Salmonella enterica Serovar Typhi Induces Host Metabolic Reprogramming to Increase Glucose Availability for Intracellular Replication

Abstract

Salmonella enterica serovar Typhi (S. Typhi) is a human-limited intracellular pathogen and the cause of typhoid fever, a severe systemic disease. Pathogen–host interaction at the metabolic level affects the pathogenicity of intracellular pathogens, but it remains unclear how S. Typhi infection influences host metabolism for its own benefit. Herein, using metabolomics and transcriptomics analyses, combined with in vitro and in vivo infection assays, we investigated metabolic responses in human macrophages during S. Typhi infection, and the impact of these responses on S. Typhi intracellular replication and systemic pathogenicity. We observed increased glucose content, higher rates of glucose uptake and glycolysis, and decreased oxidative phosphorylation in S. Typhi-infected human primary macrophages. Replication in human macrophages and the bacterial burden in systemic organs of humanized mice were reduced by either the inhibition of host glucose uptake or a mutation of the bacterial glucose uptake system, indicating that S. Typhi utilizes host-derived glucose to enhance intracellular replication and virulence. Thus, S. Typhi promotes its pathogenicity by inducing metabolic changes in host macrophages and utilizing the glucose that subsequently accumulates as a nutrient for intracellular replication. Our findings provide the first metabolic signature of S. Typhi-infected host cells and identifies a new strategy utilized by S. Typhi for intracellular replication.

Transcriptional profiling links unique human macrophage phenotypes to the growth of intracellular Salmonella enterica serovar Typhi

“…We recognize that a high MOI may promote a more pro-inflammatory innate immune response in the Salmonella exposed THP-1 macrophages than that of a lower MOI. However, the expression of classic M1 and M2 markers in our THP-1 data are consistent with a prior study of naïve versus S. Typhi challenged hMDMs that used an MOI of 10 37 . Future studies exploring alternative infection conditions will build on our work and contribute to a more comprehensive model of S. Typhi infection in human macrophages.…”

“…We compared the expression of genes in our challenged versus naïve THP-1 macrophages with a publicly available RNA-Seq dataset from human monocyte-derived macrophages (hMDMs) challenged with S . Typhi 37 . To facilitate this, we compiled a list of genes exhibiting different transcriptional levels in M1 versus M2 polarized hMDMs based on prior studies 38 , 39 (Supplementary Table S4 ).…”

“…This analysis was done with publicly available RNA-Seq data (PRJNA721701) from naïve hMDMs and hMDMs challenged with S . Typhi for 8-h 37 , as well as with the sorted populations of THP-1 macrophages challenged with S . Typhi for 18-h. Heatmaps were constructed with the Pheatmap package as described above, however, Euclidean clustering was not used.…”

“…Given the consistency in polarization phenotypes demonstrated by our THP-1 macrophages using established hMDM and THP-1 macrophage markers, we used Typhi for 8-h. The hMDM gene expression dataset is from a publicly available RNA-Seq dataset (PRJNA721701) 37 . The genes included in this heatmap are commonly used to define M1 and M2 polarization in hMDMs 38,39 .…”

“…These M1, M2, and M1/M2 marker lists were used to sort the genes differentially expressed between macrophage populations into their respective polarization categories. This analysis was done with publicly available RNA-Seq data (PRJNA721701) from naïve hMDMs and hMDMs challenged with S. Typhi for 8-h 37 , as well as with the sorted populations of THP-1 macrophages challenged with S. Typhi for 18-h. Heatmaps were constructed with the Pheatmap package as described above, however, Euclidean clustering was not used. www.nature.com/scientificreports/ Binary comparisons of the macrophage populations harboring replicating versus non-replicating S. Typhi DAVID 66,67 was used to identify GO term pathways 44,45 enriched for significantly differentially expressed genes between the replicating and non-replicating populations.…”