bims-mevinf 2023-08-13 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023‒08‒13
fourteen papers selected by
Alexander Ivanov
Engelhardt Institute of Molecular Biology

Activation of ATF3 via the Integrated Stress Response Pathway Regulates Innate Immune and Autophagy Processes to Restrict Zika Virus.
Cellular metabolism hijacked by viruses for immunoevasion: potential antiviral targets.
Excess iron aggravates the severity of COVID-19 infection.
Japanese Encephalitis virus infection in astrocytes modulate microglial function: Correlation with inflammation and oxidative stress.
Raf1 promotes successful Human Cytomegalovirus replication and is regulated by AMPK-mediated phosphorylation during infection.
Inhibition of SIRT2 promotes death of human cytomegalovirus-infected peripheral blood monocytes via apoptosis and necroptosis.
Autophagy induced by human adenovirus B7 structural protein VI inhibits viral replication.
Epidermal growth factor receptor promotes infectious spleen and kidney necrosis virus invasion via PI3K-Akt signaling pathway.
Modifications of Lipid Pathways Restrict SARS-CoV-2 Propagation in Human Induced Pluripotent Stem Cell-derived 3D Airway Organoids.
Contemporary Antiretroviral Therapy Dysregulates Iron Transport and Augments Mitochondrial Dysfunction in HIV-Infected Human Microglia and Neural-Lineage Cells.
Infection of epithelioma papulosum cyprini (EPC) cells with spring viremia of carp virus (SVCV) induces autophagy and apoptosis through endoplasmic reticulum stress.
Anxiety due to Long COVID is partially driven by activation of the tryptophan catabolite (TRYCAT) pathway.
Antioxidants and Calcium Modulators Preclude in Vitro Hepatitis B Virus-Induced Mitochondrial Damage.
Attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric manifestations of post-COVID syndrome.

bioRxiv. 2023 Jul 27. pii: 2023.07.26.550716. [Epub ahead of print]

Activation of ATF3 via the Integrated Stress Response Pathway Regulates Innate Immune and Autophagy Processes to Restrict Zika Virus.

Pheonah Badu, Cara T Pager.

Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects from a ZIKV infection arise in part from the virus triggering cellular stress pathways and perturbing transcriptional programs. To date, the underlying mechanisms of transcriptional control directing viral restriction and virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) is a stress-induced transcriptional effector that modulates the expression of genes involved in a myriad of cellular processes, including inflammation and antiviral responses, to restore cellular homeostasis. While ATF3 is known to be upregulated during ZIKV infection, the mode by which ATF3 is activated and the specific role of ATF3 during ZIKV infection is unknown. In this study, we show via inhibitor and RNA interference approaches that ZIKV infection initiates the integrated stress response pathway to activate ATF4 which in turn induces ATF3 expression. Additionally, by using a CRISPR-Cas9 system to deplete ATF3, we found that ATF3 acts to limit ZIKV gene expression in A549 cells. In particular, the ATF3-dependent anti-ZIKV response occurred through regulation of innate immunity and autophagy pathways. We show that ATF3 differentially regulates the expression of innate immune response genes and suppresses the transcription of autophagy related genes to influence autophagic flux. Our study therefore highlights an important role for the integrated stress response pathway and ATF3 in establishing an antiviral effect during ZIKV infection.Importance: ZIKV is a re-emerging mosquito-borne flavivirus associated with congenital Zika syndrome in infants and Guillain Barré syndrome in adults. As a cytoplasmic virus, ZIKV co-opts host cellular mechanisms to support viral processes and consequently, reprograms the host transcriptional profile. Such viral-directed transcriptional changes and their proor anti-viral significance remain understudied. We previously showed that ATF3, a stress-induced transcription factor, is significantly upregulated in ZIKV infected mammalian cells, along with other cellular and immune response genes. Here, we specifically define the intracellular pathway responsible for ATF3 activation and elucidate the impact of ATF3 expression on ZIKV infection. Our data provides novel insights into the role of the integrated stress response pathway in stimulating ATF3 which differentially regulates the innate immune response and autophagy at the transcript level to antagonize ZIKV gene expression. This study establishes a framework that links viral-induced stress response to transcriptional regulation of host defense pathways and thus expands the depth of knowledge on virus-mediated transcriptional mechanisms during ZIKV infection which in turn will inform future therapeutic strategies.

