bims-mevinf 2025-02-23 papers

J Virol. 2025 Feb 20. e0228224

Perturbation of de novo lipogenesis hinders MERS-CoV assembly and release, but not the biogenesis of viral replication organelles.

M Soultsioti, A W M de Jong, N Blomberg, A Tas, M Giera, E J Snijder, M Bárcena.

Coronaviruses hijack host cell metabolic pathways and resources to support their replication. They induce extensive host endomembrane remodeling to generate viral replication organelles and exploit host membranes for assembly and budding of their enveloped progeny virions. Because of the overall significance of host membranes, we sought to gain insight into the role of host factors involved in lipid metabolism in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV). We employed a single-cycle infection approach in combination with pharmacological inhibitors, biochemical assays, lipidomics, and light and electron microscopy. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), key host factors in de novo fatty acid biosynthesis, led to pronounced inhibition of MERS-CoV particle release. Inhibition of ACC led to a profound metabolic switch in Huh7 cells, altering their lipidomic profile and inducing lipolysis. However, despite the extensive changes induced by the ACC inhibitor, the biogenesis of viral replication organelles remained unaffected. Instead, ACC inhibition appeared to affect the trafficking and post-translational modifications of the MERS-CoV envelope proteins. Electron microscopy revealed an accumulation of nucleocapsids in early budding stages, indicating that MERS-CoV assembly is adversely impacted by ACC inhibition. Notably, inhibition of palmitoylation resulted in similar effects, while supplementation of exogenous palmitic acid reversed the compound's inhibitory effects, possibly reflecting a crucial need for palmitoylation of the MERS-CoV spike and envelope proteins for their role in virus particle assembly.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a zoonotic respiratory disease of limited transmissibility between humans. However, MERS-CoV is still considered a high-priority pathogen and is closely monitored by WHO due to its high lethality rate of around 35% of laboratory-confirmed infections. Like other positive-strand RNA viruses, MERS-CoV relies on the host cell's endomembranes to support various stages of its replication cycle. However, in spite of this general reliance of MERS-CoV replication on host cell lipid metabolism, mechanistic insights are still very limited. In our study, we show that pharmacological inhibition of acetyl-CoA carboxylase (ACC), a key enzyme in the host cell's fatty acid biosynthesis pathway, significantly disrupts MERS-CoV particle assembly without exerting a negative effect on the biogenesis of viral replication organelles. Furthermore, our study highlights the potential of ACC as a target for the development of host-directed antiviral therapeutics against coronaviruses.

Keywords: 2-BP; TOFA; acetyl-CoA carboxylase; coronavirus; lipid metabolism; palmitoylation

DOI: https://doi.org/10.1128/jvi.02282-24

Emerg Microbes Infect. 2025 Feb 19. 2470371

SREBP2-dependent lipid droplet formation enhances viral replication and deteriorates lung injury in mice following IAV infection.

Xinsen Li, Lu Li, Jijing Tian, Ruijing Su, Jiali Sun, Yuli Li, Lige Wang, Hongye Zhou, Shuhan Sha, Jin Xiao, Hong Dong, Caiyun Huo, Yanxin Hu, Hanchun Yang.

AbstractInfluenza A virus (IAV) is a significant zoonotic pathogen that poses a considerable challenge to public health due to its continuous mutations. Lipid droplets (LDs) have been shown to play an important role in the process of several viral infections. However, their role in IAV infection remains unclear. Here, we found that IAV infection altered the lipid metabolism and increased the content of LDs in the lungs of mice. In vitro, IAV infection also mediated the formation of LDs in A549 cells. Besides, inhibition of the formation of lipid droplets can significantly suppress IAV replication and the release of inflammatory factors, indicating that LDs could facilitate the virus replication and inflammatory response. Furthermore, we discovered that IAV infection could activate the SREBP2, a crucial lipid-regulating transcription factor that regulates the expressions of downstream proteins named HMGCR and HMGCS. HMGCR and HMGCS involved in the process of cholesterol synthesis, which further promoted the formation of LDs. Additionally, the use of fatostatin that specifically inhibits the maturation of SREBP2 was able to significantly suppress the viral replication of H5N1 in cells and effectively ameliorated IAV-induced lung injury in mice, which eventually promoted the survival rate of infected mice. Taken together, we demonstrate the essential roles of lipid metabolism and LD formation in IAV replication and pathogenesis, which may better facilitate the advancement of new strategies against IAV infection, especially the highly pathogenic H5N1 virus.

