bims-mevinf 2023-03-05 papers

bims-mevinf

Biomed News

on Metabolism in viral infections

Issue of 2023‒03‒05
fifteen papers selected by
Alexander Ivanov

Lactate is useful for the efficient replication of porcine epidemic diarrhea virus in cell culture.
Recent Developments in Glioblastoma Therapy: Oncolytic Viruses and Emerging Future Strategies.
Modulation of the Aryl Hydrocarbon Receptor Signaling Pathway Impacts on Junín Virus Replication.
Immunometabolic Signature during Respiratory Viral Infection: A Potential Target for Host-Directed Therapies.
Metabolic regulation of NK cell antiviral functions during cytomegalovirus infection.
Retroviral Infection and Commensal Bacteria Dependently Alter the Metabolomic Profile in a Sterile Organ.
Global Lipidome Profiling Revealed Multifaceted Role of Lipid Species in Hepatitis C Virus Replication, Assembly, and Host Antiviral Response.
Myeloid-Derived Suppressor Cells in Cancer and COVID-19 as Associated with Oxidative Stress.
Viral Hemorrhagic Septicemia Virus Activates Integrated Stress Response Pathway and Induces Stress Granules to Regulate Virus Replication.
Reactive oxygen species-mediated phosphorylation of JNK is involved in the regulation of BmFerHCH on Bombyx mori nucleopolyhedrovirus proliferation.
N protein of PEDV plays chess game with host proteins by selective autophagy.
Pinosrtobin from plants and propolis against human coronavirus HCoV-OC43 by modulating host AHR/CYP1A1 pathway and lipid metabolism.
Japanese Encephalitis Virus Infection Causes an Imbalance in the Activation of Mitochondrial Fusion/Fission Genes and Triggers the Activation of NOX2-mediated Oxidative Stress and Neuronal Cell Death.
Postnatal administration of S-adenosylmethionine restores developmental AHR activation-induced deficits in CD8+ T cell function during influenza A virus infection.
Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection.

Front Vet Sci. 2023 ;10 1116695

Lactate is useful for the efficient replication of porcine epidemic diarrhea virus in cell culture.

Nile Wuri, Hongchao Gou, Bin Zhang, Menglu Wang, Songqi Wang, Weixiao Zhang, Haiyan He, Xuelei Fan, Chunhong Zhang, Zhicheng Liu, Letu Geri, Haiyan Shen, Jianfeng Zhang.

  Porcine epidemic diarrhea virus (PEDV) is a deadly pathogen infecting pig herds, and has caused significant economic losses around the world. Vaccination remains the most effective way of keeping the PEDV epidemic under control. Previous studies have shown that the host metabolism has a significant impact on viral replication. In this study, we have demonstrated that two substrates of metabolic pathway, glucose and glutamine, play a key role in PEDV replication. Interestingly, the boosting effect of these compounds toward viral replication appeared to be dose-independent. Furthermore, we found that lactate, which is a downstream metabolite, promotes PEDV replication, even when added in excess to the cell culture medium. Moreover, the role of lactate in promoting PEDV was independent of the genotype of PEDV and the multiplicity of infection (MOI). Our findings suggest that lactate is a promising candidate for use as a cell culture additive for promoting PEDV replication. It could improve the efficiency of vaccine production and provide the basis for designing novel antiviral strategies.

Keywords:  glucose; glutamine; lactate; metabolites; porcine epidemic diarrhea virus

DOI:  https://doi.org/10.3389/fvets.2023.1116695
Viruses. 2023 Feb 16. pii: 547. [Epub ahead of print]15(2):

Recent Developments in Glioblastoma Therapy: Oncolytic Viruses and Emerging Future Strategies.

Azzam Hamad, Gaukhar M Yusubalieva, Vladimir P Baklaushev, Peter M Chumakov, Anastasiya V Lipatova.

