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Frontiers in Immunology 2023Cellular metabolism plays a central role in the regulation of both innate and adaptive immunity. Immune cells utilize metabolic pathways to modulate the cellular... (Review)
Review
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.
Topics: Humans; Antiviral Agents; Viruses; Metabolic Networks and Pathways; Immunity; Virus Diseases
PubMed: 37559723
DOI: 10.3389/fimmu.2023.1228811 -
Frontiers in Immunology 2023The severity of COVID-19 is associated with an elevated level of a variety of inflammatory mediators. Increasing evidence suggests that the Th17 response contributes to...
BACKGROUND
The severity of COVID-19 is associated with an elevated level of a variety of inflammatory mediators. Increasing evidence suggests that the Th17 response contributes to the severity of COVID-19 pneumonia, whereas Th22 response plays a regulatory role in SARS-CoV-2 infection. Two main types of available COVID-19 treatments are antivirals and immunomodulatory drugs; however, their effect on a cytokine profile is yet to be determined.
METHODS
This study aim to analyse a cytokine profile in peripheral blood from patients with COVID-19 (n=44) undergoing antiviral or/and immunomodulatory treatment and healthy controls (n=20). Circulating CD4+ and CD8+ T cells and their intracellular expression of IL-17A and IL-22 were assessed by flow cytometry.
RESULTS
Initial results showed an overexpression of IL-17F, IL-17A, CCL5/RANTES, GM-CSF, IL-4, IL-10, CXCL-10/IP-10 and IL-6 in COVID-19 patients compared to healthy controls. Treatment with remdesivir resulted in a significant decline in concentrations of IL-6, IL-10, IFN-alpha and CXCL10/IP-10. Immunomodulatory treatment contributed to a significant downregulation of IL-10, IFN-alpha, CXCL10/IP-10 and B7-H3 as well as upregulation of IL-22 and IL-1 beta. A combination of an antiviral and immunomodulatory treatment resulted in a significant decrease in IL-17F, IL-10, IFN-alpha, CXCL10/IP-10 and B7-H3 levels as well as an increase in IL-17A and IL-1 beta. We found significantly higher percentage of both CD4+ and CD8+ T cells producing IL-17A and CD4+ T cells producing IL-22 in patients with COVID-19.
CONCLUSION
Administration of antiviral or/and immunomodulatory treatment resulted in a significant downregulation of pro-inflammatory cytokine expression and an upregulation of T cell absolute counts in most cases, thus showing effectiveness of treatment in COVID-19. SARS-CoV-2 infection induced cytokine overexpression in hospitalized patients with COVID-19 as well as lymphopenia, particularly a decrease in CD4+ and CD8+ T cell counts. Moreover, despite the reduced counts of CD4+ and CD8+ T cells, both subsets showed overactivation and increased expression of IL-17A and IL-22, thus targeting Th17 response might alleviate inflammatory response in severe disease.
Topics: Antiviral Agents; Immunomodulating Agents; Humans; COVID-19; Case-Control Studies; Cytokines; Interleukin-17; Interleukins; Male; Female; Middle Aged; Aged; Interleukin-22
PubMed: 37483627
DOI: 10.3389/fimmu.2023.1222170 -
European Journal of Medicinal Chemistry Oct 2023The major severe complications linked to Zika virus (ZIKV) cause the global public health problems, including microcephaly and other congenital abnormalities in...
The major severe complications linked to Zika virus (ZIKV) cause the global public health problems, including microcephaly and other congenital abnormalities in newborns, and Guillain-Barré syndrome, meningoencephalitis, multi-organ failure in adults. However, neither approved vaccines nor drugs are available for ZIKV. In this study, we describe the design, synthesis and the anti-ZIKV activities of a series of anthraquinone analogs. Most of the newly synthesized compounds demonstrated moderate to excellent potency against ZIKV. Among all, compound 22, showed the most potent anti-ZIKV activity (EC value from 1.33 μM to 5.72 μM) with low cytotoxicity (CC>50 μM) in multiple cellular model. Importantly, 22 significantly improved the survival of ZIKV-infected mice (Ifnar1), alleviated ZIKV-associated pathological damages and suppressed the excessive inflammatory response and pyroptosis induced by ZIKV in vivo and in vitro. Furthermore, the molecular docking simulation analysis and the surface plasmon resonance results demonstrated the direct binding between 22 and ZIKV RdRp, and the mechanistic study revealed that 22 suppressed viral RNA synthesis by ZIKV NS5 in cells. Taken together, this study highlights that 22 may be a novel anti-ZIKV drug candidate and provides treatment options for ZIKV-associated diseases.