Keywords: Influenza A virus; SREBP2; lipid droplets; lung injury; viral replication

DOI: https://doi.org/10.1080/22221751.2025.2470371

Mol Neurobiol. 2025 Feb 20.

PARP-16 regulates the PERK and IRE-1α Mediated Unfolded Protein Response in Japanese Encephalitis Virus-Infected Neural Stem/Progenitor Cells.

Shivangi Sharma, Anirudh Satheesan, Atreye Majumdar, Sriparna Mukherjee, Anirban Basu.

The viral infection and subsequent accumulation of viral proteins in the infected cells leads to endoplasmic reticulum (ER) stress. Japanese encephalitis virus (JEV) infection in the Central Nervous System (CNS) has been shown to induce unfolded protein response (UPR). The ER stress is resolved by the UPR which comprises certain signals that are transduced from the ER either to both the cytoplasm or nucleus, resulting in the adaptation for survival or may even lead to apoptosis. Here, we demonstrate that Poly ADP-ribose polymerase-16 (PARP-16) expression is regulating the ER stress response following JEV infection of Neural Stem/Progenitor cells (NSPCs) in the BALB/c mouse model. Activation of the key sensors of UPR, namely, protein kinase R (PKR)-like ER kinase (PERK) and Inositol-requiring enzyme-1α (IRE-1α) by PARP-16 upon JEV infection, led to the activation of their downstream signalling cascade. The siRNA-mediated in vitro downregulation of PARP-16 in NSPCs alleviated the overall UPR, as the abundance of UPR markers and their downstream modulators of signalling cascade was found to be downregulated. These results highlight an important role of PARP-16 during JEV infection of NSPCs.

Keywords: ER Stress; JEV; NSPCs; Neuronal apoptosis; Neurotropic viral infection; UPR

DOI: https://doi.org/10.1007/s12035-025-04748-1

Emerg Microbes Infect. 2025 Feb 18. 2469662

Resveratrol inhibits African swine fever virus replication by exerting antiviral and antioxidative stress activities via the Nrf2 signaling pathway.

Di Liu, Lian-Feng Li, Huanjie Zhai, Tao Wang, Jing Lan, Mengxiang Cao, Meng Yao, Yijing Wang, Jia Li, Xin Song, Yuan Sun, Hua-Ji Qiu.

African swine fever (ASF) is a highly contagious and severe infectious disease caused by African swine fever virus (ASFV). The disease significantly threatens the sustainable development of the global pig industry. Unfortunately, there are currently no safe and efficacious vaccines and antiviral agents available except in Vietnam. Antioxidative stress is a critical factor in antiviral strategies. In this study, we show that ASFV infection elevates the level of reactive oxygen species (ROS) and suppresses the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in vitro and in vivo. Moreover, overexpressing Nrf2 can significantly inhibit ASFV replication. Through high-throughput screening of natural small molecules against ASFV, we identify resveratrol (RES), an Nrf2 activator, as a compound capable of inducing the cellular antiviral responses and effectively inhibiting ASFV replication in primary porcine alveolar macrophages (PAMs). Notably, untargeted metabolomics profiling reveals that glutathione is the primary differential metabolite related to the antiviral activities of RES against ASFV. Mechanistically, RES exerts its antiviral effects by inducing the production of reduced glutathione (GSH) via the activation of the Nrf2 signaling pathway and simultaneously reducing the elevated levels of ROS caused by ASFV infection. In conclusion, RES exhibits broad efficacy as a potentially effective compound for inhibiting ASFV infection and alleviating the oxidative stress induced by ASFV infection via the Nrf2 signaling pathway.

Keywords: African swine fever virus; Nrf2 signaling pathway; antiviral activity; oxidative stress; resveratrol

DOI: https://doi.org/10.1080/22221751.2025.2469662

Virology. 2025 Feb 06. pii: S0042-6822(25)00060-1. [Epub ahead of print]604 110448

ATF6-mediated mild ER stress inhibits HBV transcription and replication, which is dependent on mTOR activation.

Lin Lu, Ying Feng, Yucai Geng, Zhixiang Liu, Yan Wu, Chen Cai, Ji Zhang, Xingda Huang, Tongchun Xue, Bo Gao.