  Glioblastoma is the most aggressive form of malignant brain tumor. Standard treatment protocols and traditional immunotherapy are poorly effective as they do not significantly increase the long-term survival of glioblastoma patients. Oncolytic viruses (OVs) may be an effective alternative approach. Combining OVs with some modern treatment options may also provide significant benefits for glioblastoma patients. Here we review virotherapy for glioblastomas and describe several OVs and their combination with other therapies. The personalized use of OVs and their combination with other treatment options would become a significant area of research aiming to develop the most effective treatment regimens for glioblastomas.

Keywords:  CAR T; cancer immunotherapy; glioblastoma; immunotherapy; nanoparticles; oncolytic viruses; poliovirus; proteomics; recombinant strain; viral vector

DOI:  https://doi.org/10.3390/v15020547
Viruses. 2023 Jan 28. pii: 369. [Epub ahead of print]15(2):

Modulation of the Aryl Hydrocarbon Receptor Signaling Pathway Impacts on Junín Virus Replication.

Miguel Angel Pelaez, María Florencia Torti, Aaron Ezequiel Alvarez De Lauro, Agostina Belén Marquez, Federico Giovannoni, Elsa Beatriz Damonte, Cybele Carina García.

  Junín virus (JUNV), a member of the family Arenaviridae, is the etiological agent of the Argentine hemorrhagic fever, an endemic disease in the rural region of Argentina lacking a specific chemotherapy. Aryl hydrocarbon receptor (AHR) is expressed in several mammalian tissues and has been indicated as a sensor of ligands from variable sources and a modulator of the cell immune response. Interestingly, recent studies have suggested that the activation or depression of the AHR signaling pathway may play a role in the outcome of diverse human viral infections. In the present report, the effect of the pharmacological modulation of AHR on JUNV in vitro infection was analyzed. An initial microarray screening showed that the AHR pathway was overexpressed in JUNV-infected hepatic cells. Concomitantly, the infection of Vero and Huh-7 cells with the JUNV strains IV4454 and Candid#1 was significantly inhibited in a dose-dependent manner by treatment with CH223191, a specific AHR antagonist, as detected by infectivity assays, real-time RT-PCR and immunofluorescence detection of viral proteins. Furthermore, the pro-viral role of AHR in JUNV infection appears to be independent of the IFN-I pathway. Our findings support the promising perspectives of the pharmacological modulation of AHR as a potential target for the control of AHF.

Keywords:  Argentine hemorrhagic fever; Junín virus; arenavirus; aryl hydrocarbon receptor; host therapeutic target

DOI:  https://doi.org/10.3390/v15020369
Viruses. 2023 Feb 13. pii: 525. [Epub ahead of print]15(2):

Immunometabolic Signature during Respiratory Viral Infection: A Potential Target for Host-Directed Therapies.

Larissa Menezes Dos Reis, Marcelo Rodrigues Berçot, Bianca Gazieri Castelucci, Ana Julia Estumano Martins, Gisele Castro, Pedro M Moraes-Vieira.

  RNA viruses are known to induce a wide variety of respiratory tract illnesses, from simple colds to the latest coronavirus pandemic, causing effects on public health and the economy worldwide. Influenza virus (IV), parainfluenza virus (PIV), metapneumovirus (MPV), respiratory syncytial virus (RSV), rhinovirus (RhV), and coronavirus (CoV) are some of the most notable RNA viruses. Despite efforts, due to the high mutation rate, there are still no effective and scalable treatments that accompany the rapid emergence of new diseases associated with respiratory RNA viruses. Host-directed therapies have been applied to combat RNA virus infections by interfering with host cell factors that enhance the ability of immune cells to respond against those pathogens. The reprogramming of immune cell metabolism has recently emerged as a central mechanism in orchestrated immunity against respiratory viruses. Therefore, understanding the metabolic signature of immune cells during virus infection may be a promising tool for developing host-directed therapies. In this review, we revisit recent findings on the immunometabolic modulation in response to infection and discuss how these metabolic pathways may be used as targets for new therapies to combat illnesses caused by respiratory RNA viruses.

Keywords:  RNA viruses; host-directed therapies; immune responses; immunometabolism; inflammation; respiratory viruses

DOI:  https://doi.org/10.3390/v15020525
J Leukoc Biol. 2023 Feb 27. pii: qiad018. [Epub ahead of print]

Metabolic regulation of NK cell antiviral functions during cytomegalovirus infection.