DOI: https://doi.org/10.1101/2023.07.26.550716
Front Immunol. 2023 ;14 1228811

Cellular metabolism hijacked by viruses for immunoevasion: potential antiviral targets.

Jiaqi Li, Yanjin Wang, Hao Deng, Su Li, Hua-Ji Qiu.

  Cellular metabolism plays a central role in the regulation of both innate and adaptive immunity. Immune cells utilize metabolic pathways to modulate the cellular differentiation or death. The intricate interplay between metabolism and immune response is critical for maintaining homeostasis and effective antiviral activities. In recent years, immunometabolism induced by viral infections has been extensively investigated, and accumulating evidence has indicated that cellular metabolism can be hijacked to facilitate viral replication. Generally, virus-induced changes in cellular metabolism lead to the reprogramming of metabolites and metabolic enzymes in different pathways (glucose, lipid, and amino acid metabolism). Metabolic reprogramming affects the function of immune cells, regulates the expression of immune molecules and determines cell fate. Therefore, it is important to explore the effector molecules with immunomodulatory properties, including metabolites, metabolic enzymes, and other immunometabolism-related molecules as the antivirals. This review summarizes the relevant advances in the field of metabolic reprogramming induced by viral infections, providing novel insights for the development of antivirals.

Keywords:  adaptive immunity; immunoevasion; immunometabolism; innate immunity; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2023.1228811
Free Radic Biol Med. 2023 Aug 06. pii: S0891-5849(23)00583-X. [Epub ahead of print]

Excess iron aggravates the severity of COVID-19 infection.

Gaurav Kumar Chaubey, Rahul Dilawari, Radheshyam Modanwal, Sharmila Talukdar, Asmita Dhiman, Chaaya Iyengar Raje, Manoj Raje.

  Coronavirus disease-19 (COVID-19) can induce severe inflammation of the lungs and respiratory system. Severe COVID-19 is frequently associated with hyper inflammation and hyper-ferritinemia. High iron levels are known to trigger pro-inflammatory effects. Cumulative iron loading negatively impacts on a patients innate immune effector functions and increases the risk for infection related complications. Prognosis of severe acute respiratory SARS-CoV-2 patients may be impacted by iron excess. Iron is an essential co-factor for numerous essential cellular enzymes and vital cellular operations. Viruses hijack cells in order to replicate, and efficient replication requires an iron-replete host. Utilizing iron loaded cells in culture we evaluated their susceptibility to infection by pseudovirus expressing the SARS-CoV-2 spike protein and resultant cellular inflammatory response. We observed that, high levels of iron enhanced host cell ACE2 receptor expression contributing to higher infectivity of pseudovirus. In vitro Cellular iron overload also synergistically enhanced the levels of; reactive oxygen species, reactive nitrogen species, pro-inflammatory cytokines (IL-1β, IL-6, IL-8 & TNF-α) and chemokine (CXCL-1&CCL-4) production in response to inflammatory stimulation of cells with spike protein. These results were confirmed using an in vivo mouse model. In future, limiting iron levels may be a promising adjuvant strategy in treating viral infection.

Keywords:  COVID-19; Iron; Pro-inflammatory cytokines; Reactive nitrogen species; Reactive oxygen species; SARS-CoV-2

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.08.011
Cytokine. 2023 Aug 09. pii: S1043-4666(23)00206-5. [Epub ahead of print]170 156328

Japanese Encephalitis virus infection in astrocytes modulate microglial function: Correlation with inflammation and oxidative stress.

