bims-mevinf 2023-07-09 papers

Immunohorizons. 2023 Jul 01. 7(7): 528-542

Targeting 2-Oxoglutarate-Dependent Dioxygenases Promotes Metabolic Reprogramming That Protects against Lethal SARS-CoV-2 Infection in the K18-hACE2 Transgenic Mouse Model.

Forrest Jessop, Benjamin Schwarz, Eric Bohrnsen, Molly Miltko, Carl Shaia, Catharine M Bosio.

Dysregulation of host metabolism is a feature of lethal SARS-CoV-2 infection. Perturbations in α-ketoglutarate levels can elicit metabolic reprogramming through 2-oxoglutarate-dependent dioxygenases (2-ODDGs), leading to stabilization of the transcription factor HIF-1α. HIF1-α activation has been reported to promote antiviral mechanisms against SARS-CoV-2 through direct regulation of ACE2 expression (a receptor required for viral entry). However, given the numerous pathways HIF-1α serves to regulate it is possible that there are other undefined metabolic mechanisms contributing to the pathogenesis of SARS-CoV-2 independent of ACE2 downregulation. In this study, we used in vitro and in vivo models in which HIF-1α modulation of ACE2 expression was negated, allowing for isolated characterization of the host metabolic response within SARS-CoV-2 disease pathogenesis. We demonstrated that SARS-CoV-2 infection limited stabilization of HIF-1α and associated mitochondrial metabolic reprogramming by maintaining activity of the 2-ODDG prolyl hydroxylases. Inhibition of 2-ODDGs with dimethyloxalylglycine promoted HIF-1α stabilization following SARS-CoV-2 infection, and significantly increased survival among SARS-CoV-2-infected mice compared with vehicle controls. However, unlike previous reports, the mechanism by which activation of HIF-1α responses contributed to survival was not through impairment of viral replication. Rather, dimethyloxalylglycine treatment facilitated direct effects on host metabolism including increased glycolysis and resolution of dysregulated pools of metabolites, which correlated with reduced morbidity. Taken together, these data identify (to our knowledge) a novel function of α-ketoglutarate-sensing platforms, including those responsible for HIF-1α stabilization, in the resolution of SARS-CoV-2 infection and support targeting these metabolic nodes as a viable therapeutic strategy to limit disease severity during infection.

DOI: https://doi.org/10.4049/immunohorizons.2300048

bioRxiv. 2023 Jun 02. pii: 2023.06.02.543298. [Epub ahead of print]

Deep Phenotyping of the Lipidomic Response in COVID and non-COVID Sepsis.

Lipids may influence cellular penetrance by pathogens and the immune response that they evoke. Here we find a broad based lipidomic storm driven predominantly by secretory (s) phospholipase A 2 (sPLA 2 ) dependent eicosanoid production occurs in patients with sepsis of viral and bacterial origin and relates to disease severity in COVID-19. Elevations in the cyclooxygenase (COX) products of arachidonic acid (AA), PGD 2 and PGI 2 , and the AA lipoxygenase (LOX) product, 12-HETE, and a reduction in the high abundance lipids, ChoE 18:3, LPC-O-16:0 and PC-O-30:0 exhibit relative specificity for COVID-19 amongst such patients, correlate with the inflammatory response and link to disease severity. Linoleic acid (LA) binds directly to SARS-CoV-2 and both LA and its di-HOME products reflect disease severity in COVID-19. AA and LA metabolites and LPC-O-16:0 linked variably to the immune response. These studies yield prognostic biomarkers and therapeutic targets for patients with sepsis, including COVID-19. An interactive purpose built interactive network analysis tool was developed, allowing the community to interrogate connections across these multiomic data and generate novel hypotheses.

DOI: https://doi.org/10.1101/2023.06.02.543298

J Biol Chem. 2023 Jun 29. pii: S0021-9258(23)02015-X. [Epub ahead of print] 104987

PTBP1 suppresses porcine epidemic diarrhea virus replication via inducing protein degradation and IFN production.

Wenzhen Qin, Ning Kong, Yu Zhang, Chunmei Wang, Sujie Dong, Huanjie Zhai, Xueying Zhai, Xinyu Yang, Chenqian Ye, Manqing Ye, Wu Tong, Changlong Liu, Lingxue Yu, Hao Zheng, Hai Yu, Wen Zhang, Daoliang Lan, Guangzhi Tong, Tongling Shan.

