bims-mevinf 2023-04-23 papers

PLoS Pathog. 2023 Apr 18. 19(4): e1011317

Polyamines and eIF5A hypusination facilitate SREBP2 synthesis and cholesterol production leading to enhanced enterovirus attachment and infection.

Mason R Firpo, Natalie J LoMascolo, Marine J Petit, Priya S Shah, Bryan C Mounce.

Metabolism is key to cellular processes that underlie the ability of a virus to productively infect. Polyamines are small metabolites vital for many host cell processes including proliferation, transcription, and translation. Polyamine depletion also inhibits virus infection via diverse mechanisms, including inhibiting polymerase activity and viral translation. We showed that Coxsackievirus B3 (CVB3) attachment requires polyamines; however, the mechanism was unknown. Here, we report polyamines' involvement in translation, through a process called hypusination, promotes expression of cholesterol synthesis genes by supporting SREBP2 synthesis, the master transcriptional regulator of cholesterol synthesis genes. Measuring bulk transcription, we find polyamines support expression of cholesterol synthesis genes, regulated by SREBP2. Thus, polyamine depletion inhibits CVB3 by depleting cellular cholesterol. Exogenous cholesterol rescues CVB3 attachment, and mutant CVB3 resistant to polyamine depletion exhibits resistance to cholesterol perturbation. This study provides a novel link between polyamine and cholesterol homeostasis, a mechanism through which polyamines impact CVB3 infection.

DOI: https://doi.org/10.1371/journal.ppat.1011317

Front Microbiol. 2023 ;14 1165491

Role of asparagine biosynthesis pathway in Siniperca chuatsi rhabdovirus proliferation.

Fangying Li, Xiaozhe Fu, Xia Luo, Qiang Lin, Hongru Liang, Yinjie Niu, Lihui Liu, Ningqiu Li.

Viruses are non-living organisms that rely on host cellular metabolism to complete their life cycle. Siniperca chuatsi rhabdovirus (SCRV) has caused huge economic losses to the Chinese perch (Siniperca chuatsi) industry worldwide. SCRV replication is dependent on the cellular glutamine metabolism, while aspartate metabolism plays an important role in viral proliferation in glutamine deficiency. Herein, we investigated roles of asparagine metabolism in SCRV proliferation. Results showed that SCRV infection upregulated the expression of key enzymes in the aspartate metabolic pathway in CPB cells. And the key enzymes of malate-aspartic acid shuttle pathway upregulated during the virus invasion phase, and key enzymes of the asparagine biosynthesis pathway upregulated during the viral replication and release phase. When asparagine was added to the depleted medium, the SCRV copy number restored to 90% of those in replete medium, showing that asparagine and glutamine completely rescue the replication of SCRV. Moreover, inhibition of the aspartate- malate shuttle pathway and knockdown of the expression of key enzymes in the asparagine biosynthesis pathway significantly reduced SCRV production, indicating that the aspartic acid metabolic pathway was required to the replication and proliferation of SCRV. Above results provided references for elucidating pathogenic mechanism of SCRV by regulation of aspartate metabolism.

Keywords: Siniperca chuatsi rhabdovirus; asparagine; aspartate metabolism; aspartate–malate shuttle; viral replication

DOI: https://doi.org/10.3389/fmicb.2023.1165491

Front Cell Infect Microbiol. 2023 ;13 1165647

Development and investigation of metabolism-associated risk assessment models for patients with viral hepatitis.

Mingjiu Zhao, Yu Lei, Yanyan Zhou, Mingan Sun, Xia Li, Zhiguang Zhou, Jiaqi Huang, Xinyu Li, Bin Zhao.

Dysregulation of metabolism plays an important role in the onset and progression of multiple pathogenic diseases, including viral hepatitis. However, a model to predict viral hepatitis risk by metabolic pathways is still lacking. Thus, we developed two risk assessment models for viral hepatitis based on metabolic pathways identified through univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The first model is designed to assess the progression of the disease by evaluating changes in the Child-Pugh class, hepatic decompensation, and the development of hepatocellular carcinoma. The second model is focused on determining the prognosis of the illness, taking into account the patient's cancer status. Our models were further validated by Kaplan-Meier plots of survival curves. In addition, we investigated the contribution of immune cells in metabolic processes and identified three distinct subsets of immune cells-CD8+ T cells, macrophages, and NK cells-that have significantly affected metabolic pathways. Specifically, our findings suggest that resting or inactive macrophages and NK cells contribute to maintaining metabolic homeostasis, particularly with regard to lipid and α-amino acid metabolism, thereby potentially reducing the risk of viral hepatitis progression. Moreover, maintaining metabolic homeostasis ensures a balance between killer-proliferative and exhausted CD8+ T cells, which helps in mitigating CD8+ T cell-mediated liver damage while preserving energy reserves. In conclusion, our study offers a useful tool for early disease detection in viral hepatitis patients through metabolic pathway analysis and sheds light on the immunological understanding of the disease through the examination of immune cell metabolic disorders.

Keywords: host-pathogen interactions; immune cells; metabolism; prognosis; viral hepatitis

DOI: https://doi.org/10.3389/fcimb.2023.1165647

J Infect Dis. 2023 Apr 19. pii: jiad105. [Epub ahead of print]

Antiretroviral therapy ameliorates SIV-associated myocarditis by dampening interferon signaling and pathogen response in the heart.

Jake A Robinson, Meng Niu, Howard S Fox, Tricia H Burdo.

People with human immunodeficiency virus (HIV) (PWH) have an increased risk of developing cardiovascular disease (CVD). RNA-Seq was performed on hearts from simian immunodeficiency virus (SIV)-infected rhesus macaques with or without antiretroviral therapy (ART). SIV infection led to high plasma viral load with very little myocardial viral RNA. SIV infection promoted an inflammatory environment in the heart through interferon and pathogen signaling, in the absence of myocardial viral RNA. While ART dampened interferon and cytokine response in the heart, SIV-infected animals receiving ART had deficits in expression of genes directly involved in fatty acid (FA) metabolism relative to uninfected animals.

Keywords: HIV; RNA-Seq; SIV; interferon; metabolism; non-human primates

DOI: https://doi.org/10.1093/infdis/jiad105