Stuti Mohapatra, Triparna Chakraborty, Anirban Basu.

  BACKGROUND: Japanese Encephalitis Virus (JEV) is a neurotropic virus which has the propensity to infect neuronal and glial cells of the brain. Astrocyte-microglia crosstalk leading to the secretion of various factors plays a major role in controlling encephalitis in brain. This study focused on understanding the role of astrocytic mediators that further shaped the microglial response towards JEV infection.METHODS: After establishing JEV infection in C8D1A (mouse astrocyte cell line) and primary astrocyte enriched cultures (PAEC), astrocyte supernatant was used for preparation of conditioned media. Astrocyte supernatant was treated with UV to inactivate JEV and the supernatant was added to N9 culture media in ratio 1:1 for preparation of conditioned media. N9 microglial cells post treatment with astrocyte conditioned media and JEV infection were checked for expression of various inflammatory genes by qRT-PCR, levels of secreted cytokines in N9 cell supernatant were checked by cytometric bead array. N9 cell lysates were checked for expression of proteins - pNF-κβ, IBA-1, NS3 and RIG-I by western blotting. Viral titers were measured in N9 supernatant by plaque assays. Immunocytochemistry experiments were done to quantify the number of infected microglial cells after astrocyte conditioned medium treatment. Expression of different antioxidant enzymes was checked in N9 cells by western blotting, levels of reactive oxygen species (ROS) was detected by fluorimetry using DCFDA dye.
RESULTS: N9 microglial cells post treatment with JEV-infected astrocyte conditioned media and JEV infection were activated, showed an upsurge in expression of inflammatory genes and cytokines both at the transcript and protein levels. These N9 cells showed a decrease in quantity of viral titers and associated viral proteins in comparison to control cells (not treated with conditioned media but infected with JEV). Also, N9 cells upon conditioned media treatment and JEV infection were more prone to undergo oxidative stress as observed by the decreased expression of antioxidant enzymes SOD-1, TRX-1 and increased secretion of reactive oxygen species (ROS).
CONCLUSION: Astrocytic mediators like TNF-α, MCP-1 and IL-6 influence microglial response towards JEV infection by promoting inflammation and oxidative stress in them. As a result of increased microglial inflammation and secretion of ROS, viral replication is lessened in conditioned media treated and JEV infected microglial cells as compared to control cells with no conditioned media treatment but only JEV infection.

Keywords:  Astrocyte; Conditioned Media; Cytokine; Inflammation; JEV; Microglia; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.cyto.2023.156328
bioRxiv. 2023 Jul 26. pii: 2023.07.26.550702. [Epub ahead of print]

Raf1 promotes successful Human Cytomegalovirus replication and is regulated by AMPK-mediated phosphorylation during infection.

Diana M Dunn, Ludia J Pack, Joshua C Munger.

Raf1 is a key player in growth factor receptor signaling, which has been linked to multiple viral infections, including Human Cytomegalovirus (HCMV) infection. Although HCMV remains latent in most individuals, it can cause acute infection in immunocompromised populations such as transplant recipients, neonates, and cancer patients. Current treatments are suboptimal, highlighting the need for novel treatments. Multiple points in the growth factor signaling pathway are important for HCMV infection, but the relationship between HCMV and Raf1, a component of the mitogen-activated protein kinase (MAPK) cascade, is not well understood. The AMP-activated protein kinase (AMPK) is a known regulator of Raf1, and AMPK activity is both induced by infection and important for HCMV replication. Our data indicate that HCMV infection induces AMPK-specific changes in Raf1 phosphorylation, including increasing phosphorylation at Raf1-Ser621, a known AMPK phospho-site, which results in increased binding to the 14-3-3 scaffolding protein, an important aspect of Raf1 activation. Inhibition of Raf1, either pharmacologically or via shRNA or CRISPR-mediated targeting, inhibits viral replication and spread in both fibroblasts and epithelial cells. Collectively, our data indicate that HCMV infection and AMPK activation modulate Raf1 activity, which are important for viral replication.Importance: Growth factor signaling plays a critical role in many aspects of viral infection. Here we show that a component of one of these pathways, Raf1, contributes to successful infection of Human Cytomegalovirus (HCMV). We find that AMP-activated protein kinase (AMPK), which is known to be important for HCMV infection, modulates Raf1 phosphorylation throughout infection, and contributes to Raf1 binding to its activating co-factor, 14-3-3. In addition, inhibition of Raf1 inhibits HCMV infection and viral spread. These results suggest a link between two cellular pathways that are important for HCMV replication, AMPK signaling and growth factor receptor signaling, that converge as an important aspect of HCMV infection. This could lead to the potential for new therapeutic targets in immunocompromised individuals afflicted by acute HCMV infection.

