Toxoplasma gondii Is Dependent on Glutamine and Alters Migratory Profile of Infected Host Bone Marrow Derived Immune Cells through SNAT2 and CXCR4 Pathways

Abstract

The obligate intracellular parasite, Toxoplasma gondii, disseminates through its host inside infected immune cells. We hypothesize that parasite nutrient requirements lead to manipulation of migratory properties of the immune cell. We demonstrate that 1) T. gondii relies on glutamine for optimal infection, replication and viability, and 2) T. gondii-infected bone marrow-derived dendritic cells (DCs) display both “hypermotility” and “enhanced migration” to an elevated glutamine gradient in vitro. We show that glutamine uptake by the sodium-dependent neutral amino acid transporter 2 (SNAT2) is required for this enhanced migration. SNAT2 transport of glutamine is also a significant factor in the induction of migration by the small cytokine stromal cell-derived factor-1 (SDF-1) in uninfected DCs. Blocking both SNAT2 and C-X-C chemokine receptor 4 (CXCR4; the unique receptor for SDF-1) blocks hypermotility and the enhanced migration in T. gondii-infected DCs. Changes in host cell protein expression following T. gondii infection may explain the altered migratory phenotype; we observed an increase of CD80 and unchanged protein level of CXCR4 in both T. gondii-infected and lipopolysaccharide (LPS)-stimulated DCs. However, unlike activated DCs, SNAT2 expression in the cytosol of infected cells was also unchanged. Thus, our results suggest an important role of glutamine transport via SNAT2 in immune cell migration and a possible interaction between SNAT2 and CXCR4, by which T. gondii manipulates host cell motility.

Metabolic Needs and Capabilities of Toxoplasma gondii through Combined Computational and Experimental Analysis

“…major and may potentially represent an additional level of versatility in meeting the need of a carbon source, similarly to the previously observed in T . gondii utilization of glutamine [ 45 , 46 ]. We could envision such need as the parasite uses various host cells, where the set of available substrates may vary between cell types.…”

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

“…Glutamine deprivation inhibits the formation of infectious virions, while alpha ketoglutarate supplementation rescues ATP production and viral growth under conditions of glutamine deprivation ( 107 ). Also, glutamine uptake by the sodium-dependent neutral amino acid transporter 2 is required for motility and migration of T. gondii infected DCs ( 109 ).…”

Glutamine-Induced Secretion of Intestinal Secretory Immunoglobulin A: A Mechanistic Perspective

“…Inhibition of GABA synthesis and signaling in T. gondii -infected DCs or blockade of GABAA receptor impairs function of DCs in vitro , including their transmigration capacity, motility, and chemotactic response to CCL19 (59). Glutamine increases the migration of T. gondii -infected bone marrow-derived DCs, while 2-(methylamino)-isobutyrate (MeAIB; inhibitor of glutamine transport by SNAT2), or methionine sulfoximine (MSO, a glutamine synthetase inhibitor) blocks glutamine-enhanced migration of T. gondii -infected bone marrow-derived DCs (60). Lower concentrations of glutamine diminish the function of monocyte-derived macrophages, such as cytokine synthesis, phagocytosis, and antigen presentation (61–63).…”