bims-mevinf Biomed News
on Metabolism in viral infections
Issue of 2024–03–24
six papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology
  1. Bovine parainfluenza virus type 3 infections induce ER stress-mediated autophagy to facilitate virus replication.
  2. Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication and pathogenicity.
  3. Identification and verification of the role of key metabolites and metabolic pathways on ASFV replication.
  4. Hypoxia inducible factor-1α facilitates transmissible gastroenteritis virus replication by inhibiting type I and type III interferon production.
  5. Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8+ T cell memory development.
  6. Deoxycholic acid inhibits ASFV replication by inhibiting MAPK signaling pathway.
  1. Vet Microbiol. 2024 Mar 12. pii: S0378-1135(24)00073-7. [Epub ahead of print]292 110051
    Bovine parainfluenza virus type 3 infections induce ER stress-mediated autophagy to facilitate virus replication.
    Yu Han, Chongyang Wang, Chongsheng Bai, Enying Diao, Binxuan Yuan, Kejia Lu, Xiaoyu Dong, Riteng Zhang, Bin Han, Haijin Liu, Juan Wang, Xinglong Wang, Sa Xiao, Zengqi Yang.
      Bovine Parainfluenza Virus Type 3 (BPIV3) serves as a crucial pathogen in cattle, adept at triggering severe respiratory symptoms. This investigation explores the intricate interplay of endoplasmic reticulum stress (ER stress), unfolded protein response (UPR), and autophagy upon BPIV3 infection. In this study, we initially confirm a substantial increase in glucose regulatory protein 78 (GRP78) expression, accompanied by noticeable morphological changes and significant expansion of the ER lumen observed through transmission electron microscopy upon BPIV3 infection. Our findings indicate that ER Stress is induced during BPIV3 infection in vitro. Subsequently, we illustrate that BPIV3 triggers ER Stress to facilitate viral replication through heightened autophagy through treatment with the ER stress inhibitor 4-phenylbutyrate (4-PBA) and utilizing small interfering RNA (siRNA) technology to knock down GRP78. Additionally, we observe that the activation of ER stress initiates the UPR via PERK and ATF6 pathways, with the IRE1 pathway not contributing to the regulation of ER stress-mediated autophagy. Moreover, intervention with the PERK inhibitor GSK2606414, ATF6 inhibitor Ceapin-A7, and siRNA technology successfully reverses BPIV3-induced autophagy. In summary, these findings propose that BPIV3 induces ER stress to enhance viral replication through increased autophagy, with the PERK and ATF6 pathways playing a significant role in ER stress-mediated autophagy.
    Keywords:  Autophagy; Bovine parainfluenza virus type 3; Endoplasmic reticulum stress; Unfolded protein response; Viral replication
    DOI:  https://doi.org/10.1016/j.vetmic.2024.110051
  2. Cell Rep. 2024 Mar 14. pii: S2211-1247(24)00293-6. [Epub ahead of print]43(3): 113965
    Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication and pathogenicity.
    Zemin Yang, Bryan A Johnson, Victoria A Meliopoulos, Xiaohui Ju, Peipei Zhang, Michael P Hughes, Jinjun Wu, Kaitlin P Koreski, Jemma E Clary, Ti-Cheng Chang, Gang Wu, Jeff Hixon, Jay Duffner, Kathy Wong, Rene Lemieux, Kumari G Lokugamage, R Elias Alvarado, Patricia A Crocquet-Valdes, David H Walker, Kenneth S Plante, Jessica A Plante, Scott C Weaver, Hong Joo Kim, Rachel Meyers, Stacey Schultz-Cherry, Qiang Ding, Vineet D Menachery, J Paul Taylor.