DOI: https://doi.org/10.1101/2023.07.26.550702
Antiviral Res. 2023 Aug 09. pii: S0166-3542(23)00176-6. [Epub ahead of print]217 105698

Inhibition of SIRT2 promotes death of human cytomegalovirus-infected peripheral blood monocytes via apoptosis and necroptosis.

Jennifer Cheung, Stacy Remiszewski, Lillian W Chiang, Ejaz Ahmad, Mohan Pal, Sm Ashikur Rahman, Zaneta Nikolovska-Coleska, Gary C Chan.

  Peripheral blood monocytes are the cells predominantly responsible for systemic dissemination of human cytomegalovirus (HCMV) and a significant cause of morbidity and mortality in immunocompromised patients. HCMV establishes a silent/quiescent infection in monocytes, which is defined by the lack of viral replication and lytic gene expression. The absence of replication shields the virus within infected monocytes from the current available antiviral drugs that are designed to suppress active replication. Our previous work has shown that HCMV stimulates a noncanonical phosphorylation of Akt and the subsequent upregulation of a distinct subset of prosurvival proteins in normally short-lived monocytes. In this study, we found that SIRT2 activity is required for the unique activation profile of Akt induced within HCMV-infected monocytes. Importantly, both therapeutic and prophylactic treatment with a novel SIRT2 inhibitor, FLS-379, promoted death of infected monocytes via both the apoptotic and necroptotic cell death pathways. Mechanistically, SIRT2 inhibition reduced expression of Mcl-1, an Akt-dependent antiapoptotic Bcl-2 family member, and enhanced activation of MLKL, the executioner kinase of necroptosis. We have previously reported HCMV to block necroptosis by stimulating cellular autophagy. Here, we additionally demonstrate that inhibition of SIRT2 suppressed Akt-dependent HCMV-induced autophagy leading to necroptosis of infected monocytes. Overall, our data show that SIRT2 inhibition can simultaneously promote death of quiescently infected monocytes by two distinct death pathways, apoptosis and necroptosis, which may be vital for limiting viral dissemination to peripheral organs in immunosuppressed patients.

Keywords:  Apoptosis; Cytomegalovirus; Monocyte; Necroptosis; Sirtuin 2; Small-molecule inhibitor

DOI:  https://doi.org/10.1016/j.antiviral.2023.105698
Virol Sin. 2023 Aug 05. pii: S1995-820X(23)00100-1. [Epub ahead of print]

Autophagy induced by human adenovirus B7 structural protein VI inhibits viral replication.

Linlin Zhang, Yali Duan, Wei Wang, Qi Li, Jiao Tian, Yun Zhu, Ran Wang, Zhengde Xie.

  Human adenovirus-B7 (HAdV-B7) causes severe acute lower respiratory tract infections in children. None of the child-specific antiviral drugs and vaccine against HAdV-B7 is available currently, and the pathogenesis is unclear. Autophagy, as part of innate immunity, plays an important role in resistance to viral infection by degrading the virus and promoting the development of innate and adaptive immunity. This study provided evidence that HAdV-B7 infection induced complete autophagic flux, and the pharmacological induction of autophagy decreased HAdV-B7 replication. In this process, the host protein Bcl2-associated athanogene 3 (BAG3) mediated autophagy to inhibit the replication of HAdV-B7 by binding to the PPSY structural domain of viral protein pVI through its WW structural domain. These findings further our understanding of the host immune response during viral infection and will help to develop broad anti-HAdV therapies.

