Microbiota and Pathogen Proteases Modulate Type III Secretion Activity in Enterohemorrhagic Escherichia coli
Authors: Meredith M Curtis
Vanessa Sperandio
Elizabeth A Cameron
Aman Kumar
Gary M Dunny
Journal: mBio (2018)
Discipline: MICROBIOLOGY
Keywords: Bacteroides; EspP; enterohemorrhagic E. coli (EHEC); microbiota; type three secretion.
Affiliations: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USA., Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA .

Abstract:  Enteric pathogens have complex interactions with the gut microbiota. Most of what is known about them has focused on microbiota-derived metabolites or small molecules that serve as nutrients and/or signals to aid in growth or transcriptionally regulate virulence gene expression. A common virulence strategy is to express a type III secretion system (T3SS), which is a molecular syringe deployed by many Gram-negative pathogens to hijack host cell function. Enterohemorrhagic Escherichiacoli (EHEC) requires its T3SS to colonize the intestinal tract and cause disease. Here we report that a prominent member of the intestinal microbiota, Bacteroides thetaiotamicron (Bt), secretes proteases that cleave the translocon of the T3SS of EHEC to enhance effector translocation into host cells. This is in contrast from an endogenous protease from EHEC itself (namely, EspP) that cleaves the translocon protein EspB in a different site to limit effector translocation. The EspB protein forms the T3SS pore in mammalian cells, and pore proteins are conserved in the T3SSs from several pathogens. This is the first demonstration of a commensal species directly processing a pathogen's T3SS, posing a new paradigm for how the microbiota can influence the severity of disease caused by bacterial pathogens. Because T3SSs are employed by many pathogens, this phenomenon has broad implications to commensal-pathogen relationships.IMPORTANCE The gut microbiota is usually regarded as providing colonization resistance against enteric pathogens. However, some pathogens evolved to thrive with the aid of certain members of the microbiota. Several Gram-negative bacteria employ type three secretion systems (T3SSs), which are molecular syringes that deliver effector proteins to host cells, hijacking host cell function. Here we show that the T3SS of enterohemorrhagic E. coli (EHEC) is cleaved by self and microbiota-derived proteases. Self-cleavage limits effector translocation, while cleavage by the microbiota member Bacteroides thetaiotamicron (Bt) exacerbates effector translocation and lesion formation on epithelial cells. 

Retracted: No

PubPeer comments:
 In Figure 2A, it appears that there may be 14 bands in the Western blot but there are only 13 sample labels. Could the authors please comment as to if there is an extra band or a missing sample label? (**To readers the colored green red blue boxes are in the original Figure and have no bearing on my comment**) ![file] , 
 #1 There is a missing label of DMEM only in the end of the lysate ,