterial effector proteins.

【 授权许可】

CC BY