Keywords:  Autophagy; Bcl2-associated athanogene 3 (BAG3); Human adenovirus B7 (HAdV-B7); Virus replication

DOI:  https://doi.org/10.1016/j.virs.2023.08.002
J Gen Virol. 2023 Aug;104(8):

Epidermal growth factor receptor promotes infectious spleen and kidney necrosis virus invasion via PI3K-Akt signaling pathway.

Yinjie Niu, Xiaozhe Fu, Qiang Lin, Hongru Liang, Xia Luo, Shaozhi Zuo, Lihui Liu, Ningqiu Li.

  Infectious spleen and kidney necrosis virus disease (ISKNVD) caused significant economic losses to the fishery industry. Epidermal growth factor receptor (EGFR), phosphatidylinositide 3-kinase (PI3K) played an important role in ISKNV invasion. However, the molecular regulatory mechanisms among EGFR, PI3K-Akt, and ISKNV invasion are not clear. In this study, ISKNV infection rapidly induced EGFR activation. While, EGFR activation promoted virus entry, but EGFR inhibitors and specific RNA (siRNA) decreased virus invasion. The PI3K-Akt as downstream signalling of EGFR was activated upon ISKNV infection. Consistent with the trends of EGFR, Akt activation increased ISKNV entry into cells, Akt inhibition by specific inhibitor or siRNA decreased ISKNV invasion. Akt silencing combination with EGFR activation showed that EGFR activation regulation ISKNV invasion is required for activation of the Akt signalling pathway. Those data demonstrated that ISKNV-induced EGFR activation positively regulated virus invasion by PI3K-Akt pathway and provided a better understanding of the mechanism of EGFR-PI3K-Akt involved in ISKNV invasion.

Keywords:  PI3K-Akt signaling pathway; epidermal growth factor receptor; infectious spleen and kidney necrosis virus; viral invasion

DOI:  https://doi.org/10.1099/jgv.0.001882
J Adv Res. 2023 Aug 07. pii: S2090-1232(23)00209-6. [Epub ahead of print]

Modifications of Lipid Pathways Restrict SARS-CoV-2 Propagation in Human Induced Pluripotent Stem Cell-derived 3D Airway Organoids.

Ping-Hsing Tsai, Jun-Ren Sun, Yueh Chien, Man Sheung Chan, Winnie Khor, Hsin-Chou Yang, Chih-Heng Huang, Chia-Ni Hsiung, Teh-Yang Hwa, Yi-Ying Lin, Chih-Ling Yeh, Mong-Lien Wang, Yi-Ping Yang, Yuh-Min Chen, Fu-Ting Tsai, Meng-Shiue Lee, Yun-Hsiang Cheng, Shan-Ko Tsai, Ping-Cheng Liu, Shih-Jie Chou, Shih-Hwa Chiou.