Maria Cimpean, Megan A Cooper.

  Natural killer (NK) cells quickly mount cytotoxic responses, produce cytokines, and proliferate in response to infected or transformed cells. Moreover, they can develop memory, with enhanced effector responses following activation, in some cases with antigen-specificity. To optimally execute these functions, NK cells undergo metabolic reprogramming. Here, we discuss the interplay between metabolism and NK cell function in the context of viral infections. We review findings supporting metabolic regulation of NK cell effector functions, with a focus on NK cell antiviral infection in the context of cytomegalovirus in the mouse (MCMV) and human (HCMV).

Keywords:  cytokines; cytomegalovirus infection; cytotoxicity; interferon gamma; memory; metabolism; natural killer cells; proliferation

DOI:  https://doi.org/10.1093/jleuko/qiad018
Viruses. 2023 Jan 29. pii: 386. [Epub ahead of print]15(2):

Retroviral Infection and Commensal Bacteria Dependently Alter the Metabolomic Profile in a Sterile Organ.

Jessica Spring, Vera Beilinson, Brian C DeFelice, Juan M Sanchez, Michael Fischbach, Alexander Chervonsky, Tatyana Golovkina.

  Both viruses and bacteria produce "pathogen associated molecular patterns" that may affect microbial pathogenesis and anti-microbial responses. Additionally, bacteria produce metabolites, while viruses could change the metabolic profiles of the infected cells. Here, we used an unbiased metabolomics approach to profile metabolites in spleens and blood of murine leukemia virus-infected mice monocolonized with Lactobacillus murinus to show that viral infection significantly changes the metabolite profile of monocolonized mice. We hypothesize that these changes could contribute to viral pathogenesis or to the host response against the virus and thus open a new avenue for future investigations.

Keywords:  commensal bacteria; metabolites; microbiota; retroviruses

DOI:  https://doi.org/10.3390/v15020386
Viruses. 2023 Feb 07. pii: 464. [Epub ahead of print]15(2):

Global Lipidome Profiling Revealed Multifaceted Role of Lipid Species in Hepatitis C Virus Replication, Assembly, and Host Antiviral Response.

Khursheed Ul Islam, Saleem Anwar, Ayyub A Patel, Mohammed Tarek Mirdad, Mahmoud Tarek Mirdad, Md Iqbal Azmi, Tanveer Ahmad, Zeeshan Fatima, Jawed Iqbal.

  Hepatitis C virus (HCV) is a major human pathogen that requires a better understanding of its interaction with host cells. There is a close association of HCV life cycle with host lipid metabolism. Lipid droplets (LDs) have been found to be crucial organelles that support HCV replication and virion assembly. In addition to their role in replication, LDs also have protein-mediated antiviral properties that are activated during HCV infection. Studies have shown that HCV replicates well in cholesterol and sphingolipid-rich membranes, but the ways in which HCV alters host cell lipid dynamics are not yet known. In this study, we performed a kinetic study to check the enrichment of LDs at different time points of HCV infection. Based on the LD enrichment results, we selected early and later time points of HCV infection for global lipidomic study. Early infection represents the window period for HCV sensing and host immune response while later infection represents the establishment of viral RNA replication, virion assembly, and egress. We identified the dynamic profile of lipid species at early and later time points of HCV infection by global lipidomic study using mass spectrometry. At early HCV infection, phosphatidylinositol phospholipids (PIPs), lysophosphatidic acid (LPA), triacyl glycerols (TAG), phosphatidylcholine (PC), and trihexosylceramides (Hex3Cer) were observed to be enriched. Similarly, free fatty acids (FFA), phosphatidylethanolamine (PE), N-acylphosphatidylethanolamines (NAPE), and tri acylglycerols were enriched at later time points of HCV infection. Lipids enriched at early time of infection may have role in HCV sensing, viral attachment, and immune response as LPA and PIPs are important for immune response and viral attachment, respectively. Moreover, lipid species observed at later infection may contribute to HCV replication and virion assembly as PE, FFA, and triacylglycerols are known for the similar function. In conclusion, we identified lipid species that exhibited dynamic profile across early and later time points of HCV infection compared to mock cells, which could be therapeutically relevant in the design of more specific and effective anti-viral therapies.

