Abstract
Sensing and responding to environmental cues is a fundamental characteristic of bacterial physiology and virulence. Here we identify polyamines as novel environmental signals essential for virulence of Salmonella enterica serovar Typhimurium, a major intracellular pathogen and a model organism for studying typhoid fever. Central to its virulence are two major virulence loci Salmonella Pathogenicity Island 1 and 2 (SPI1 and SPI2). SPI1 promotes invasion of epithelial cells, whereas SPI2 enables S. Typhimurium to survive and proliferate within specialized compartments inside host cells. In this study, we show that an S. Typhimurium polyamine mutant is defective for invasion, intracellular survival, killing of the nematode Caenorhabditis elegans and systemic infection of the mouse model of typhoid fever. Virulence of the mutant could be restored by genetic complementation, and invasion and intracellular survival could, as well, be complemented by the addition of exogenous putrescine and spermidine to the bacterial cultures prior to infection. Interestingly, intracellular survival of the polyamine mutant was significantly enhanced above the wild type level by the addition of exogenous putrescine and spermidine to the bacterial cultures prior to infection, indicating that these polyamines function as an environmental signal that primes S. Typhimurium for intracellular survival. Accordingly, experiments addressed at elucidating the roles of these polyamines in infection revealed that expression of genes from both of the major virulence loci SPI1 and SPI2 responded to exogenous polyamines and was reduced in the polyamine mutant. Together our data demonstrate that putrescine and spermidine play a critical role in controlling virulence in S. Typhimurium most likely through stimulation of expression of essential virulence loci. Moreover, our data implicate these polyamines as key signals in S. Typhimurium virulence.
Highlights
Typhimurium Polyamines are present in all living cells and in the intestinal lumen making them accessible upon ingestion and transfer of Polyamines are required for induction of SPI1 and SPI2 The reduced virulence potential for the polyamine mutant was paralleled by reduced expression of both SPI1 and SPI2 genes
The expression of these loci is tightly controlled by multiple regulators operating at different levels in the respective transcriptional hierarchies leading to the correct spatio-temporal induction and level of SPI1 and SPI2 encoded proteins
That the master regulator of SPI1, hilA, the t3ss1 inv operon and the sip-operon of SPI1 encoding SPI1 effectors and T3SS1 translocons were significantly down-regulated in the polyamine mutant
Summary
Typhimurium) is a Gram-negative facultative intracellular pathogen able to cause a wide variety of food- and water-borne diseases ranging from selflimiting gastroenteritis to systemic and life-threatening infections. Following invasion of the epithelial cell layer Salmonella escapes to the underlying tissues [7] where it is taken up by phagocytes like macrophages and dendritic cells [8,9] as reviewed in [10]. It will rapidly spread through the lymphoid and blood systems to the spleen and liver resulting in a life-threatening systemic infection
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