  BACKGROUND: Modifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required.METHODS: Here we generated induced pluripotent stem cell-derived airway organoids (iPSC-AOs) that resemble the human native airway. Single-cell sequencing (ScRNAseq) and microscopic examination verified the cellular heterogeneity and microstructures of iPSC-AOs, respectively. We subjected iPSC-AOs to SARS-CoV-2 infection and investigated the treatment effect of lipid modifiers statin drugs on viral pathogenesis, gene expression, and the intracellular trafficking of the SARS-CoV-2 entry receptor angiotensin-converting enzyme-2 (ACE-2).
RESULTS: In SARS-CoV-2-infected iPSC-AOs, immunofluorescence staining detected the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins and bioinformatics analysis further showed the aberrant enrichment of lipid-associated pathways. In addition, SARS-CoV-2 hijacked the host RNA replication machinery and generated the new isoforms of a high-density lipoprotein constituent apolipoprotein A1 (APOA1) and the virus-scavenging protein deleted in malignant brain tumors 1 (DMBT1). Manipulating lipid homeostasis using cholesterol-lowering drugs (e.g. Statins) relocated the viral entry receptor angiotensin-converting enzyme-2 (ACE-2) and decreased N protein expression, leading to the reduction of SARS-CoV-2 entry and replication. The same lipid modifications suppressed the entry of luciferase-expressing SARS-CoV-2 pseudoviruses containing the S proteins derived from different SARS-CoV-2 variants, i.e. wild-type, alpha, delta, and omicron.
CONCLUSIONS: Together, our data demonstrated that modifications of lipid pathways restrict SARS-CoV-2 propagation in the iPSC-AOs, which the inhibition is speculated through the translocation of ACE2 from the cell membrane to the cytosol. Considering the highly frequent mutation and generation of SARS-CoV-2 variants, targeting host metabolisms of cholesterol or other lipids may represent an alternative approach against SARS-CoV-2 infection.

Keywords:  Single cell RNA-sequencing; airway organoid; angiotensin-converting enzyme 2; induced pluripotent stem cell; severe acute respiratory syndrome coronavirus 2

DOI:  https://doi.org/10.1016/j.jare.2023.08.005
Int J Mol Sci. 2023 Jul 31. pii: 12242. [Epub ahead of print]24(15):

Contemporary Antiretroviral Therapy Dysregulates Iron Transport and Augments Mitochondrial Dysfunction in HIV-Infected Human Microglia and Neural-Lineage Cells.

Harpreet Kaur, Paige Minchella, David Alvarez-Carbonell, Neeraja Purandare, Vijay K Nagampalli, Daniel Blankenberg, Todd Hulgan, Mariana Gerschenson, Jonathan Karn, Siddhesh Aras, Asha R Kallianpur.

  HIV-associated cognitive dysfunction during combination antiretroviral therapy (cART) involves mitochondrial dysfunction, but the impact of contemporary cART on chronic metabolic changes in the brain and in latent HIV infection is unclear. We interrogated mitochondrial function in a human microglia (hμglia) cell line harboring inducible HIV provirus and in SH-SY5Y cells after exposure to individual antiretroviral drugs or cART, using the MitoStress assay. cART-induced changes in protein expression, reactive oxygen species (ROS) production, mitochondrial DNA copy number, and cellular iron were also explored. Finally, we evaluated the ability of ROS scavengers or plasmid-mediated overexpression of the antioxidant iron-binding protein, Fth1, to reverse mitochondrial defects. Contemporary antiretroviral drugs, particularly bictegravir, depressed multiple facets of mitochondrial function by 20-30%, with the most pronounced effects in latently infected HIV+ hμglia and SH-SY5Y cells. Latently HIV-infected hμglia exhibited upregulated glycolysis. Increases in total and/or mitochondrial ROS, mitochondrial DNA copy number, and cellular iron accompanied mitochondrial defects in hμglia and SH-SY5Y cells. In SH-SY5Y cells, cART reduced mitochondrial iron-sulfur-cluster-containing supercomplex and subunit expression and increased Nox2 expression. Fth1 overexpression or pre-treatment with N-acetylcysteine prevented cART-induced mitochondrial dysfunction. Contemporary cART impairs mitochondrial bioenergetics in hμglia and SH-SY5Y cells, partly through cellular iron accumulation; some effects differ by HIV latency.

Keywords:  HIV; antiretroviral drug; combination antiretroviral therapy; human microglia; iron; metabolic reprogramming; mitochondrial dysfunction; neural cell

DOI:  https://doi.org/10.3390/ijms241512242
Microb Pathog. 2023 Aug 07. pii: S0882-4010(23)00326-1. [Epub ahead of print]183 106293

Infection of epithelioma papulosum cyprini (EPC) cells with spring viremia of carp virus (SVCV) induces autophagy and apoptosis through endoplasmic reticulum stress.

