bims-mevinf 2024-01-07 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2024‒01‒07
nine papers selected by
Alexander Ivanov, Engelhardt Institute of Molecular Biology

HIF-1-mediated regulation of LDH gene unravels key insights into MCDV-1 pathogenesis in mud crabs Scylla paramamosain.
Mammalian Target of Rapamycin Complex 1 Activation in Macrophages Contributes to Persistent Lung Inflammation following Respiratory Tract Viral Infection.
Viperin mutation is linked to immunity, immune cell dynamics, and metabolic alteration during VHSV infection in zebrafish.
Plant extracts modulate cellular stress to inhibit replication of mouse Coronavirus MHV-A59.
Intermittent cytomegalovirus infection alters neurobiological metabolism and induces cognitive deficits in mice.
Membrane lipid composition of bronchial epithelial cells influences antiviral responses during rhinovirus infection.
Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy.
Approaches to Evaluating Necroptosis in Virus-Infected Cells.
Complement components regulates ferroptosis in CVB3 viral myocarditis by interatction with TFRC.

Dev Comp Immunol. 2023 Dec 29. pii: S0145-305X(23)01280-6. [Epub ahead of print]153 105127

HIF-1-mediated regulation of LDH gene unravels key insights into MCDV-1 pathogenesis in mud crabs Scylla paramamosain.

Yu-Kun Jie, Jia-Wei Xie, Chang-Hong Cheng, Jian-Jun Jiang, Hong-Ling Ma, Guang-Xin Liu, Si-Gang Fan, Yi-Qin Deng, Juan Feng, Zhi-Xun Guo.

  Hypoxia-inducible factors -1 (HIF-1) is a crucial transcription factor that regulates the expression of glycolytic genes. Our previous study proved that the Mud crab dicistrovirus-1 (MCDV-1) can induce aerobic glycolysis that favors viral replication in mud crab Scylla paramamosain. However, the role of HIF-1 on key glycolytic genes during the MCDV-1 infection has not been examined. In this study, the intricate interplay between HIF-1 and the key glycolysis enzyme, lactate dehydrogenase (LDH), was investigated after MCDV-1 infection. The expression of LDH was significant increased after MCDV-1 infection. Additionally, the expression of HIF-1α was upregulated following MCDV-1 infection, potentially attributed to the downregulation of prolyl hydroxylase domains 2 expression. Subsequent examination of the SpLDH promoter identified the presence of hypoxia response elements (HREs), serving as binding sites for HIF-1α. Intriguingly, experimental evidence demonstrated that SpHIF-1α actively promotes SpLDH transcription through these HREs. To further elucidate the functional significance of SpHIF-1α, targeted silencing was employed, resulting in a substantial reduction in SpLDH expression, activity, and lactate concentrations in MCDV-1-infected mud crabs. Notably, SpHIF-1α-silenced mud crabs exhibited higher survival rates and lower viral loads in hepatopancreas tissues following MCDV-1 infection. These results highlight the critical role of SpHIF-1α in MCDV-1 pathogenesis by regulating LDH gene dynamics, providing valuable insights into the molecular mechanisms underlying the virus-host interaction.

Keywords:  Aerobic glycolysis; HIF-1; LDH; MCDV-1; Scylla paramamosain

DOI:  https://doi.org/10.1016/j.dci.2023.105127
Am J Pathol. 2023 Dec 28. pii: S0002-9440(23)00485-6. [Epub ahead of print]

Mammalian Target of Rapamycin Complex 1 Activation in Macrophages Contributes to Persistent Lung Inflammation following Respiratory Tract Viral Infection.

Brydie R Huckestein, Kelly Zeng, Rosemary Westcott, Jonathan K Alder, Danielle Antos, Jay K Kolls, John F Alcorn.

