Research Article: Salmonella Modulation of Host Cell Gene Expression Promotes Its Intracellular Growth

Date Published: October 3, 2013

Publisher: Public Library of Science

Author(s): Sebastian Hannemann, Beile Gao, Jorge E. Galán, Raphael H. Valdivia.


Salmonella Typhimurium has evolved a complex functional interface with its host cell largely determined by two type III secretion systems (T3SS), which through the delivery of bacterial effector proteins modulate a variety of cellular processes. We show here that Salmonella Typhimurium infection of epithelial cells results in a profound transcriptional reprogramming that changes over time. This response is triggered by Salmonella T3SS effector proteins, which stimulate unique signal transduction pathways leading to STAT3 activation. We found that the Salmonella-stimulated changes in host cell gene expression are required for the formation of its specialized vesicular compartment that is permissive for its intracellular replication. This study uncovers a cell-autonomous process required for Salmonella pathogenesis potentially opening up new avenues for the development of anti-infective strategies that target relevant host pathways.

Partial Text

Bacterial pathogens that have sustained long-standing associations with their hosts have developed complex functional interfaces shaped by the concerted activities of molecules from the host and the pathogen [1]–[4]. For many pathogens, this functional interface is largely dependent on the activity of specialized protein secretion machines known as type III secretion systems (T3SSs), which deliver bacterial effector proteins into host cells to modulate a variety of cellular processes [1], [5]. One example of such a pathogen is Salmonella enterica serovar Typhimurium (S. Typhimurium), a cause of human gastroenteritis, which interacts with host cells through the activities of two T3SSs encoded within its pathogenicity islands 1 (SPI-1) and 2 (SPI-2) [6]–[8]. The SPI-1 T3SS mediates bacterial entry into non-phagocytic epithelial cells, while the SPI-2 T3SS is required for the building and maintenance of a specialized membranous compartment that harbors the intracellular bacteria. Bacterial internalization is mediated by the SPI-1 T3SS effectors SopE, SopE2, and SopB, which activate the Rho family of GTPases Rac1, Cdc42 and RhoG [9], [10]. In addition these bacterial effectors stimulate a transcriptional reprogramming in host cells, which leads to the production of pro-inflammatory cytokines believed to be essential for the initiation of the inflammatory diarrhea that characterizes acute Salmonella infection [11], [12]. The early transcriptional responses stimulated by Salmonella upon infection of intestinal epithelial cells exhibit many of the hallmarks of the responses seen after the stimulation of innate immune receptors [13]. However, the Salmonella-induced responses are unique in that this pathogen is capable of stimulating them independently of innate immune receptors [12], which are largely inactive in intestinal epithelial cells due to robust negative regulatory mechanisms [14]–[16]. Indeed, inflammation is essential for Salmonella growth in the intestine since without inflammation this pathogen cannot gain access to essential nutrients [17] and cannot effectively compete with the normal microbial flora [18]. Therefore, despite exhibiting the fingerprints of an innate immune response, the early transcriptional responses stimulated by Salmonella can be best characterized as a pathogen-driven process triggered by specific adaptations to cope with the host environment rather than as a hard-wired host defense response to conserved bacterial products.

It is well established that the interaction of microbial pathogens with mammalian cells often leads to significant changes in host-cell gene expression [13]. These responses are most often the result of the stimulation of innate immune receptors by conserved bacterial products, which lead to “hard-wired” transcriptional outputs. Salmonella, however, has evolved the additional ability to stimulate transcriptional responses independent of the activation of innate immune receptors [11], [12], [43]. This specific adaptation, which requires effectors of the SPI-1 T3SS, allows Salmonella to potentially trigger this response in cells, such as those of the intestinal epithelium, that are subject to robust regulatory mechanisms to prevent the stimulation of innate immune receptors [14]–[16]. In this study we have defined a host-cell signaling pathway leading to Salmonella-induced changes in gene expression in epithelial cells and found that STAT3 plays a central role in their orchestration. We have found that Salmonella activates STAT3 through a non-canonical pathway that does not require JAK kinases. Instead, this pathway is triggered by the SPI-1 T3SS effectors SopE, SopE2 and SopB, which through Rho-family GTPases, stimulate PAK and Abl tyrosine kinases leading to STAT3 activation (Fig. 6).




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