bims-mevinf 2025-10-26 papers

PLoS Pathog. 2025 Oct 24. 21(10): e1013646

Influenza virus infection reprograms cholesterol biosynthesis to facilitate virus replication by the TAK1-RORγ axis.

Jingting Zhang, Ruixuan Cao, Yujie Wang, Yuling Sun, Xiaoyue Ji, Penggang Liu, Kaituo Liu, Jing Sun, Xiaojun Chen, Demin Cai, Pinghu Zhang, Xiaoquan Wang, Xiufan Liu, Xiulong Xu.

Infection and replication of enveloped viruses require host cells to supply substantial amounts of cellular cholesterol for processes such as binding, entry, trafficking, assembly, and budding. However, the mechanisms by which influenza A virus (IAV) regulates cholesterol biosynthesis remain poorly understood. In this study, we demonstrate that IAV infection induces the expression of the retinoic acid-related orphan receptor γ (RORγ), an orphan nuclear receptor, which cooperates with the sterol regulatory element-binding protein-2 (SREBP2) to regulate the expression of the 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase (HMGCR), a key enzyme in cholesterol biosynthesis. RORγ knockout and treatment with two RORγ inhibitors, XY018 and GSK805, suppress IAV-induced HMGCR expression, cholesterol biosynthesis, and viral replication. Notably, exogenous cholesterol rescues the inhibitory effect of XY018 on viral replication. Mechanistically, we show that IAV infection activates RORγ expression through the TGF-β-activated kinase 1 (TAK1) and its downstream kinases, the c-Jun N-terminal kinase (JNK) and the IκB kinase (IKK), which in turn activate AP1 and NF-κB. In vivo, RORγ knockout reduces IAV replication, alleviates body weight loss, and prolongs survival in infected mice. Furthermore, XY018 treatment reduces both viral replication and inflammation in the lungs of IAV-infected mice. Our findings provide novel mechanistic insights into how IAV infection upregulates cholesterol biosynthesis to facilitate viral replication.

DOI: https://doi.org/10.1371/journal.ppat.1013646

Front Cell Infect Microbiol. 2025 ;15 1648576

Low temperature increases adenovirus replication via intracellular alkalization.

Wenwu Sun, Zhuang Ma, Jianping Cao, Junli Zhang.

Changes in environmental temperature contribute to a higher incidence of respiratory tract viral infections during the colder months of the year. However, the effect of low temperature on the replication of viruses in pulmonary epithelial cells is still elusive. In this work, we measured the change of intracellular pH (pHi) and the replication of adenovirus in A549 cells. We observed that exposure of cells to a cooler temperature (33°C) resulted in increases in both intracellular pH and adenovirus replication. In addition, the enhanced replication of adenovirus induced by 33°C was attenuated by inhibition of glycolysis with either 2-deoxy-D-glucose (2-DG) or PFK158. Moreover, oligomycin, which stimulates the glycolytic flux, led to a significant increase in viral replication at 37°C. Further experiments showed that low-temperature-promoted virus replication and intracellular alkalization were efficiently inhibited by the acidification of the extracellular medium. Taken together, these data suggest that intracellular alkalization and glycolysis caused by low temperature enhance adenovirus replication in host cells.

Keywords: adenovirus replication; glycolysis; intracellular alkalization; low temperature; the common cold

DOI: https://doi.org/10.3389/fcimb.2025.1648576

Front Cell Infect Microbiol. 2025 ;15 1540290

Metabolomic profiling and identification of potential biomarkers of highly pathogenic avian influenza (H5N1) in chicken.

Althaf Mohammed Kadamthodi, Anuradha Panwar, Akhila Hosur Shrungeswara, Periyasamy Vijayakumar, Thottethodi Subrahmanya Keshava Prasad, Ashwin Ashok Raut, Anamika Mishra.