Respiratory tract virus infections cause millions of hospitalizations worldwide each year. Severe infections lead to lung damage that coincides with persistent inflammation and a lengthy repair period. Vaccination and antiviral therapy help to mitigate severe infections before or during the acute stage of disease, but there are currently limited specific treatment options available to individuals experiencing the long-term sequelae of respiratory viral infection. C57BL/6 mice were infected with influenza A/PR/8/34 as a model for severe viral lung infection and allowed to recover for 21 days. Mice were treated with rapamycin, a well-characterized mammalian target of rapamycin complex 1 (mTORC1) inhibitor, on days 12 to 20 after infection, a time period after viral clearance. Persistent inflammation following severe influenza infection in mice was primarily driven by macrophages and T cells. Uniform manifold approximation and projection analysis of flow cytometry data revealed that lung macrophages had high activation of mTORC1, an energy-sensing kinase involved in inflammatory immune cell effector functions. Rapamycin treatment reduced lung inflammation and the frequency of exudate macrophages, T cells, and B cells in the lung, while not impacting epithelial progenitor cells or adaptive immune memory. These data highlight mTORC1's role in sustaining persistent inflammation following clearance of a viral respiratory pathogen and suggest a possible intervention for post-viral chronic lung inflammation.

DOI: https://doi.org/10.1016/j.ajpath.2023.11.017
Front Immunol. 2023 ;14 1327749

Viperin mutation is linked to immunity, immune cell dynamics, and metabolic alteration during VHSV infection in zebrafish.

K A S N Shanaka, Sumi Jung, K P Madushani, Myoung-Jin Kim, Jehee Lee.

  Viperin is a prominent antiviral protein found in animals. The primary function of Viperin is the production of 3'-deoxy-3',4'-didehydro-cytidine triphosphate (ddhCTP), an inhibitory nucleotide involved in viral RNA synthesis. Studies in mammalian models have suggested that ddhCTP interferes with metabolic proteins. However, this hypothesis has yet to be tested in teleost. In this study, the role of Viperin in regulating metabolic alterations during viral hemorrhagic septicemia virus (VHSV) infection was tested. When infected with VHSV, viperin -/- fish showed considerably higher mortality rates. VHSV copy number and the expression of the NP gene were significantly increased in viperin -/- fish. Metabolic gene analysis revealed significant differences in soda, hif1a, fasn, and acc expression, indicating their impact on metabolism. Cholesterol analysis in zebrafish larvae during VHSV infection showed significant upregulation of cholesterol production without Viperin. In vitro analysis of ZF4 cells suggested a considerable reduction in lipid production and a significant upregulation of reactive oxygen species (ROS) generation with the overexpression of viperin. Neutrophil and macrophage recruitment were significantly modulated in viperin -/- fish compared to the wild-type (WT) fish. Thus, we have demonstrated that Viperin plays a role in interfering with metabolic alterations during VHSV infection.

Keywords:  RNA virus; VHSV; Viperin; antiviral protein; zebrafish

DOI:  https://doi.org/10.3389/fimmu.2023.1327749
Heliyon. 2024 Jan 15. 10(1): e23403

Plant extracts modulate cellular stress to inhibit replication of mouse Coronavirus MHV-A59.

Karol Prieto, Cindy Arévalo, Paola Lasso, Carolina Carlosama, Claudia Urueña, Susana Fiorentino, Alfonso Barreto.

  The Covid-19 infection outbreak led to a global epidemic, and although several vaccines have been developed, the appearance of mutations has allowed the virus to evade the immune response. Added to this is the existing risk of the appearance of new emerging viruses. Therefore, it is necessary to explore novel antiviral therapies. Here, we investigate the potential in vitro of plant extracts to modulate cellular stress and inhibit murine hepatitis virus (MHV)-A59 replication. L929 cells were treated with P2Et (Caesalpinia spinosa) and Anamu SC (Petiveria alliacea) plant extracts during infection and virus production, ROS (reactive oxygen species), UPR (unfolded protein response), and autophagy were assessed. P2Et inhibited virus replication and attenuated both ROS production and UPR activation induced during infection. In contrast, the sustained presence of Anamu SC during viral adsorption and replication was required to inhibit viral infection, tending to induce pro-oxidant effects, and increasing UPR gene expression. Notably, the loss of the PERK protein resulted in a slight decrease in virus yield, suggesting a potential involvement of this UPR pathway during replication. Intriguingly, both extracts either maintained or increased the calreticulin surface exposure induced during infection. In conclusion, our findings highlight the development of antiviral natural plant extracts that differentially modulate cellular stress.

Keywords:  Antiviral activity; Autophagy; Calreticulin; Coronavirus; Endoplasmic reticulum stress; Natural products

DOI:  https://doi.org/10.1016/j.heliyon.2023.e23403
Brain Behav Immun. 2024 Jan 03. pii: S0889-1591(23)00415-4. [Epub ahead of print]

Intermittent cytomegalovirus infection alters neurobiological metabolism and induces cognitive deficits in mice.