Chronic hepatitis B (CHB) remains a serious global health problem. In our previous investigation, HBV was found to activate a mild ER stress, which facilitated the establishment of persistent HBV infection. However, the role of ER stress manipulation in HBV replication and its underlying mechanisms remain still unclear. Our data showed that mild ER stress inhibited HBV transcription and replication, while severe ER stress enhanced them. Mechanistically, in contrary to the effect on HBV replication, mild ER stress activated whereas severe ER stress inhibited mTOR signaling in HBV-infected cells. Further, mTOR signaling was revealed to be critical for mild ER stress-mediated HBV inhibition. Furthermore, ATF6 but not PERK or IRE1α was found to be involved in mild ER stress-mediated mTOR and the following HBV inhibition. Moreover, ATF6, per se, could inhibit HBV transcription and replication via activating mTOR signaling. Together, ATF6-mediated mild ER stress inhibited HBV transcription and replication through mTOR activation, which might present as an important therapeutic target for CHB patients.

Keywords: ATF6; HBV replication; HBV transcription; Mild ER stress; mTOR signaling

DOI: https://doi.org/10.1016/j.virol.2025.110448

Mol Plant Pathol. 2025 Feb;26(2): e70066

Reprogrammed Plant Metabolism During Viral Infections: Mechanisms, Pathways and Implications.

Tong Jiang, Tianwen Hao, Wenjing Chen, Chengliang Li, Shuqi Pang, Chenglong Fu, Jie Cheng, Chaobo Zhang, Mansour Ghorbanpour, Shuo Miao.

Plant viruses pose a significant threat to global agriculture, leading to substantial crop losses that jeopardise food security and disrupt ecosystem stability. These viral infections often reprogramme plant metabolism, compromising key pathways critical for growth and defence. For instance, infections by cucumber mosaic virus alter amino acid and secondary metabolite biosynthesis, including flavonoid and phenylpropanoid pathways, thereby weakening plant defences. Similarly, tomato bushy stunt virus disrupts lipid metabolism by altering the synthesis and accumulation of sterols and phospholipids, which are essential for viral replication and compromise membrane integrity. Recent advancements in gene-editing technologies, such as CRISPR/Cas9, and metabolomics offer innovative strategies to mitigate these impacts. Precise genetic modifications can restore or optimise disrupted metabolic pathways, enhancing crop resilience to viral infections. Metabolomics further aids in identifying metabolic biomarkers linked to viral resistance, guiding breeding programmes aimed at developing virus-resistant plants. By reducing the susceptibility of crops to viral infections, these approaches hold significant potential to reduce dependence on chemical pesticides, increase crop yields and promote sustainable agricultural practices. Future research should focus on expanding our understanding of virus-host interactions at the molecular level while exploring the long-term ecological impacts of viral infections. Interdisciplinary approaches integrating multi-omics technologies and sustainable management strategies will be critical in addressing the challenges posed by plant viruses and ensuring global agricultural stability.

Keywords: antiviral defence mechanisms; metabolic reprogramming; metabolism; plant virus; plant–virus interactions

DOI: https://doi.org/10.1111/mpp.70066

Nat Commun. 2025 Feb 20. 16(1): 1803

Zika virus NS1 drives tunneling nanotube formation for mitochondrial transfer and stealth transmission in trophoblasts.

Rafael T Michita, Long B Tran, Steven J Bark, Deepak Kumar, Shay A Toner, Joyce Jose, Indira U Mysorekar, Anoop Narayanan.

Zika virus (ZIKV) is unique among orthoflaviviruses in its vertical transmission capacity in humans, yet the underlying mechanisms remain incompletely understood. Here, we show that ZIKV induces tunneling nanotubes (TNTs) in placental trophoblasts which facilitate transfer of viral particles, proteins, mitochondria, and RNA to neighboring uninfected cells. TNT formation is driven exclusively via ZIKV non-structural protein 1 (NS1). Specifically, the N-terminal 1-50 amino acids of membrane-bound ZIKV NS1 are necessary for triggering TNT formation in host cells. Trophoblasts infected with TNT-deficient ZIKVΔTNT mutant virus elicited a robust antiviral IFN-λ 1/2/3 response relative to WT ZIKV, suggesting TNT-mediated trafficking allows ZIKV cell-to-cell transmission camouflaged from host defenses. Using affinity purification-mass spectrometry of cells expressing wild-type NS1 or non-TNT forming NS1, we found mitochondrial proteins are dominant NS1-interacting partners. We demonstrate that ZIKV infection or NS1 expression induces elevated mitochondria levels in trophoblasts and that mitochondria are siphoned via TNTs from healthy to ZIKV-infected cells. Together our findings identify a stealth mechanism that ZIKV employs for intercellular spread among placental trophoblasts, evasion of antiviral interferon response, and the hijacking of mitochondria to augment its propagation and survival and offers a basis for novel therapeutic developments targeting these interactions to limit ZIKV dissemination.

DOI: https://doi.org/10.1038/s41467-025-56927-2