Abstract
The pathogenesis of Salmonella Typhimurium depends on the bacterium’s ability to survive and replicate within host cells. The formation and maintenance of a unique membrane-bound compartment, termed the Salmonella-containing vacuole (SCV), is essential for S. Typhimurium pathogenesis. SCV-bound S. Typhimurium induces formation of filamentous tubules that radiate outwards from the SCV, termed Salmonella-induced filaments (SIFs). SIF formation is concomitant with the onset of replication within host epithelial cells. SIF biogenesis, formation and maintenance of the SCV, and the intracellular positioning of the SCV within the host cell requires translocation of bacterial proteins (effectors) into the host cell. Effectors secreted by the type III secretion system encoded on Salmonella pathogenicity island 2 (T3SS2) function to interfere with host cellular processes and promote both intracellular survival and replication of S. Typhimurium. Seven T3SS2-secreted effectors, SifA, SopD2, PipB2, SteA, SseJ, SseF, and SseG have previously been implicated to play complementary, redundant, and/or antagonistic roles with respect to SIF biogenesis, intracellular positioning of the SCV, and SCV membrane dynamics modulation during infection. We undertook a systematic study to delineate the contribution of each effector to these processes by (i) deleting all seven of these effectors in a single S. Typhimurium strain; and (ii) deleting combinations of multiple effectors based on putative effector function. Using this deletion mutant library, we show that each of SIF biogenesis, intracellular SCV localization, intramacrophage replication, colonization, and virulence depends on the activities of multiple effectors. Together, our data demonstrates the complex interplay between these seven effectors and highlights the necessity to study T3SS2-secreted effectors as groups, rather than studies of individual effectors.
Highlights
IntroductionTyphimurium) is a Gram-negative foodborne pathogen that commonly causes non-typhoidal salmonellosis (gastroenteritis) in humans
We demonstrate that LAMP1+-tubule extension, intracellular positioning, intramacrophage replication, and replication in vivo all require the action of multiple effectors
Through an extensive literature search we identified seven effectors of interest implicated in Salmonella-induced filaments (SIFs) biogenesis, Salmonella-containing vacuole (SCV) membrane maintenance, and intracellular SCV localization
Summary
Typhimurium) is a Gram-negative foodborne pathogen that commonly causes non-typhoidal salmonellosis (gastroenteritis) in humans. The success of Salmonella as an intracellular pathogen is largely due to its ability to evade host defense mechanisms by invading and residing within intestinal epithelial cells and phagocytic cells of the host [1,2]. Upon invasion of the host cell, S. Typhimurium resides within a unique compartment called the Salmonella-containing vacuole (SCV). Formation and maintenance of the SCV during infection is critical to survival within phagocytes and plays an important role in promoting S. Typhimurium replication in non-phagocytic cells [3]
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