Keywords:  antiviral response; fatty acids; glycerolipids; glycerophospholipids; hepatitis C virus; lipidome

DOI:  https://doi.org/10.3390/v15020464
Vaccines (Basel). 2023 Jan 19. pii: 218. [Epub ahead of print]11(2):

Myeloid-Derived Suppressor Cells in Cancer and COVID-19 as Associated with Oxidative Stress.

Celia María Curieses Andrés, José Manuel Pérez de la Lastra, Celia Andrés Juan, Francisco J Plou, Eduardo Pérez-Lebeña.

  Myeloid-derived suppressor cells MDSCs are a heterogeneous population of cells that expand beyond their physiological regulation during pathologies such as cancer, inflammation, bacterial, and viral infections. Their key feature is their remarkable ability to suppress T cell and natural killer NK cell responses. Certain risk factors for severe COVID-19 disease, such as obesity and diabetes, are associated with oxidative stress. The resulting inflammation and oxidative stress can negatively impact the host. Similarly, cancer cells exhibit a sustained increase in intrinsic ROS generation that maintains the oncogenic phenotype and drives tumor progression. By disrupting endoplasmic reticulum calcium channels, intracellular ROS accumulation can disrupt protein folding and ultimately lead to proteostasis failure. In cancer and COVID-19, MDSCs consist of the same two subtypes (PMN-MSDC and M-MDSC). While the main role of polymorphonuclear MDSCs is to dampen the response of T cells and NK killer cells, they also produce reactive oxygen species ROS and reactive nitrogen species RNS. We here review the origin of MDSCs, their expansion mechanisms, and their suppressive functions in the context of cancer and COVID-19 associated with the presence of superoxide anion •O2- and reactive oxygen species ROS.

Keywords:  COVID-19; RNS and RHS; ROS; antimicrobial; cancer; innate immunity; myeloid-derived suppressor cells; reactive species

DOI:  https://doi.org/10.3390/vaccines11020218
Viruses. 2023 Feb 07. pii: 466. [Epub ahead of print]15(2):

Viral Hemorrhagic Septicemia Virus Activates Integrated Stress Response Pathway and Induces Stress Granules to Regulate Virus Replication.

Barkha Ramnani, Shelby Powell, Adarsh G Shetty, Praveen Manivannan, Brian R Hibbard, Douglas W Leaman, Krishnamurthy Malathi.

  Virus infection activates integrated stress response (ISR) and stress granule (SG) formation and viruses counteract by interfering with SG assembly, suggesting an important role in antiviral defense. The infection of fish cells by Viral Hemorrhagic Septicemia Virus (VHSV), activates the innate immune recognition pathway and the production of type I interferon (IFN). However, the mechanisms by which VHSV interacts with ISR pathway regulating SG formation is poorly understood. Here, we demonstrate that fish cells respond to heat shock, oxidative stress and VHSV infection by forming SG that localized key SG marker, Ras GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1). We show that PKR-like endoplasmic reticulum kinase (PERK), but not (dsRNA)-dependent protein kinase (PKR), is required for VHSV-induced SG formation. Furthermore, in VHSV Ia infected cells, PERK activity is required for IFN production, antiviral signaling and viral replication. SG formation required active virus replication as individual VHSV Ia proteins or inactive virus did not induce SG. Cells lacking G3BP1 produced increased IFN, antiviral genes and viral mRNA, however viral protein synthesis and viral titers were reduced. We show a critical role of the activation of ISR pathway and SG formation highlighting a novel role of G3BP1 in regulating VHSV protein translation and replication.

Keywords:  G3BP1; PERK; VHSV; eIF2α phosphorylation; interferon; stress granule; translation

DOI:  https://doi.org/10.3390/v15020466
Int J Biol Macromol. 2023 Feb 25. pii: S0141-8130(23)00728-6. [Epub ahead of print]235 123834

Reactive oxygen species-mediated phosphorylation of JNK is involved in the regulation of BmFerHCH on Bombyx mori nucleopolyhedrovirus proliferation.