      G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibits stress granule assembly and interacts with G3BP1/2 via an ITFG motif, including residue F17, in the N protein. Prior studies examining the impact of the G3PB1-N interaction on SARS-CoV-2 replication have produced inconsistent findings, and the role of this interaction in pathogenesis is unknown. Here, we use structural and biochemical analyses to define the residues required for G3BP1-N interaction and structure-guided mutagenesis to selectively disrupt this interaction. We find that N-F17A mutation causes highly specific loss of interaction with G3BP1/2. SARS-CoV-2 N-F17A fails to inhibit stress granule assembly in cells, has decreased viral replication, and causes decreased pathology in vivo. Further mechanistic studies indicate that the N-F17-mediated G3BP1-N interaction promotes infection by limiting sequestration of viral genomic RNA (gRNA) into stress granules.
    Keywords:  CP: Microbiology; G3BP; NTF2L domain; SARS-CoV-2 replication and pathogenesis; host-pathogen interaction; nucleocapsid protein; stress granule; vRNA sequestration
    DOI:  https://doi.org/10.1016/j.celrep.2024.113965
  3. iScience. 2024 Apr 19. 27(4): 109345
    Identification and verification of the role of key metabolites and metabolic pathways on ASFV replication.
    Zunji Shi, Xing Yang, Xijuan Shi, Dajun Zhang, Dengshuai Zhao, Yu Hao, Jinke Yang, Xintian Bie, Wenqian Yan, Guohui Chen, Lingling Chen, Xiangtao Liu, Haixue Zheng, Keshan Zhang.
      African swine fever virus (ASFV) infection usually causes viremia within a few days. However, the metabolic changes in pig serum after ASFV infection remain unclear. In this study, serum samples collected from ASFV-infected pigs at different times were analyzed using pseudotargeted metabolomics method. Metabolomic analysis revealed the dopaminergic synapse pathway has the highest rich factor in both ASFV5 and ASFV10 groups. By disrupting the dopamine synaptic pathway, dopamine receptor antagonists inhibited ASFV replication and L-dopa promoted ASFV replication. In addition, guanosine, one of the top20 changed metabolites in both ASFV5 and ASFV10 groups suppressed the replication of ASFV. Taken together, this study revealed the changed serum metabolite profiles of ASFV-infected pigs at various times after infection and verified the effect of the changed metabolites and metabolic pathways on ASFV replication. These findings may contribute to understanding the pathogenic mechanisms of ASFV and the development of target drugs to control ASF.
    Keywords:  Metabolomics; Porcine medicine; Virology
    DOI:  https://doi.org/10.1016/j.isci.2024.109345
  4. Vet Microbiol. 2024 Mar 16. pii: S0378-1135(24)00077-4. [Epub ahead of print]292 110055
    Hypoxia inducible factor-1α facilitates transmissible gastroenteritis virus replication by inhibiting type I and type III interferon production.
    Yunhang Zhang, Xue Rui, Yang Li, Yue Zhang, Yifei Cai, Chen Tan, Ning Yang, Yuanyuan Liu, Yuguang Fu, Guangliang Liu.
      Transmissible gastroenteritis virus (TGEV) is characterized by watery diarrhea, vomiting, and dehydration and is associated with high mortality especially in newborn piglets, causing significant economic losses to the global pig industry. Hypoxia inducible factor-1α (HIF-1α) has been identified as a key regulator of TGEV-induced inflammation, but understanding of the effect of HIF-1α on TGEV infection remains limited. This study found that TGEV infection was associated with a marked increase in HIF-1α expression in ST cells and an intestinal organoid epithelial monolayer. Furthermore, HIF-1α was shown to facilitate TGEV infection by targeting viral replication, which was achieved by restraining type I and type III interferon (IFN) production. In vivo experiments in piglets demonstrated that the HIF-1α inhibitor BAY87-2243 significantly reduced HIF-1α expression and inhibited TGEV replication and pathogenesis by activating IFN production. In summary, we unveiled that HIF-1α facilitates TGEV replication by restraining type I and type III IFN production in vitro, ex vivo, and in vivo. The findings from this study suggest that HIF-1α could be a novel antiviral target and candidate drug against TGEV infection.
