Amino Acids As Mediators of Metabolic Cross Talk between Host and Pathogen

Abstract

The interaction between host and pathogen decidedly shapes the outcome of an infection, thus understanding this interaction is critical to the treatment of a pathogen-induced infection. Although research in this area of cell biology has yielded surprising findings regarding interactions between host and pathogen, understanding of the metabolic cross talk between host and pathogen is limited. At the site of infection, host and pathogen share similar or identical nutritional substrates and generate common metabolic products, thus metabolic cross talk between host and pathogen could profoundly affect the pathogenesis of an infection. In this review, we present results of a recent discovery of a metabolic interaction between host and pathogen from an amino acid (AA) metabolism-centric point of view. The host depends on AA metabolism to support defensive responses against pathogens, while the pathogens modulate AA metabolism for its own advantage. Some AA, such as arginine, asparagine, and tryptophan, are central points of competition between the host and pathogen. Thus, a better understanding of AA-mediated metabolic cross talk between host and pathogen will provide insight into fruitful therapeutic approaches to manipulate and prevent progression of an infection.

Keywords: amino acids; arginine; asparagine; infection; metabolism.

Figure 1

Extensive amino acid (AA) metabolism and communication between the host and Salmonella or Shigella. Salmonella (A, 1–2 h postinfection) or Shigella infection induces a rapid state of AA starvation through aseptic membrane damage (AMD), which inhibits the activation of mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 negatively controls the autophagy response, which is responsible for targeting and degradating Salmonella or Shigella. However, Salmonella escapes from the autophagy-mediated degradation through replenishment of intracellular AA pools to reactivate mTORC1 signaling at a later phase of the infection (B).

Figure 2

Competition between the host and Leishmania or Streptococcus pyogenes for arginine. (A) After Leishmania invasion, the infected macrophage produces nitric oxide (NO) from arginine via NO synthase (NOS) to kill Leishmania while Leishmania uses macrophage arginase I (a) to limit the amount of arginine available for synthesis of NO via NOS by macrophages. Mechanistically, the increase in Th2 cytokines during Leishmania infection, such as interleukin (IL)-4 and IL-5, induces the expression of arginase I in macrophages to produce polyamines. Leishmania directly activates signal transducer and activator of transcription-6 (STAT6) to increase the expression of arginase I in macrophages. Leishmania also uses the arginine transporter (amino acid permease 3, AAP3) (b) to compete with macrophages for arginine. During macrophage invasion by Leishmania, there is a coordinated arginine deprivation response mediated via the mitogen-activated protein kinase 2 (MPK2) cell signaling pathway, which upregulates arginine transport away from the macrophage. Leishmania uses polyamines to produce trypanothione that neutralizes effects of reactive oxygen species (ROS) released from macrophages. (B) Streptococcus pyogenes uses the arginine deiminase (ADI) pathway to limit available arginine for NO production by macrophages. This pathway includes the ArcD antiporter, which concomitantly transports ornithine out and arginine into the cell, enzymes which convert arginine to ornithine, CO₂, NH₃, and one molecule of adenosine triphosphate (ATP). The NH₃ can be utilized to buffer against acid stress.

Figure 3

The role of asparagine in Mycobacterium tuberculosis and group A Streptococcus (GAS) infections. (A) Asparagine supports M. tuberculosis resistance to acid stress. M. tuberculosis expresses an asparagine transporter (AnsP2), which captures asparagine from macrophages, and asparaginase (AnsA), which hydrolyzes asparagine into aspartate and ammonia. Ammonia can react with protons in the phagosome to form ammonium ions. AnsA can also be secreted into the lumen of the phagosome of the macrophage through the type VII secretion system to hydrolyze asparagine to aspartate and ammonia. (B) Asparagine regulates GAS proliferation and expression of virulence factors. GAS infection creates endoplasmic reticulum stress (ERS) in host cells through effects of its streptolysin toxins on extracellular calcium signaling. ERS activates the protein kinase-like endoplasmic reticulum kinase (PERK), which induces the activation of the transcription factor activating transcription factor 4 (ATF4) to increase in the expression of asparagine synthetase and the production of asparagine. Asparagine promotes GAS proliferation and the expression of its virulence factors.

Figure 4

Tryptophan competition between host and Clostridium difficile or HIV. Upon C. difficile infection, tryptophan supports optimal effector T cell responses against C. difficile. C. difficile promotes activation of indoleamine 2,3-dioxygenase (IDO) via an unknown mechanism to convert tryptophan to kynurenine to deplete the tryptophan pool and diminish responses of effector T cells in the host. Kynurenine also promotes apoptosis of neutrophils, inhibits the production of reactive oxygen species from neutrophils, and enhances the generation of regulatory T cells (Treg) through the aryl hydrocarbon receptor (AhR). HIV induces expression of IDO through transactivator regulatory protein (Tat) and IFN-γ, leading to tryptophan catabolism, expansion of Tregs, loss of CD4⁺ T-helper cells, and functional impairment of T-cell responses.