Porcine epidemic diarrhea virus (PEDV) causes severe morbidity and mortality among newborn piglets. It significantly threatens the porcine industry in China and around the globe. To accelerate the developmental pace of drugs or vaccines against PEDV, a deeper understanding of the interaction between viral proteins and host factors is crucial. The RNA-binding protein, polypyrimidine tract-binding protein 1 (PTBP1), is crucial for controlling RNA metabolism and biological processes. The present work focused on exploring the effect of PTBP1 on PEDV replication. PTBP1 was upregulated during PEDV infection. The PEDV nucleocapsid (N) protein was degraded through the autophagic and proteasomal degradation pathways. Moreover, PTBP1 recruits MARCH8 (an E3 ubiquitin ligase) and NDP52 (a cargo receptor) for N protein catalysis and degradation through selective autophagy. Furthermore, PTBP1 induces the host innate antiviral response via upregulating the expression of MyD88, which then regulates TRAF3/TRAF6 expression and induces the phosphorylation of TBK1 and IRF3. These processes activate the typeⅠIFN signaling pathway to antagonize PEDV replication. Collectively, this work illustrates a new mechanism related to PTBP1-induced viral restriction, where PTBP1 degrades the viral N protein and induces typeⅠIFN production to suppress PEDV replication.

Keywords: IFN-I; N protein; PEDV; PTBP1; selective autophagy

DOI: https://doi.org/10.1016/j.jbc.2023.104987

Heliyon. 2023 Jun;9(6): e17158

Transcriptome analysis of human macrophages upon chikungunya virus (CHIKV) infection reveals regulation of distinct signaling and metabolic pathways during the early and late stages of infection.

Priyanshu Srivastava, Sakshi Chaudhary, Surbhi Malhotra, Binuja Varma, Sujatha Sunil.

Macrophages are efficient reservoirs for viruses that enable the viruses to survive over a longer period of infection. Alphaviruses such as chikungunya virus (CHIKV) are known to persist in macrophages even after the acute febrile phase. The viral particles replicate in macrophages at a very low level over extended period of time and are localized in tissues that are often less accessible by treatment. Comprehensive experimental studies are thus needed to characterize the CHIKV-induced modulation of host genes in these myeloid lineage cells and in one such pursuit, we obtained global transcriptomes of a human macrophage cell line infected with CHIKV, over its early and late timepoints of infection. We analyzed the pathways, especially immune related, perturbed over these timepoints and observed several host factors to be differentially expressed in infected macrophages in a time-dependent manner. We postulate that these pathways may play crucial roles in the persistence of CHIKV in macrophages.

Keywords: CHIKV; Macrophages; Metabolic pathways; Transcriptome

DOI: https://doi.org/10.1016/j.heliyon.2023.e17158

J Cell Sci. 2023 07 01. pii: jcs261121. [Epub ahead of print]136(13):

How host ER membrane chaperones and morphogenic proteins support virus infection.

Tai-Ting Woo, Jeffrey M Williams, Billy Tsai.

The multi-functional endoplasmic reticulum (ER) is exploited by viruses to cause infection. Morphologically, this organelle is a highly interconnected membranous network consisting of sheets and tubules whose levels are dynamic, changing in response to cellular conditions. Functionally, the ER is responsible for protein synthesis, folding, secretion and degradation, as well as Ca2+ homeostasis and lipid biosynthesis, with each event catalyzed by defined ER factors. Strikingly, these ER host factors are hijacked by viruses to support different infection steps, including entry, translation, replication, assembly and egress. Although the full repertoire of these ER factors that are hijacked is unknown, recent studies have uncovered several ER membrane machineries that are exploited by viruses - ranging from polyomavirus to flavivirus and coronavirus - to facilitate different steps of their life cycle. These discoveries should provide better understanding of virus infection mechanisms, potentially leading to the development of more effective anti-viral therapies.

Keywords: Coronavirus; ER membrane complex; ER morphogenesis; Endoplasmic reticulum; Flavivirus; Polyomavirus

DOI: https://doi.org/10.1242/jcs.261121