    Keywords:  HIF-1α; In vivo; Intestinal organoid monolayer; TGEV; Type I and type III IFN production
    DOI:  https://doi.org/10.1016/j.vetmic.2024.110055
  5. Proc Natl Acad Sci U S A. 2024 Mar 26. 121(13): e2306763121
    Expression of the monocarboxylate transporter MCT1 is required for virus-specific mouse CD8+ T cell memory development.
    Stefania D'Aria, Céline Maquet, Shuang Li, Suveera Dhup, Anouk Lepez, Arnaud Kohler, Vincent F Van Hée, Rajesh K Dadhich, Marine Frenière, Fabienne Andris, Ivan Nemazanyy, Pierre Sonveaux, Bénédicte Machiels, Laurent Gillet, Michel Y Braun.
      Lactate-proton symporter monocarboxylate transporter 1 (MCT1) facilitates lactic acid export from T cells. Here, we report that MCT1 is mandatory for the development of virus-specific CD8+ T cell memory. MCT1-deficient T cells were exposed to acute pneumovirus (pneumonia virus of mice, PVM) or persistent γ-herpesvirus (Murid herpesvirus 4, MuHV-4) infection. MCT1 was required for the expansion of virus-specific CD8+ T cells and the control of virus replication in the acute phase of infection. This situation prevented the subsequent development of virus-specific T cell memory, a necessary step in containing virus reactivation during γ-herpesvirus latency. Instead, persistent active infection drove virus-specific CD8+ T cells toward functional exhaustion, a phenotype typically seen in chronic viral infections. Mechanistically, MCT1 deficiency sequentially impaired lactic acid efflux from activated CD8+ T cells, caused an intracellular acidification inhibiting glycolysis, disrupted nucleotide synthesis in the upstream pentose phosphate pathway, and halted cell proliferation which, ultimately, promoted functional CD8+ T cell exhaustion instead of memory development. Taken together, our data demonstrate that MCT1 expression is mandatory for inducing T cell memory and controlling viral infection by CD8+ T cells.
    Keywords:  T cell exhaustion; T cell memory development; lactate transport; monocarboxylate transporters (MCTs); virus latency
    DOI:  https://doi.org/10.1073/pnas.2306763121
  6. Int J Biol Macromol. 2024 Mar 15. pii: S0141-8130(24)01744-6. [Epub ahead of print] 130939
    Deoxycholic acid inhibits ASFV replication by inhibiting MAPK signaling pathway.
    Qi Gao, Yifan Xu, Yongzhi Feng, Xiaoyu Zheng, Ting Gong, Qiyuan Kuang, Qinxin Xiang, Lang Gong, Guihong Zhang.
      African swine fever (ASF) is an acute, febrile, highly contagious infection of pigs caused by the African swine fever virus (ASFV). The purpose of this study is to understand the molecular mechanism of ASFV infection and evaluate the effect of DCA on MAPK pathway, so as to provide scientific basis for the development of new antiviral drugs. The transcriptome analysis found that ASFV infection up-regulated the IL-17 and MAPK signaling pathways to facilitate viral replication. Metabolome analysis showed that DCA levels were up-regulated after ASFV infection, and that exogenous DCA could inhibit activation of the MAPK pathway by ASFV infection and thus inhibit viral replication. Dual-luciferase reporter assays were used to screen the genes of ASFV and revealed that I73R could significantly up-regulate the transcription level of AP-1 transcription factor in the MAPK pathway. Confocal microscopy demonstrated that I73R could promote AP-1 entry into the nucleus, and that DCA could inhibit the I73R-mediated nuclear entry of AP-1, inhibiting MAPK pathway, and I73R interacts with AP-1. These results indicated that DCA can inhibit ASFV-mediated activation of the MAPK pathway, thus inhibiting ASFV replication. This study provides a theoretical basis for research on ASF pathogenesis and for antiviral drug development.
    Keywords:  African swine fever virus; Deoxycholic acid; MAPK signaling pathway
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.130939
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