Glutamine addiction in virus-infected mammalian cells: A target of the innate immune system?

Control of core cell metabolism is a key aspect of the evolutionary conflict between viruses and the host's defence mechanisms. From their side, the invading viruses press the accelerator on their host cell's glycolysis, fatty acid, and glutaminolytic metabolic processes among others. It is also well established that activation of innate immune system responses modulates facets of metabolism such as that of polyamine, cholesterol, tryptophan and many more. But what about glutamine, a proteogenic amino acid that is a crucial nutrient for multiple cellular biosynthetic processes? Although mammalian cells can normally synthesize glutamine de novo, it has been noted that infections with genetically and phylogenetically diverse viruses are followed by the acquisition of a dependency on supplies of exogenous glutamine i.e. "glutamine addiction". Here we present our novel hypothesis that glutamine metabolism is also a target of the innate immune system, possibly through the action of interferons, as part of the evolutionary conserved antiviral metabolic reprogramming.

Mitochondrial MTHFD isozymes display distinct expression, regulation, and association with cancer.

Mitochondrial folate metabolism is central to the generation of nucleotides, fuelling methylation reactions, and redox homeostasis. Uniquely among the reactions of the mitochondrial folate pathway, the key step of the oxidation of 5,10-methylene-tetrahydrofolate (CH2-THF) can be catalysed by two isozymes, MTHFD2 and MTHFD2L. The MTHFD2 enzyme has recently received considerable attention as an oncogenic enzyme upregulated in several tumour types, which is additionally required by cancer cells in vitro and in vivo. However, much less is currently known about MTHFD2L and its expression in cancer. In this study, we examine and compare the expression and regulation of the two mitochondrial MTHFD isozymes in normal human and cancer cells. We found that normal and cancer cells express both enzymes, although MTHFD2 has a much higher baseline expression. Unlike MTHFD2, the MTHFD2L isozyme does not show an association with proliferation and growth factor stimulation. In addition, we did not find evidence of a compensatory increase of MTHFD2L following suppression of its isozyme. This study supports that MTHFD2L is unlikely to have an important function in increased proliferation or cancer. Furthermore, therapeutic strategies aiming to block the mitochondrial folate pathway in cancer should focus on MTHFD2, with MTHFD2L being unlikely to be involved in the development of chemoresistance to targeting of its mitochondrial isozyme.

Gene expression changes in HLA mismatched mixed lymphocyte cultures reveal genes associated with allorecognition.

Human leucocyte antigen (HLA) compatibility is the main factor determining the occurrence of graft-vs-host disease (GVHD) in patients. It has also been shown that minor histocompatibility antigen differences as well as genetic polymorphisms that are not sequenced by standard methodology for HLA typing can play a role. We used mixed lymphocyte cultures (MLCs) as a functional cellular test and investigated gene expression changes driven by HLA incompatibility in an effort to better understand the mechanisms involved in the disease. Gene expression profile of HLA matched and HLA mismatched MLC identified differentially regulated genes and pathways. We found that a great number of genes related to immune function were differentially regulated; these genes were also found to be associated with GVHD and graft rejection. The majority of differentially regulated genes were interferon-gamma (IFNγ)-inducible genes and IFNγ neutralisation in MLCs abrogated their induction. The microRNA-155, a recently identified target for acute GVHD (aGVHD), was also found to be significantly induced in HLA mismatched MLC but not in the matched setting and its induction was not diminished by blocking IFNγ. In this proof-of-principle study we show gene expression changes in mismatched MLC that represent alloreactive responses, correlate with markers involved in GVHD and can potentially be useful in the study of the biological processes involved in this disease.