bims-mevinf 2025-03-23 papers

bioRxiv. 2025 Mar 06. pii: 2025.03.06.641752. [Epub ahead of print]

Human cytomegalovirus promotes de novo PC synthesis during early virus replication.

Ian Kline, Rebekah L Mokry, Yuecheng Xi, Magí Passols Manzano, Sidnie Layesa, Nowroz Sohrab Ali, Melissa A Moy, Felicia D Goodrum, John G Purdy.

Human cytomegalovirus (HCMV) infection reprograms metabolism, including lipid synthesis. While several metabolite-related pathways have been demonstrated to have altered activity in infected cells, the alteration of lipid-related pathways by HCMV has not been examined beyond fatty acid synthesis and elongation. In this study, we addressed this lack of understanding by focusing on phosphatidylcholine (PC), a class of lipids we previously showed is increased by HCMV infection in human foreskin fibroblasts. Here, we found that HCMV infection increases the abundance of PCs in several different fibroblasts and, similarly, in endothelial and epithelial cells. Additionally, HCMV elevates PC levels regardless of the level of confluency, type of growth medium, and presence of serum. Next, we investigated if HCMV alters the activity in the three PC synthesis pathways. We demonstrate that HCMV infection promotes the activity in the de novo PC synthesis pathway using a 13 C-choline isotopic tracer and liquid chromatography high resolution tandem mass spectrometry (LC-MS/MS). Infection did not alter the activity in the other two pathways. Moreover, we examined the kinetics of PC remodeling by HCMV and found that the de novo synthesis pathway is promoted and the PC lipidome shifts 24 hours post infection. That led us to examining if the early stages of replication are sufficient to alter PC levels. After inhibiting late virus replication, we found that HCMV alters the PC lipidome independent of late gene expression. Overall, this work suggests that an immediate-early or early viral protein promotes the reprogramming of host lipid metabolism to ensure the synthesis of a lipidome necessary to support HCMV replication.
IMPORTANCE: Human cytomegalovirus (HCMV) is a common herpesvirus that establishes a lifelong and persistent infection in its human host (1). HCMV infection in most people does not cause overt disease (1). However, in immunocompromised individuals, severe CMV-associated disease can lead to permanent disabilities and even death (1, 2). Additionally, congenital CMV is the leading infectious cause of birth defects (3, 4). Viruses have evolved to hijack host metabolic pathways to facilitate their replication cycle. In this study, we determine that HCMV promotes the activity in the de novo pathway of phosphatidylcholine (PC) synthesis. We demonstrate that the activity in the other PC synthesis pathways, the PEMT and Lands cycle, is unaltered by HCMV infection. Moreover, we found that HCMV infection alters metabolic activity to increase the PC lipidome before 48 hpi. Additionally, we demonstrate that changes in PC lipids during virus replication is independent of late gene expression. Together, our findings demonstrate that infection promotes the de novo PC pathway to increase PC lipids during the early stages of virus replication.

DOI: https://doi.org/10.1101/2025.03.06.641752

Adv Sci (Weinh). 2025 Mar 16. e2407695

Shrimp Virus Regulates ROS Dynamics via the Nrf2 Pathway to Facilitate Viral Replication.

Honghui He, Kai Yuan, Junming Pan, Shaoping Weng, Chaozheng Li, Yihong Chen, Jianguo He.

Reactive oxygen species (ROS) of hosts are widely involved in intracellular signaling and against pathogens. Viruses manipulate ROS homeostasis of hosts as a strategy to evade ROS-mediated negative effects of their infection, but the mechanisms remain unclear. The economically important aquaculture shrimp, Litopenaeus vannamei, is selected to investigate the molecular mechanism of how white spot syndrome virus (WSSV) regulates ROS dynamics and enhances viral replication. WSSV protein wsv220 binds to the repressor of shrimp nuclear factor erythroid 2-related factor 2 (LvNrf2), called Kelch-like ECH-associated protein 1 (LvKeap1), disrupting LvNrf2/LvKeap1 complex and facilitating LvNrf2 nuclear translocation. This activation of LvNrf2 causes up-regulation of antioxidant genes, including glucose-6-phosphate dehydrogenase (LvG6PDH), which increases nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) production, effectively eliminating excessive ROS. Moreover, WSSV exploits LvNrf2 to establish a positive feedback loop by up-regulating viral immediate early gene wsv051, which further enhances wsv220 expression. Knockdown of LvNrf2 or LvG6PDH reduces WSSV replication and increases host ROS levels. Therefore, WSSV hijacks LvNrf2 pathway to maintain ROS homeostasis and establishes a positive feedback loop to facilitate WSSV replication. These findings reveal a novel molecular mechanism of viral manipulation of host ROS dynamics and suggest potential antiviral strategies targeting LvNrf2 pathway.

Keywords: reactive oxygen species; redox homeostasis; rf2 pathway; shrimp; white spot syndrome virus

DOI: https://doi.org/10.1002/advs.202407695

Cell Rep. 2025 Mar 17. pii: S2211-1247(25)00182-2. [Epub ahead of print]44(3): 115411

Multi-platform omics analysis of Nipah virus infection reveals viral glycoprotein modulation of mitochondria.