Topics: Animals; Mice; Zika Virus; Antiviral Agents; Molecular Docking Simulation; Virus Replication; Zika Virus Infection
PubMed: 37421888
DOI: 10.1016/j.ejmech.2023.115620 -
Frontiers in Immunology 2023Human Immunodeficiency Virus (HIV) has plagued human society for a long time since its discovery, causing a large number of patients to suffer and costing hundreds of... (Review)
Review
Human Immunodeficiency Virus (HIV) has plagued human society for a long time since its discovery, causing a large number of patients to suffer and costing hundreds of millions of medical services every year. Scientists have found that HIV and antiretroviral therapy accelerate immune aging by inducing mitochondrial dysfunction, and that terminal effector memory T cells (TEMRA cells) are crucial in immune aging. This specific subset of effector memory T cells has terminally differentiated properties and exhibits high cytotoxicity and proinflammatory capacity. We therefore explored and described the interplay between exhaustion features, essential markers, functions, and signaling pathways from previous studies on HIV, antiretroviral therapy, immune senescence, and TEMRA cells. Their remarkable antiviral capacity is then highlighted by elucidating phenotypic changes in TEMRA cells during HIV infection, describing changes in TEMRA cells before, during, and after antiretroviral therapy and other drug treatments. Their critical role in complications and cytomegalovirus (CMV)-HIV superinfection is highlighted. These studies demonstrate that TEMRA cells play a key role in the antiviral response and immune senescence during HIV infection. Finally, we review current therapeutic strategies targeting TEMRA cells that may be clinically beneficial, highlight their potential role in HIV-1 vaccine development, and provide perspectives and predictions for related future applications.
Topics: Humans; HIV Infections; CD8-Positive T-Lymphocytes; Cellular Senescence; Cell Differentiation; Antiviral Agents
PubMed: 37901239
DOI: 10.3389/fimmu.2023.1284293 -
International Journal of Infectious... Sep 2023We analyzed the expression of inflammatory and antiviral genes in the nasopharynx of SARS-CoV-2 infected patients and their association with the severity of COVID-19...
OBJECTIVES
We analyzed the expression of inflammatory and antiviral genes in the nasopharynx of SARS-CoV-2 infected patients and their association with the severity of COVID-19 pneumonia.
METHODS
We conducted a cross-sectional study on 223 SARS-CoV-2 infected patients. Clinical data were collected from medical records, and nasopharyngeal samples were collected in the first 24 hours after admission to the emergency room. The gene expression of eight proinflammatory/antiviral genes (plasminogen activator urokinase receptor [PLAUR], interleukin [IL]-6, IL-8, interferon [IFN]-β, IFN-stimulated gene 15 [ISG15], retinoic acid-inducible gene I [RIG-I], C-C motif ligand 5 [CCL5], and chemokine C-X-C motif ligand 10 [CXCL10]) were quantified by real-time polymerase chain reaction. Outcome variables were: (i) pneumonia; (ii) severe pneumonia or acute respiratory distress syndrome. Statistical analysis was performed using multivariate logistic regression analyses.
RESULTS
We enrolled 84 mild, 88 moderate, and 51 severe/critical cases. High expression of PLAUR (adjusted odds ratio [aOR] = 1.25; P = 0.032, risk factor) and low expression of CXCL10 (aOR = 0.89; P = 0.048, protective factor) were associated with pneumonia. Furthermore, lower values of ISG15 (aOR = 0.88, P = 0.021), RIG-I (aOR = 0.87, P = 0.034), CCL5 (aOR = 0.73, P <0.001), and CXCL10 (aOR = 0.84, P = 0.002) were risk factors for severe pneumonia/acute respiratory distress syndrome.
CONCLUSION
An unbalanced early innate immune response to SARS-CoV-2 in the nasopharynx, characterized by high expression of PLAUR and low expression of antiviral genes (ISG15 and RIG-I), and chemokines (CCL5 and CXCL10), was associated with COVID-19 severity.
