Impact of Salmonella Infection on Host Hormone Metabolism Revealed by Metabolomics

Abstract

The interplay between pathogens and their hosts has been studied for decades using targeted approaches, such as the analysis of mutants and host immunological responses. Although much has been learned from such studies, they focus on individual pathways and fail to reveal the global effects of infection on the host. To alleviate this issue, high-throughput methods, such as transcriptomics and proteomics, have been used to study host-pathogen interactions. Recently, metabolomics was established as a new method to study changes in the biochemical composition of host tissues. We report a metabolomic study of Salmonella enterica serovar Typhimurium infection. Our results revealed that dozens of host metabolic pathways are affected by Salmonella in a murine infection model. In particular, multiple host hormone pathways are disrupted. Our results identify unappreciated effects of infection on host metabolism and shed light on mechanisms used by Salmonella to cause disease and by the host to counter infection.Salmonella enterica serovar Typhimurium has been used as a model organism to study host-pathogen interactions for decades (12, 18, 37). Although much is known regarding the effects of Salmonella on the host, most studies have focused on the analysis of individual host metabolic pathways. A few global studies on the effect of Salmonella infection on the host have been performed, using both transcriptomic and proteomic techniques (29,40). However, the effect of Salmonella on the biochemical composition of host tissues remains unknown. Recently, techniques that detect and quantify multiple small metabolites in complex biological samples have been developed, giving rise to the field of metabolomics (19,25,39). Metabolomic studies have relied mainly on the use of chromatography coupled to mass spectrometry (MS) or nuclear magnetic resonance spectroscopy to identify and quantify metabolites in biological samples. Because these techniques require extensive sample preparation and, in some cases, have limited sensitivity, high-throughput studies have been impractical. More powerful techniques, such as direct-infusion ultrahighresolution Fourier transform ion cyclotron resonance (DI-FT-ICR) MS, have been developed with the potential to identify and quantify hundreds of metabolites with higher mass accuracy and without the need for extensive sample preparation, thus allowing comprehensive metabolic fingerprinting (11). We used DI-FT-ICR MS to investigate the impact of Salmonella infection on host metabolism using a murine typhoid infection model. To our knowledge, this is the first comprehensive metabolomic analysis of the effect of bacterial infection on host metabolism. Our study revealed a profound impact of Salmonella on host metabolism, with dozens of pathways being affected. Interestingly, some of the most impacted pathways are involved in host hormone signaling. Hormones are important mammalian signaling molecules and are fundamental for host metabolic and immune homeostasis (5, 9). The disruption of such pathways by ...

Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis

“…Decreases observed in levels of -6 PUFAs and lysolipids from infected blood during 3 dpi suggests that both arms of AA production were disrupted. These results are consistent with other metabolomics studies of infection whose results have indicated the importance of eicosanoids and lysolipids during infection (45,50,63). However, it appears that decreases in levels of eicosanoids and lysolipids are not universal traits during bacterial infections.…”

“…Serum profiles of patients infected with Mycobacterium leprae revealed increased levels of anti-inflammatory PUFAs and accumulation of phospholipids (12,45). Feces and liver profiles from mice subjected to infection with Salmonella enterica serovar Typhimurium showed increases in levels of eicosanoid biosynthesis products (50). Not all types of infections evoke the activity of PLA 2 enzymes as an immune defense mechanism against invading pathogens.…”

“…Recent studies have shown that metabolomics can be used to identify metabolites whose levels are altered in response to an infection (10,(49)(50)(51). In particular, with respect to bacterial infections, the rapid emergence of multidrug-resistant Gram-positive and Gram-negative bacteria fuels the need for novel strategies in diagnosis and treatment (11).…”

“…A/J mice were infected (by subcutaneous injection) with B. anthracis vegetative cells or spores to first determine the LD 50 for these forms of bacilli. The LD 50 for the vegetative cell infection was determined to be 1.5 ϫ 10 3 cells, while that of the spore infection was determined to be 1.0 ϫ 10 2 spores (see Fig. S1A and B in the supplemental material).…”

The Deubiquitinase Activity of the Salmonella Pathogenicity Island 2 Effector, SseL, Prevents Accumulation of Cellular Lipid Droplets

“…FTICR MS. Mass spectrometry (MS) analysis was performed essentially as previously described (4). Dried extracts were dissolved in 100 l of 50% acetonitrile (in water) per 10 mg of the starting materials, vortexed, and cleared by centrifugation.…”