Ying-Xue Liu, Jia-Yue Yang, Jun-Long Sun, An-Cheng Wang, Xing-Ya Wang, Lin-Bao Zhu, Hui-Hua Cao, Zhi-Hao Huang, Shi-Huo Liu, Jia-Ping Xu.

  c-Jun N-terminal kinase (JNK) phosphorylation is widely observed during virus infection, modulating various aspects of the virus-host interaction. In our previous research, we have proved that B. mori ferritin heavy-chain homolog (BmFerHCH), an inhibitor of reactive oxygen species (ROS), facilitates B. mori nucleopolyhedrovirus (BmNPV) proliferation. However, one question remains: Which downstream signaling pathways does BmFerHCH regulate by inhibiting ROS? Here, we first determined that silencing BmFerHCH inhibits BmNPV proliferation, and this inhibition depends on ROS. Then, we substantiated that BmNPV infection activates the JNK signaling pathway. Interestingly, the JNK phosphorylation during BmNPV infection is activated by ROS. Further, we found that the enhanced nuclear translocation of phospho-JNK induced by BmNPV infection was dramatically reduced by pretreatment with the antioxidant N-acetylcysteine (NAC), whereas there was more detectable phospho-JNK in the cytoplasm. Next, we investigated how changes in BmFerHCH expression affect JNK phosphorylation. BmFerHCH overexpression suppressed the phosphorylation of JNK and nuclear translocation of phospho-JNK during BmNPV infection, whereas BmFerHCH knockdown facilitated phosphorylation of JNK and nuclear translocation of phospho-JNK. By measuring the viral load, we found the inhibitory effect of BmFerHCH knockdown on BmNPV infection depends on phosphorylated JNK. In addition, the JNK signaling pathway was involved in BmNPV-triggered apoptosis. Hence, we hypothesize that ROS-mediated JNK phosphorylation is involved in the regulation of BmFerHCH on BmNPV proliferation. These results elucidate the molecular mechanisms and signaling pathways of BmFerHCH-mediated response to BmNPV infection.

Keywords:  BmNPV; Bombyx mori; Ferritin heavy-chain homolog; JNK phosphorylation; ROS

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.123834
Autophagy. 2023 Mar 02. 1-15

N protein of PEDV plays chess game with host proteins by selective autophagy.

Xueying Zhai, Ning Kong, Yu Zhang, Yiyi Song, Wenzhen Qin, Xinyu Yang, Chenqian Ye, Manqing Ye, Wu Tong, Changlong Liu, Hao Zheng, Hai Yu, Wen Zhang, Xia Yang, Gaiping Zhang, Guangzhi Tong, Tongling Shan.

  Macroautophagy/autophagy is a cellular degradation and recycling process that maintains the homeostasis of organisms. The protein degradation role of autophagy has been widely used to control viral infection at multiple levels. In the ongoing evolutionary arms race, viruses have developed various ways to hijack and subvert autophagy in favor of its replication. It is still unclear exactly how autophagy affects or inhibits viruses. In this study, we have found a novel host restriction factor, HNRNPA1, that could inhibit PEDV replication by degrading viral nucleocapsid (N) protein. The restriction factor activates the HNRNPA1-MARCHF8/MARCH8-CALCOCO2/NDP52-autophagosome pathway with the help of transcription factor EGR1 targeting the HNRNPA1 promoter. HNRNPA1 could also promote the expression of IFN to facilitate the host antiviral defense response for antagonizing PEDV infection through RIGI protein interaction. During viral replication, we found that PEDV can, in contrast, degrade the host antiviral proteins HNRNPA1 and others (FUBP3, HNRNPK, PTBP1, and TARDBP) through its N protein through the autophagy pathway. These results reveal the dual function of selective autophagy in PEDV N and host proteins, which could promote the ubiquitination of viral particles and host antiviral proteins and degradation both of the proteins to regulate the relationship between virus infection and host innate immunity.Abbreviations: 3-MA: 3-methyladenine; ATG: autophagy related; Baf A1: bafilomycin A1; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; ChIP: chromatin immunoprecipitation; Co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; GPI: glycosyl-phosphatidylinositol; hpi: hours post infection; MARCHF8/MARCH8: membrane-associated ring-CH-type finger 8; MOI: multiplicity of infection; N protein: nucleocapsid protein; PEDV: porcine epidemic diarrhea virus; siRNA: small interfering RNA; TCID50: 50% tissue culture infectious doses.