Introduction: Highly Pathogenic Avian Influenza (HPAI) H5N1 is a significant zoonotic pathogen with the potential to cause pandemics. Its high prevalence and mortality rates in poultry, along with a recent expansion in host range, underscore the urgent need to understand the molecular mechanisms underlying its pathogenesis and host-pathogen interactions. Metabolomics, the comprehensive study of small-molecule metabolites within biological systems, offers a promising approach to unravel these mechanisms and aid in the development of effective control strategies against HPAI H5N1.
Methods: To investigate the metabolomic alterations associated with HPAI H5N1 infection, serum and lung samples were collected from specific pathogen-free (SPF) chickens that were either infected with HPAI H5N1 or mock-infected as controls. Metabolomic profiling was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) under both positive and negative ionization modes. The resulting data were analyzed to identify metabolites that were significantly altered in response to infection.
Results: The metabolomic analysis revealed substantial changes in both lung and serum samples following HPAI H5N1 infection. Specifically, 31 and 13 altered metabolites were identified in the lung, and 22 and 15 in the serum, under positive and negative ionization modes, respectively. Notably, key metabolites such as sphingosine, psychosine sulfate, and L-serine, which are known to influence viral endocytosis and cell signaling, were significantly altered in infected chickens.
Discussion: The observed changes in sphingolipid and tryptophan metabolism provide insights into the mechanisms underlying lung and central nervous system (CNS) pathology associated with HPAI H5N1 infection. This study represents the first comprehensive metabolomic profiling of HPAI H5N1-infected chickens, offering valuable information for the development of novel therapeutics and control strategies. The identification of specific metabolite alterations may guide future research aimed at mitigating the impact of this highly pathogenic virus.

Keywords: H5N1; SPF chicken; Sphingolipid metabolism; metabolomics; tryptophan metabolism

DOI: https://doi.org/10.3389/fcimb.2025.1540290

J Virol. 2025 Oct 21. e0110925

25-Hydroxycholesterol restricts human norovirus replication in human intestinal enteroids.

Verónica Costantini, Wadzanai P Mboko, Helen Wall, Kimberly Huynh, Anna M Montmayeur, Geun Woo Park, Ruijie Xu, Jan Vinjé, Preeti Chhabra.

Norovirus is the leading cause of acute gastroenteritis worldwide. Since the development of human intestinal enteroid (HIE) cell culture systems, significant advancements have been made in exploring and evaluating therapeutic strategies to combat human norovirus infections. Here, we investigate whether 25-hydroxycholesterol (25-HC), a key regulator of cholesterol homeostasis and bile acid production, can restrict human norovirus replication in jejunal HIE monolayers. Jejunal HIE monolayers derived from two donors (J2 and J3 cell lines) were treated with increasing concentrations of 25-HC (ranging from 0.0001 µM to 5 µM) for 24 hours. Monolayers were then infected with norovirus GII.1[P33] or GII.4 Sydney[P31] and incubated for 24 hours at 37°C and 5% CO2. Viral RNA was quantified by reverse transcription-quantitative PCR at 1 hour post-infection (hpi) and 24 hpi. Regardless of HIE cell line or norovirus genotype, a dose-dependent restriction of human norovirus replication was observed after 25-HC treatment (0.07-1.23 log decrease). The top upregulated pathways associated with the 25-HC treatment included innate immunity and pro-inflammatory pathways, while the top downregulated pathways included cholesterol biosynthesis pathways. The 25-HC resulted in upregulation of genes associated with innate immune response, including C-C motif chemokine 2 (CCL2), CCL20, intercellular adhesion molecule 1 (ICAM1), and interleukin 23A (IL23A), and downregulation of genes related to cholesterol biosynthesis, including proprotein convertase subtilisin/kexin type 9 and acetyl-CoA acetyltransferase (ACAT2). Our data suggest that modulating the downstream signaling pathway of 25-HC has therapeutic potential as a strategy to control human norovirus infections and enhance antiviral immune responses.IMPORTANCEHuman noroviruses are a leading cause of both epidemic and endemic acute gastroenteritis worldwide. Currently, there are no licensed vaccines or antiviral treatments available. The immune response to human norovirus infection remains incompletely understood. The development of the human intestinal enteroid (HIE) system has revolutionized norovirus research by enabling detailed investigations into viral replication, evaluation of potential control strategies, and analysis of host cellular responses involving both innate and adaptive immunity. In recent years, 25-hydroxycholesterol (25-HC) has emerged as a key regulator of cellular metabolism and antiviral defense. In this study, we investigated the antiviral effects of 25-HC on human norovirus using the HIE culture system. Our findings highlight the therapeutic potential of 25-HC in controlling human norovirus infections and enhancing antiviral immune responses, thereby contributing to a deeper understanding of host restriction mechanisms in viral infections.

Keywords: 25-hydroxycholestrol; human intestinal enteroids; norovirus

DOI: https://doi.org/10.1128/jvi.01109-25