The recent global pandemic illustrates the importance of understanding the host cellular infection processes of emerging zoonotic viruses. Nipah virus (NiV) is a deadly zoonotic biosafety level 4 encephalitic and respiratory paramyxovirus. Our knowledge of the molecular cell biology of NiV infection is extremely limited. This study identified changes in cellular components during NiV infection of human cells using a multi-platform, high-throughput transcriptomics, proteomics, lipidomics, and metabolomics approach. Remarkably, validation via multi-disciplinary approaches implicated viral glycoproteins in enriching mitochondria-associated proteins despite an overall decrease in protein translation. Our approach also allowed the mapping of significant fluctuations in the metabolism of glucose, lipids, and several amino acids, suggesting periodic changes in glycolysis and a transition to fatty acid oxidation and glutamine anaplerosis to support mitochondrial ATP synthesis. Notably, these analyses provide an atlas of cellular changes during NiV infections, which is helpful in designing therapeutics against the rapidly growing Henipavirus genus and related viral infections.

Keywords: CP: Microbiology; Nipah virus; host; infection; lipidomics; metabolism; metabolomics; omics; paramyxovirus; proteomics; transcriptomics

DOI: https://doi.org/10.1016/j.celrep.2025.115411

Proc Natl Acad Sci U S A. 2025 Mar 25. 122(12): e2420441122

Deficiency in platelet 12-lipoxygenase exacerbates inflammation and disease severity during SARS-CoV-2 infection.

Ana Claudia Dos S P Andrade, Emile Lacasse, Isabelle Dubuc, Leslie Gudimard, Annie Gravel, Florian Puhm, Gabriel Campolina-Silva, Celso Queiroz-Junior, Isabelle Allaeys, Julien Prunier, Oumaima Azeggouar Wallen, Élizabeth Dumais, Clémence Belleannée, Arnaud Droit, Nicolas Flamand, Éric Boilard, Louis Flamand.

Platelets, known for maintaining blood balance, also participate in antimicrobial defense. Upon severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, platelets become hyperactivated, releasing molecules such as cytokines, granule contents, and bioactive lipids. The key effector biolipids produced by platelets include 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-hydroxyeicosatrienoic acid (12-HETrE), produced by 12-lipoxygenase (12-LOX), and prostaglandins and thromboxane, produced by cyclooxygenase-1. While prostaglandin E2 and thromboxane B2 were previously associated with lung inflammation in severe COVID-19, the role of platelet 12-LOX in SARS-CoV-2 infection remains unclear. Using mice deficient for platelets' 12-LOX, we report that SARS-CoV-2 infection resulted in higher lung inflammation characterized by histopathological tissue analysis, increased leukocyte infiltrates, and cytokine production relative to wild-type mice. In addition, distinct platelet and lung transcriptomic changes, including alterations in NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) inflammasome-related gene expression, were observed. Mass spectrometry lipidomic analysis in 12-LOX-deficient-infected mice revealed significant changes in bioactive lipid content, including reduced levels of 12-HETrE that inversely correlated with disease severity. Finally, platelet 12-LOX deficiency was associated with increased morbidity and lower survival rates relative to wild type (WT) mice. Overall, this study highlights the complex interplay between 12-LOX-related lipid metabolism and inflammatory responses during SARS-CoV-2 infection. The findings provide valuable insights into potential therapeutic targets aimed at mitigating severe outcomes, emphasizing the pivotal role of platelet enzymes in the host response to viral infections.

Keywords: 12-HETrE; Inflammation; SARS-CoV-2; platelet type-12 lipoxygenase; platelets

DOI: https://doi.org/10.1073/pnas.2420441122

medRxiv. 2025 Mar 03. pii: 2025.02.28.25323089. [Epub ahead of print]

An Allele of the MTHFR one-carbon metabolism gene predicts severity of COVID-19.

IMPACC Network

While the public health burden of SARS-CoV-2 infection has lessened due to natural and vaccine-acquired immunity, the emergence of less virulent variants, and antiviral medications, COVID-19 continues to take a significant toll. There are > 10,000 new hospitalizations per week in the U.S., many of whom develop post-acute sequelae of SARS-CoV-2 (PASC), or "long COVID", with long-term health issues and compromised quality of life. Early identification of individuals at high risk of severe COVID-19 is key for monitoring and supporting respiratory status and improving outcomes. Therefore, precision tools for early detection of patients at high risk of severe disease can reduce morbidity and mortality. Here we report an untargeted and longitudinal metabolomic study of plasma derived from adult patients with COVID-19. One-carbon metabolism, a pathway previously shown as critical for viral propagation and disease progression, and a potential target for COVID-19 treatment, scored strongly as differentially abundant in patients with severe COVID-19. A follow-up targeted metabolite profiling revealed that one arm of the one-carbon metabolism pathway, the methionine cycle, is a major driver of the metabolic profile associated with disease severity. The methionine cycle produces S-adenosylmethionine (SAM), the methyl group donor important for methylation of DNA, RNA, and proteins, and its high abundance was reported to correlate with disease severity. Further, genomic data from the profiled patients revealed a genetic contributor to methionine metabolism and identified the C677T allele of the MTHFR gene as a pre-existing predictor of disease trajectory - patients homozygous for the MTHFR C677T have higher incidence of experiencing severe disease. Our results raise the possibility that screening for the common genetic MTHFR variant may be an actionable approach to stratify risk of COVID severity and may inform novel precision COVID-19 treatment strategies.

DOI: https://doi.org/10.1101/2025.02.28.25323089