Keywords:  HNRNPA1; IFN; PEDV; nucleocapsid protein; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2023.2181615
Antiviral Res. 2023 Feb 28. pii: S0166-3542(23)00048-7. [Epub ahead of print] 105570

Pinosrtobin from plants and propolis against human coronavirus HCoV-OC43 by modulating host AHR/CYP1A1 pathway and lipid metabolism.

Liyun Zhao, Liyuan Yao, Rui Chen, Jiani He, Tingting Lin, Silin Qiu, Guohua Chen, Hongfeng Chen, Sheng-Xiang Qiu.

Coronaviruses, as enveloped positive-strand RNA viruses, manipulate host lipid compositions to enable robust viral replication. Temporal modulation of the host lipid metabolism is a potential novel strategy against coronaviruses. Here, the dihydroxyflavone pinostrobin (PSB) was identified through bioassay that inhibited the increment of human coronavirus OC43 (HCoV-OC43) in human ileocecal colorectal adenocarcinoma cells. Lipid metabolomic studies showed that PSB interfered with linoleic acid and arachidonic acid metabolism pathways. PSB significantly decreased the level of 12, 13- epoxyoctadecenoic (12, 13-EpOME) and increased the level of prostaglandin E2. Interestingly, exogenous supplement of 12, 13-EpOME in HCoV-OC43-infected cells significantly stimulated HCoV-OC43 virus replication. Transcriptomic analyses showed that PSB is a negative modulator of aryl hydrocarbon receptor (AHR)/cytochrome P450 (CYP) 1A1signaling pathway and its antiviral effects can be counteracted by supplement of FICZ, a well-known AHR agonist. Integrative analyses of metabolomic and transcriptomic indicated that PSB could affect linoleic acid and arachidonic acid metabolism axis through AHR/CYP1A1 pathway. These results high light the importance of the AHR/CYP1A1 pathway and lipid metabolism in the anti-coronavirus activity of the bioflavonoid PSB.

DOI: https://doi.org/10.1016/j.antiviral.2023.105570
Neurochem Res. 2023 Mar 01.

Japanese Encephalitis Virus Infection Causes an Imbalance in the Activation of Mitochondrial Fusion/Fission Genes and Triggers the Activation of NOX2-mediated Oxidative Stress and Neuronal Cell Death.

Gajendra Singh, Alok Kumar.

  Mitochondria dysfunction may be an important contributor to Japanese encephalitis (JE) viral infection disease pathogenesis. In the current study, we define whether changes in mitochondrial DNA copy number (which is the biomarker for mitochondrial function) and alteration in mitochondria dynamics (fusion and fission) contribute to the pathology of the JE virus in vivo mice model. We found decreased mitochondria copy number, reduced activation of mitochondrial fission (FIS1/DRP1), and increased activation of mitochondrial fusion (MFN1/MFN2/OPA1) genes that are associated with increased NOX2-mediated ROS generation and neuronal cell death following JE virus infection. Furthermore, we found that antioxidant glutathione level decreases. In summary, the following study demonstrates that JE viral infection causes an imbalance in mitochondrial fission/fusion gene activation and promotes NOX2-mediated oxidative stress and cell death, suggesting that intervention in mitochondrial dynamics might be a potential therapeutic strategy for combating oxidative stress and inflammatory process in JE viral infection.

Keywords:  JE viral infection; Mitochondria copy number; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion

DOI:  https://doi.org/10.1007/s11064-023-03898-9
Toxicol Sci. 2023 Feb 27. pii: kfad019. [Epub ahead of print]

Postnatal administration of S-adenosylmethionine restores developmental AHR activation-induced deficits in CD8+ T cell function during influenza A virus infection.