Mark A A Harrison, Sara L Morris, Grace A Rudman, Daniel J Rittenhouse, Chandler H Monk, Siva S V P Sakamuri, Md Mehedi Hasan, Mst Shamima Khatun, Hanyun Wang, Lucas P Garfinkel, Elizabeth B Norton, Sangku Kim, Jay K Kolls, S Michal Jazwinski, Ricardo Mostany, Prasad V G Katakam, Elizabeth B Engler-Chiurazzi, Kevin J Zwezdaryk.

  Risk factors contributing to dementia are multifactorial. Accumulating evidence suggests a role for pathogens as risk factors, but data is largely correlative with few causal relationships. Here, we demonstrate that intermittent murine cytomegalovirus (MCMV) infection of mice, alters blood brain barrier (BBB) permeability and metabolic pathways. Increased basal mitochondrial function is observed in brain microvessels cells (BMV) exposed to intermittent MCMV infection and is accompanied by elevated levels of superoxide. Further, mice score lower in cognitive assays compared to age-matched controls who were never administered MCMV. Our data show that repeated systemic infection with MCMV, increases markers of neuroinflammation, alters mitochondrial function, increases markers of oxidative stress and impacts cognition. Together, this suggests that viral burden may be a risk factor for dementia. These observations provide possible mechanistic insights through which pathogens may contribute to the progression or exacerbation of dementia.

Keywords:  Aging; Alzheimer’s disease; Blood brain barrier; Brain microvascular endothelial cells; Cognitive decline; Cytomegalovirus; Dementia; Metabolism; Oxidative stress; Pathogen

DOI:  https://doi.org/10.1016/j.bbi.2023.12.033
Tissue Barriers. 2024 Jan 05. 2300580

Membrane lipid composition of bronchial epithelial cells influences antiviral responses during rhinovirus infection.

Madhuriben H Panchal, Emily J Swindle, Theresa J Pell, Wendy C Rowan, Caroline E Childs, James Thompson, Benjamin L Nicholas, Ratko Djukanovic, Victoria M Goss, Anthony D Postle, Donna E Davies, Cornelia Blume.

  Lipids and their mediators have important regulatory functions in many cellular processes, including the innate antiviral response. The aim of this study was to compare the lipid membrane composition of in vitro differentiated primary bronchial epithelial cells (PBECs) with ex vivo bronchial brushings and to establish whether any changes in the lipid membrane composition affect antiviral defense of cells from donors without and with severe asthma. Using mass spectrometry, we showed that the lipid membrane of in vitro differentiated PBECs was deprived of polyunsaturated fatty acids (PUFAs) compared to ex vivo bronchial brushings. Supplementation of the culture medium with arachidonic acid (AA) increased the PUFA-content to more closely match the ex vivo membrane profile. Rhinovirus (RV16) infection of AA-supplemented cultures from healthy donors resulted in significantly reduced viral replication while release of inflammatory mediators and prostaglandin E2 (PGE2) was significantly increased. Indomethacin, an inhibitor of prostaglandin-endoperoxide synthases, suppressed RV16-induced PGE2 release and significantly reduced CXCL-8/IL-8 release from AA-supplemented cultures indicating a link between PGE2 and CXCL8/IL-8 release. In contrast, in AA-supplemented cultures from severe asthmatic donors, viral replication was enhanced whereas PTGS2 expression and PGE2 release were unchanged and CXCL8/IL-8 was significantly reduced in response to RV16 infection. While the PTGS2/COX-2 pathway is initially pro-inflammatory, its downstream products can promote symptom resolution. Thus, reduced PGE2 release during an RV-induced severe asthma exacerbation may lead to prolonged symptoms and slower recovery. Our data highlight the importance of reflecting the in vivo lipid profile in in vitro cell cultures for mechanistic studies.

Keywords:  Bronchial epithelium; arachidonic acid; membrane lipids; rhinovirus; severe asthma

DOI:  https://doi.org/10.1080/21688370.2023.2300580
EMBO Mol Med. 2024 Jan 02.

Methotrimeprazine is a neuroprotective antiviral in JEV infection via adaptive ER stress and autophagy.

