Curcumin Increases the Pathogenicity of Salmonella enterica Serovar Typhimurium in Murine Model

Abstract

Curcumin has gained immense importance for its vast therapeutic and prophylactic applications. Contrary to this, our study reveals that it regulates the defense pathways of Salmonella enterica serovar Typhimurium (S. Typhimurium) to enhance its pathogenicity. In a murine model of typhoid fever, we observed higher bacterial load in Peyer's patches, mesenteric lymph node, spleen and liver, when infected with curcumin-treated Salmonella. Curcumin increased the resistance of S. Typhimurium against antimicrobial agents like antimicrobial peptides, reactive oxygen and nitrogen species. This increased tolerance might be attributed to the up-regulation of genes involved in resistance against antimicrobial peptides - pmrD and pmrHFIJKLM and genes with antioxidant function - mntH, sodA and sitA. We implicate that iron chelation property of curcumin have a role in regulating mntH and sitA. Interestingly, we see that the curcumin-mediated modulation of pmr genes is through the PhoPQ regulatory system. Curcumin downregulates SPI1 genes, required for entry into epithelial cells and upregulates SPI2 genes required to intracellular survival. Since it is known that the SPI1 and SPI2 system can be regulated by the PhoPQ system, this common regulator could explain curcumin's mode of action. This data urges us to rethink the indiscriminate use of curcumin especially during Salmonella outbreaks.

Curcumin Reduces the Motility of Salmonella enterica Serovar Typhimurium by Binding to the Flagella, Thereby Leading to Flagellar Fragility and Shedding

“…Curcumin reduced the expression of SPI-1, a T3SS required for invasion of host cells, but enhanced that of SPI-2, a T3SS required for intramacrophage survival (61). It increased the pathogenicity of Salmonella (61,62). Thus, although curcumin hinders motility, one of the important virulence determinants of Salmonella, it also has a positive effect on Salmonella pathogenicity.…”

“…However, other T3SSs of Salmonella, Salmonella pathogenicity island 1 (SPI-1) and SPI-2, are significantly altered upon curcumin treatment (61). Curcumin reduced the expression of SPI-1, a T3SS required for invasion of host cells, but enhanced that of SPI-2, a T3SS required for intramacrophage survival (61).…”

Differential Modulation of Intracellular Survival of Cytosolic and Vacuolar Pathogens by Curcumin

“…To validate our hypothesis, the macrophage cells (RAW 264.7 cells) were pretreated with IFN-␥ to induce the generation of ROS and RNIs in the cells (39), and the survival of the pathogens was analyzed in these cells with and without curcumin treatment. It was observed that S. Typhimurium and S. aureus, both susceptible to oxidative and nitrosative stress (9,30,42) (Fig. 2), showed increased proliferation in the IFN-␥-primed cells treated with curcumin compared to that in curcumin-untreated but IFN-␥-primed cells (Fig.…”

“…The intracellular survival assay was performed as described previously (30). Briefly, RAW 264.7 cells were seeded into a 24-well plate and were either mock treated or treated with gamma interferon (IFN-␥; 20 U/ml, 12 h), curcumin (10 M, 2 h), or erythromycin (100 g/ml, 1 h).…”

“…RAW 264.7 cells were grown on the coverslips placed in a 24-well plate and were infected as described for the intracellular survival assay (30). Cells were fixed with 3.5% (wt/vol) paraformaldehyde at different time points.…”