bims-mevinf 2023-06-11 papers

Issue of 2023‒06‒11
six papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology

Clin Infect Dis. 2023 Jun 07. pii: ciad348. [Epub ahead of print]

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency and COVID-19.

Ariel Israel, Matitiahu Berkovitch, Eugene Merzon, Avivit Golan-Cohen, Ilan Green, Eytan Ruppin, Shlomo Vinker, Eli Magen.

In this cohort study conducted in a national healthcare organization in Israel, we found that individuals with Glucose-6-phosphate dehydrogenase (G6PD) deficiency have an increased risk of COVID-19 infection and severity, with higher rates of hospitalization and diagnosed long COVID.

DOI: https://doi.org/10.1093/cid/ciad348

bioRxiv. 2023 May 17. pii: 2023.05.17.541212. [Epub ahead of print]

Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose limitation.

Matthew H Raymonda, Irene Rodríguez-Sánchez, Xenia L Schafer, Leonid Smorodintsev-Schiller, Isaac S Harris, Joshua Munger.

Human cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV U L 38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally-induced metabolic alterations might induce novel therapeutic vulnerabilities in virally infected cells. Here, we explore how HCMV infection and the U L 38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of U L 38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through U L 38's inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Further, expression of U L 38 or the inactivation of TSC2 results in anabolic rigidity in that the resulting increased levels of fatty acid biosynthesis are insensitive to glucose limitation. This failure to regulate fatty acid biosynthesis in response to glucose availability sensitizes cells to glucose limitation, resulting in cell death unless fatty acid biosynthesis is inhibited. These experiments identify a regulatory circuit between glycolysis and fatty acid biosynthesis that is critical for cell survival upon glucose limitation and highlight a metabolic vulnerability associated with viral infection and the inactivation of normal metabolic regulatory controls.Importance: Viruses modulate host cell metabolism to support the mass production of viral progeny. For Human Cytomegalovirus, we find that the viral U L 38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as U L 38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that U L 38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of U L 38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis.

DOI: https://doi.org/10.1101/2023.05.17.541212

Mucosal Immunol. 2023 Jun 06. pii: S1933-0219(23)00042-9. [Epub ahead of print]

Indoleamine 2,3-dioxygenase 1 regulates cell permissivity to astrovirus infection.

Valerie Cortez, Brandi Livingston, Bridgett Sharp, Virginia Hargest, James B Papizan, Natalie Pedicino, Sarah Lanning, Summer Vaughn Jordan, Jacob Gulman, Peter Vogel, Rebecca M DuBois, Jeremy Chase Crawford, David F Boyd, Shondra M Pruett-Miller, Paul G Thomas, Stacey Schultz-Cherry.

Astroviruses cause a spectrum of disease spanning asymptomatic infections to severe diarrhea, but little is understood about their pathogenesis. We previously determined that small intestinal goblet cells were the main cell type infected by murine astrovirus-1. Here, we focused on the host immune response to infection and inadvertently discovered a role for indoleamine 2,3-dioxygenase 1 (Ido1), a host tryptophan-catabolizing enzyme, in the cellular tropism of murine and human astroviruses. We identified that Ido1 expression was highly enriched among infected goblet cells, and spatially corresponded to the zonation of infection. Because Ido1 can act as a negative regulator of inflammation, we hypothesized it could dampen host antiviral responses. Despite robust interferon signaling in goblet cells, as well as tuft cell and enterocyte bystanders, we observed delayed cytokine induction and suppressed levels of fecal lipocalin-2. Although we found Ido-/- animals were more resistant to infection, this was not associated with fewer goblet cells nor could it be rescued by knocking out interferon responses, suggesting that Ido1 instead regulates cell permissivity. We characterized IDO1-/- Caco-2 cells and observed impaired differentiation as well as significantly reduced human astrovirus-1 infection. Together this study establishes the precise cellular targets of these viruses and highlights a role for Ido1 in epithelial cell maturation.

Keywords: 3-dioxygenase 1; astrovirus; enteric virus; goblet cell; indoleamine 2; single-cell RNA sequencing

DOI: https://doi.org/10.1016/j.mucimm.2023.05.011

J Gen Virol. 2023 Jun;104(6):

Oncogenic viruses and host lipid metabolism: a new perspective.

Zhiyuan Gong, Zhiyong Yan, Wen Liu, Bing Luo.

As noncellular organisms, viruses do not have their own metabolism and rely on the metabolism of host cells to provide energy and metabolic substances for their life cycles. Increasing evidence suggests that host cells infected with oncogenic viruses have dramatically altered metabolic requirements and that oncogenic viruses produce substances used for viral replication and virion production by altering host cell metabolism. We focused on the processes by which oncogenic viruses manipulate host lipid metabolism and the lipid metabolism disorders that occur in oncogenic virus-associated diseases. A deeper understanding of viral infections that cause changes in host lipid metabolism could help with the development of new antiviral agents as well as potential new therapeutic targets.

Keywords: antiviral agents; lipid metabolism; oncogenic viruses; viral diseases

DOI: https://doi.org/10.1099/jgv.0.001861

Signal Transduct Target Ther. 2023 Jun 07. 8(1): 237

Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection.

Peiran Chen, Mandi Wu, Yaqing He, Binghua Jiang, Ming-Liang He.

The coronavirus disease 2019 (COVID-19) caused by coronavirus SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis, bringing enormous burden to our society. Most patients infected by SARS-CoV-2 are asymptomatic or have mild symptoms. Although only a small proportion of patients progressed to severe COVID-19 with symptoms including acute respiratory distress syndrome (ARDS), disseminated coagulopathy, and cardiovascular disorders, severe COVID-19 is accompanied by high mortality rates with near 7 million deaths. Nowadays, effective therapeutic patterns for severe COVID-19 are still lacking. It has been extensively reported that host metabolism plays essential roles in various physiological processes during virus infection. Many viruses manipulate host metabolism to avoid immunity, facilitate their own replication, or to initiate pathological response. Targeting the interaction between SARS-CoV-2 and host metabolism holds promise for developing therapeutic strategies. In this review, we summarize and discuss recent studies dedicated to uncovering the role of host metabolism during the life cycle of SARS-CoV-2 in aspects of entry, replication, assembly, and pathogenesis with an emphasis on glucose metabolism and lipid metabolism. Microbiota and long COVID-19 are also discussed. Ultimately, we recapitulate metabolism-modulating drugs repurposed for COVID-19 including statins, ASM inhibitors, NSAIDs, Montelukast, omega-3 fatty acids, 2-DG, and metformin.

DOI: https://doi.org/10.1038/s41392-023-01510-8

Rev Med Virol. 2023 Jun 09. e2465

Virus infection participates in the occurrence and development of human diseases through monoamine oxidase.

Yujie Sun, Wen Liu, Bing Luo.

Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems through catalytic oxidation and deamination. MAO dysfunction is closely related to human neurological and psychiatric diseases and cancers. However, little is known about the relationship between MAO and viral infections in humans. This review summarises current research on how viral infections participate in the occurrence and development of human diseases through MAO. The viruses discussed in this review include hepatitis C virus, dengue virus, severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, Japanese encephalitis virus, Epstein-Barr virus, and human papillomavirus. This review also describes the effects of MAO inhibitors such as phenelzine, clorgyline, selegiline, M-30, and isatin on viral infectious diseases. This information will not only help us to better understand the role of MAO in the pathogenesis of viruses but will also provide new insights into the treatment and diagnosis of these viral diseases.

Keywords: disease; monoamine oxidase; monoamine oxidase inhibitors; neurotransmitters; virus

DOI: https://doi.org/10.1002/rmv.2465