Christina M Post, Jason R Myers, Bethany Winans, B Paige Lawrence.

Developmental exposures can influence life-long health; yet, counteracting negative consequences is challenging due to poor understanding of cellular mechanisms. The aryl hydrocarbon receptor (AHR) binds many small molecules, including numerous pollutants. Developmental exposure to the signature environmental AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly dampens adaptive immune responses to influenza A virus (IAV) in adult offspring. CD8+ cytotoxic T lymphocytes (CTL) are crucial for successful infection resolution, which depends on the number generated and the complexity of their functionality. Prior studies showed developmental AHR activation significantly reduced the number of virus-specific CD8+ T cells, but impact on their functions is less clear. Other studies showed developmental exposure was associated with differences in DNA methylation in CD8+ T cells. Yet, empirical evidence that differences in DNA methylation are causally related to altered CD8+ T cell function is lacking. The two objectives were to ascertain whether developmental AHR activation affects CTL function, and whether differences in methylation contribute to reduced CD8+ T cell responses to infection. Developmental AHR triggering significantly reduced CTL polyfunctionality, and modified the transcriptional program of CD8+ T cells. S-adenosylmethionine (SAM), which increases DNA methylation, but not Zebularine, which diminishes DNA methylation, restored polyfunctionality and boosted the number of virus-specific CD8+ T cells. These findings suggest that diminished methylation, initiated by developmental exposure to an AHR-binding chemical, contributes to durable changes in antiviral CD8+ CTL functions later in life. Thus, deleterious consequence of development exposure to environmental chemicals are not permanently fixed, opening the door for interventional strategies to improve health.

DOI: https://doi.org/10.1093/toxsci/kfad019
Front Immunol. 2022 ;13 1032113

Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection.

Shohei Harabuchi, Omar Khan, Hamid Bassiri, Taku Yoshida, Yohei Okada, Masaomi Takizawa, Osamu Ikeda, Akihiro Katada, Taku Kambayashi.

  Introduction: Activation of T cell receptor (TCR) signaling is critical for clonal expansion of CD8+ T cells. However, the effects of augmenting TCR signaling during chronic antigen exposure is less understood. Here, we investigated the role of diacylglycerol (DAG)-mediated signaling downstream of the TCR during chronic lymphocytic choriomeningitis virus clone 13 (LCMV CL13) infection by blocking DAG kinase zeta (DGKζ), a negative regulator of DAG.Methods: We examined the activation, survival, expansion, and phenotype of virus-specific T cell in the acute and chronic phases of LCMV CL13-infected in mice after DGKζ blockade or selective activation of ERK.
Results: Upon LCMV CL13 infection, DGKζ deficiency promoted early short-lived effector cell (SLEC) differentiation of LCMV-specific CD8+ T cells, but this was followed by abrupt cell death. Short-term inhibition of DGKζ with ASP1570, a DGKζ-selective pharmacological inhibitor, augmented CD8+ T cell activation without causing cell death, which reduced virus titers both in the acute and chronic phases of LCMV CL13 infection. Unexpectedly, the selective enhancement of ERK, one key signaling pathway downstream of DAG, lowered viral titers and promoted expansion, survival, and a memory phenotype of LCMV-specific CD8+ T cells in the acute phase with fewer exhausted T cells in the chronic phase. The difference seen between DGKζ deficiency and selective ERK enhancement could be potentially explained by the activation of the AKT/mTOR pathway by DGKζ deficiency, since the mTOR inhibitor rapamycin rescued the abrupt cell death seen in virus-specific DGKζ KO CD8+ T cells.
Discussion: Thus, while ERK is downstream of DAG signaling, the two pathways lead to distinct outcomes in the context of chronic CD8+ T cell activation, whereby DAG promotes SLEC differentiation and ERK promotes a memory phenotype.

Keywords:  ERK (extracellular signal-regulated kinase); T cell exhaustion; TCR T cell receptor; chronic viral infection; diacylglycerol kinase (DGK)

DOI:  https://doi.org/10.3389/fimmu.2022.1032113