Deciphering Interplay between Salmonella Invasion Effectors

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Abstract
Bacterial pathogens have evolved a specialized type III secretion system (T3SS) to translocate virulence effector proteins directly into eukaryotic target cells. Salmonellae deploy effectors that trigger localized actin reorganization to force their own entry into non-phagocytic host cells. Six effectors (SipC, SipA, SopE/2, SopB, SptP) can individually manipulate actin dynamics at the plasma membrane, which acts as a ‘signaling hub’ during Salmonella invasion. The extent of crosstalk between these spatially coincident effectors remains unknown. Here we describe trans and cis binary entry effector interplay (BENEFIT) screens that systematically examine functional associations between effectors following their delivery into the host cell. The results reveal extensive ordered synergistic and antagonistic relationships and their relative potency, and illuminate an unexpectedly sophisticated signaling network evolved through longstanding pathogen–host interaction. Critical to the onset of Salmonella infection is the ability of bacteria to force their own entry (‘invade’) into intestinal cells of their mammalian host from where they replicate, spread and cause damage. To achieve this invasion, Salmonella deliver a cocktail of proteins directly into host target cells. These proteins override host cell communications and remodel cell structure, tricking the normally dormant cells into engulfing the invaders. Although we are beginning to understand the functions of each delivered protein, little is known about how their activities are coordinated. Here we describe new techniques that systematically examine the interplay between the delivered bacterial proteins within the host cell. The results illuminate an unexpectedly complex network of interrelated relationships that must be precisely coordinated to promote bacterial invasion. The data provide new insights into how this important pathogen triggers invasion of host cells during infection.