Xue Jiao, Yu-Ting Lu, Bo Wang, Zheng-Yao Guo, Ai-Dong Qian, Yue-Hong Li.

  Spring viremia of carp virus (SVCV) is a lethal freshwater pathogen of cyprinid fish that has caused significant economic losses to aquaculture. To reduce the economic losses caused by SVCV, its pathogenic mechanism needs to be studied more thoroughly. Here, we report for the first time that SVCV infection of Epithelioma papulosum cyprini (EPC) cells can induce cellular autophagy and apoptosis through endoplasmic reticulum stress. The presence of autophagic vesicles in infected EPC cells was shown by transmission electron microscopy. Quantitative fluorescence PCR and Western blot results showed that p62 mRNA expression was decreased, and the expression of Beclin1 and LC3 mRNA was increased. The p62 protein was decreased, and the Beclin1 protein and LC3 were increased in the endoplasmic reticulum stress activation state. To further clarify the mode of death of SVCV-infected EPC cells, we examined caspase3, caspase9, BCL-2, and Bax mRNA, which showed that they were all increased. Apoptosis of SVCV-infected cells increased upon activation of endoplasmic reticulum stress. Our results suggest that endoplasmic reticulum stress can regulate SVCV infection-induced autophagy and apoptosis. The results of this study provide theoretical data for the pathogenesis of SVCV and lay the foundation for future drug development and vaccine construction.

Keywords:  Apoptosis; Autophagy; Endoplasmic reticulum stress; Epithelioma papulosum cyprinid (EPC) cells; Spring viremia of carp virus (SVCV)

DOI:  https://doi.org/10.1016/j.micpath.2023.106293
Asian J Psychiatr. 2023 Aug 06. pii: S1876-2018(23)00279-4. [Epub ahead of print]88 103723

Anxiety due to Long COVID is partially driven by activation of the tryptophan catabolite (TRYCAT) pathway.

Hussein Kadhem Al-Hakeim, Anwar Khairi Abed, Abbas F Almulla, Shatha Rouf Moustafa, Michael Maes.

  This study examines whether activation of the tryptophan catabolite (TRYCAT) pathway is associated with anxiety symptoms due to Long COVID. We selected 90 participants, 60 Long COVID patients and 30 individuals without any symptoms following acute COVID-19 infection. Using cluster analysis and the Hamilton Anxiety Rating scale (HAMA) score, the pure HAMA anxiety score, serum tryptophan (TRP) and kynurenine (KYN), the KYN/TRP ratio (all measured during Long COVID), and oxygen saturation (SpO2) (measured during the acute phase of COVID-19), we were able to classify Long COVID patients into two distinct clusters with an adequate silhouette cohesion and separation index (0.58): cluster 1 (n = 61) and cluster 2 (n = 29). Cluster 2 patients had lower SpO2 and TRP levels, as well as higher KYN, KYN/TRP ratio, and HAMA scores than cluster 1. Regression analysis revealed that the KYN/TRP ratio explained 14.4 % of the variance in the HAMA score (F = 14.81, df = 1/88, p = 0.001). In addition, regression analysis revealed that SpO2 partially explained the variance in serum TRP (r = 0.396, p = 0.005), KYN/TRP ratio (r = - 0.248, p = 0.018), and the HAMA score (r = - 0.279, p = 0.008). The current data imply that decreased SpO2 during the acute phase of COVID-19 infection is predictive of anxiety caused by Long COVID. Our data reveal that around 32 % of Long COVID patients have elevated IDO activity in association with elevated anxiety.

Keywords:  Anxiety; Inflammation; Kynurenine; Mood disorders; Neuro-immune; Tryptophan

DOI:  https://doi.org/10.1016/j.ajp.2023.103723
Turk J Gastroenterol. 2023 Aug 11.