Surendra K Prajapat, Laxmi Mishra, Sakshi Khera, Shadrack D Owusu, Kriti Ahuja, Puja Sharma, Eira Choudhary, Simran Chhabra, Niraj Kumar, Rajan Singh, Prem S Kaushal, Dinesh Mahajan, Arup Banerjee, Rajender K Motiani, Sudhanshu Vrati, Manjula Kalia.

  Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment.

Keywords:  Antipsychotic; Microglia; Neuroinflammation; Phenothiazines; Trifluoperazine

DOI:  https://doi.org/10.1038/s44321-023-00014-w
Subcell Biochem. 2023 ;106 37-75

Approaches to Evaluating Necroptosis in Virus-Infected Cells.

Crystal A Lawson, Derek J Titus, Heather S Koehler.

  The immune system functions to protect the host from pathogens. To counter host defense mechanisms, pathogens have developed unique strategies to evade detection or restrict host immune responses. Programmed cell death is a major contributor to the multiple host responses that help to eliminate infected cells for obligate intracellular pathogens like viruses. Initiation of programmed cell death pathways during the early stages of viral infections is critical for organismal survival as it restricts the virus from replicating and serves to drive antiviral inflammation immune recruitment through the release of damage-associated molecular patterns (DAMPs) from the dying cell. Necroptosis has been implicated as a critical programmed cell death pathway in a diverse set of diseases and pathological conditions including acute viral infections. This cell death pathway occurs when certain host sensors are triggered leading to the downstream induction of mixed-lineage kinase domain-like protein (MLKL). MLKL induction leads to cytoplasmic membrane disruption and subsequent cellular destruction with the release of DAMPs. As the role of this cell death pathway in human disease becomes apparent, methods identifying necroptosis patterns and outcomes will need to be further developed. Here, we discuss advances in our understanding of how viruses counteract necroptosis, methods to quantify the pathway, its effects on viral pathogenesis, and its impact on cellular signaling.

Keywords:  E3L; Herpesviruses; Influenza viruses; Necroptosis; Poxviruses; Programmed cell death; Z-nucleic acid binding protein; vIRA

DOI:  https://doi.org/10.1007/978-3-031-40086-5_2
Free Radic Biol Med. 2023 Dec 31. pii: S0891-5849(23)01200-5. [Epub ahead of print]

Complement components regulates ferroptosis in CVB3 viral myocarditis by interatction with TFRC.

Lu Yi, Yezhen Yang, Yanan Hu, Zhixiang Wu, Min Kong, Bojiao Zuoyuan, Xiaowei Xin, Zuocheng Yang.

  BACKGROUND: Dysregulated cell death machinery and an excessive inflammatory response in Coxsackievirus B3(CVB3)-infected myocarditis are hallmarks of an abnormal host response. Complement C4 and C3 are considered the central components of the classical activation pathway and often participate in the response process in the early stages of virus infection.METHODS: In our study, we constructed a mouse model of CVB3-related viral myocarditis via intraperitoneal injection of Fer-1 and detected myocarditis and ferroptosis markers in the mouse myocardium. Then, we performed co-IP and protein mass spectrometry analyses to explore which components interact with the ferroptosis gene transferrin receptor (TFRC). Finally, functional experiments were conducted to verify the role of complement components in regulating ferroptosis in CVB3 infection.
RESULTS: It showed that the ferroptosis inhibitor Fer-1 could alleviate the inflammation in viral myocarditis as well as ferroptosis. Mechanistically, during CVB3 infection, the key factor TFRC was activated and inhibited by Fer-1. Fer-1 effectively prevented the consumption of complement C3 and overload of the complement product C4b. Interestingly, we found that TFRC directly interacts with complement C4, leading to an increase in the product of C4b and a decrease in the downstream complement C3. Functional experiments have also confirmed that regulating the complement C4/C3 pathway can effectively rescue cell ferroptosis caused by CVB3 infection.
CONCLUSIONS: In this study, we found that ferroptosis occurs through crosstalk with complement C4 in viral myocarditis through interaction with TFRC and that regulating the complement C4/C3 pathway may rescue ferroptosis in CVB3-infected cardiomyocytes.

Keywords:  CVB3 myocarditis; Complement components; Ferroptosis; Inflammation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.12.038