Bacterial Pathogens Hijack the Innate Immune Response by Activation of the Reverse Transsulfuration Pathway

Abstract

The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of S-adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape. IMPORTANCE Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.

H2S and reactive sulfur signaling at the host-bacterial pathogen interface

“…In infected macrophages and in mice, Helicobacter pylori was found to induce the expression of the host transsulfuration pathway enzyme CSE ( Fig. 2A), resulting in increased cystathionine production that enhances H. pylori survival in these models (99). Any connection of cystathionine to host or bacterially derived H 2 S was not elucidated in this work.…”

“…antibiotic and oxidative stress (22,24,25,99). In infected macrophages and in mice, Helicobacter pylori was found to induce the expression of the host transsulfuration pathway enzyme CSE ( Fig.…”

Hypusination Orchestrates the Antimicrobial Response of Macrophages

“…Proteomic analysis was performed as described ( Gobert et al, 2019 ; Noto et al, 2019 ). After infections, macrophages were lysed in 50 mM Tris-HCl pH 7.6, 150 mM NaCl, 1% NP-40, and 2 mM EDTA and protein concentrations were determined by BCA.…”

Astrocyte-derived small extracellular vesicles promote synapse formation via fibulin-2-mediated TGF-β signaling

“…Further analysis of these 33 proteins using PANTHER revealed enrichment in protein classes commonly found in EVs, including cell adhesion molecules, extracellular matrix (ECM) proteins, cytoskeletal proteins, and signaling molecules (Jimenez et al, 2019) (Figure 2B). Because astrocyte and C6 glioma SEVs are of similar glial origin and had many proteins present at similar levels in the proteomics dataset, we were able to use Benjamini-Hochberg statistics (Gobert et al, 2019;Mishra et al, 2018;Voss et al, 2015) to identify significantly enriched proteins in astrocyte-derived SEVs compared to C6 SEVs (see STAR methods). Based on this analysis, 12 out of the 33 proteins were significantly enriched in astrocytederived SEVs compared to C6 SEVs (Figure 2C).…”