Antioxidants and Calcium Modulators Preclude in Vitro Hepatitis B Virus-Induced Mitochondrial Damage.

Kehkshan Jabeen, Aneela Javed, Sobia Manzoor, Shaheen Shahzad.

BACKGROUND/AIMS: Hepatitis B virus induces mitochondrial damage via the production of reactive oxygen species and concomitant with deregulation of calcium homeostasis. The current study evaluates the potential of antioxidant and calcium modulators for inhibition of hepatitis B virus-induced mitochondrial damage using in vitro cell culture models.MATERIALS AND METHODS: Hepatitis B virus-induced mitochondrial fragmentation was observed by immunofluorescence confocal micros- copy in hepatitis B virus-infected cell lines (HepG2 and HepAD38). Differential protein expression of mitochondrial fragmentation mark- ers, dynamin-related protein 1 and phospho-dynamin-related protein 1, were evaluated both pre- and posttreatment with antioxidant N-acetyl-l-cysteine and calcium modulators like 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakisacetoxymethyl ester, ethylene-bis (oxyethylenenitrilo) tetraacetic acid glycol ether diamine tetraacetic acid-acetoxymethyl ester, and ruthenium amine complex by western blot analysis.
RESULTS: A slight reduction in mitochondrial fragmentation in both cell lines was observed post-antioxidant treatment with a partial prevention observed with calcium modulators. The expression of phospho-dynamin-related protein 1 was significantly upregulated (P = .0007, P = .003) in both hepatitis B virus-infected cell lines compared to uninfected cells. In line with these observations, the expres- sion of dynamin-related protein 1 and phospho-dynamin-related protein 1 was found to be significantly downregulated with N-acetyl- l-cysteine treatment in both cell lines (P = .003, P = .002), respectively. A nonsignificant trend was observed in the case of calcium modulators treatment.
CONCLUSIONS: Current study indicates that the mitochondrial fragmentation induced by hepatitis B virus infection can be reduced after antioxidant treatment pointing toward exploring better drug targets for the prevention of hepatitis B virus-induced mitochondrial frag- mentation and associated liver damage.

DOI: https://doi.org/10.5152/tjg.2023.21290
Front Neurosci. 2023 ;17 1237153

Attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric manifestations of post-COVID syndrome.

Ricardo A L Sousa, Asmaa Yehia, Osama A Abulseoud.

  Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), is associated with the persistence of pre-existing or the emergence of new neurological and psychiatric manifestations as a part of a multi-system affection known collectively as "post-COVID syndrome." Cognitive decline is the most prominent feature among these manifestations. The underlying neurobiological mechanisms remain under intense investigation. Ferroptosis is a form of cell death that results from the excessive accumulation of intracellular reactive iron, which mediates lipid peroxidation. The accumulation of lipid-based reactive oxygen species (ROS) and the impairment of glutathione peroxidase 4 (GPX4) activity trigger ferroptosis. The COVID-19-associated cytokine storm enhances the levels of circulating pro-inflammatory cytokines and causes immune-cell hyper-activation that is tightly linked to iron dysregulation. Severe COVID-19 presents with iron overload as one of the main features of its pathogenesis. Iron overload promotes a state of inflammation and immune dysfunction. This is well demonstrated by the strong association between COVID-19 severity and high levels of ferritin, which is a well-known inflammatory and iron overload biomarker. The dysregulation of iron, the high levels of lipid peroxidation biomarkers, and the inactivation of GPX4 in COVID-19 patients make a strong case for ferroptosis as a potential mechanism behind post-COVID neuropsychiatric deficits. Therefore, here we review the characteristics of iron and the attenuation of ferroptosis as a potential therapeutic target for neuropsychiatric post-COVID syndrome.

Keywords:  SARS-CoV-2; ferroptosis; long COVID; post-COVID syndrome; therapeutic target

DOI:  https://doi.org/10.3389/fnins.2023.1237153