Topics: Humans; COVID-19; SARS-CoV-2; Cross-Sectional Studies; Ligands; Chemokines; Antiviral Agents; Immunity, Innate; Pneumonia; Interleukin-6; Respiratory Distress Syndrome; Nasopharynx
PubMed: 37290572
DOI: 10.1016/j.ijid.2023.06.001 -
Journal of Biomedical Science Oct 2023RNA has emerged as a revolutionary and important tool in the battle against emerging infectious diseases, with roles extending beyond its applications in vaccines, in... (Review)
Review
RNA has emerged as a revolutionary and important tool in the battle against emerging infectious diseases, with roles extending beyond its applications in vaccines, in which it is used in the response to the COVID-19 pandemic. Since their development in the 1990s, RNA interference (RNAi) therapeutics have demonstrated potential in reducing the expression of disease-associated genes. Nucleic acid-based therapeutics, including RNAi therapies, that degrade viral genomes and rapidly adapt to viral mutations, have emerged as alternative treatments. RNAi is a robust technique frequently employed to selectively suppress gene expression in a sequence-specific manner. The swift adaptability of nucleic acid-based therapeutics such as RNAi therapies endows them with a significant advantage over other antiviral medications. For example, small interfering RNAs (siRNAs) are produced on the basis of sequence complementarity to target and degrade viral RNA, a novel approach to combat viral infections. The precision of siRNAs in targeting and degrading viral RNA has led to the development of siRNA-based treatments for diverse diseases. However, despite the promising therapeutic benefits of siRNAs, several problems, including impaired long-term protein expression, siRNA instability, off-target effects, immunological responses, and drug resistance, have been considerable obstacles to the use of siRNA-based antiviral therapies. This review provides an encompassing summary of the siRNA-based therapeutic approaches against viruses while also addressing the obstacles that need to be overcome for their effective application. Furthermore, we present potential solutions to mitigate major challenges.
Topics: Humans; RNA, Small Interfering; Pandemics; COVID-19; RNA Interference; Viruses; Antiviral Agents; RNA, Viral
PubMed: 37845731
DOI: 10.1186/s12929-023-00981-9 -
Journal of Virology Jul 2023Pseudorabies virus (PRV), the causative pathogen of Aujeszky's disease, is one of the most important pathogens threatening the global pig industry. Although vaccination...
Pseudorabies virus (PRV), the causative pathogen of Aujeszky's disease, is one of the most important pathogens threatening the global pig industry. Although vaccination has been used to prevent PRV infection, the virus cannot be eliminated in pigs. Thus, novel antiviral agents as complementary to vaccination are urgently needed. Cathelicidins (CATHs) are host defense peptides that play an important role in the host immune response against microbial infections. In the study, we found that the chemical synthesized chicken cathelicidin B1 (CATH-B1) could inhibit PRV regardless of whether CATH-B1 was added pre-, co-, or post-PRV infection and . Furthermore, coincubation of CATH-B1 with PRV directly inactivated virus infection by disrupting the virion structure of PRV and mainly inhibited virus binding and entry. Importantly, pretreatment of CATH-B1 markedly strengthened the host antiviral immunity, as indicated by the increased expression of basal interferon-β (IFN-β) and several IFN-stimulated genes (ISGs). Subsequently, we investigated the signaling pathway responsible for CATH-B1-induced IFN-β production. Our results showed that CATH-B1 induced phosphorylation of interferon regulatory transcription factor 3 (IRF3) and further led to production of IFN-β and reduction of PRV infection. Mechanistic studies revealed that the activation of Toll-like receptor 4 (TLR4), endosome acidification, and the following c-Jun N-terminal kinase (JNK) was responsible for CATH-B1-induced IRF3/IFN-β pathway activation. Collectively, CATH-B1 could markedly inhibit PRV infection via inhibiting virus binding and entry, direct inactivation, and regulating host antiviral response, which provided an important theoretical basis for the development of antimicrobial peptide drugs against PRV infection. Although the antiviral activity of cathelicidins could be explained by direct interfering with the viral infection and regulating host antiviral response, the specific mechanism of cathelicidins regulating host antiviral response and interfering with pseudorabies virus (PRV) infection remains elusive. In this study, we investigated the multiple roles of cathelicidin CATH-B1 against PRV infection. Our study showed that CATH-B1 could suppress the binding and entry stages of PRV infection and direct disrupt PRV virions. Remarkably, CATH-B1 significantly increased basal interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression levels. Furthermore, TLR4/c-Jun N-terminal kinase (JNK) signaling was activated and involved in IRF3/IFN-β activation in response to CATH-B1. In conclusion, we elucidate the mechanisms by which the cathelicidin peptide direct inactivates PRV infection and regulates host antiviral IFN-β signaling.
Topics: Swine; Animals; Herpesvirus 1, Suid; Cathelicidins; Toll-Like Receptor 4; Interferon-beta; Antiviral Agents; Pseudorabies
PubMed: 37314341
DOI: 10.1128/jvi.00706-23 -
MBio Aug 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent causing the global pandemic of COVID-19. SARS-CoV-2 genome encodes a main protease (nsp5, also...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent causing the global pandemic of COVID-19. SARS-CoV-2 genome encodes a main protease (nsp5, also called Mpro) and a papain-like protease (nsp3, also called PLpro), which are responsible for processing viral polyproteins to assemble a functional replicase complex. In this study, we found that Mpro of SARS-CoV-2 can cleave human MAGED2 and other mammalian orthologs at Gln-263. Moreover, SARS-CoV and MERS-CoV Mpro can also cleave human MAGED2, suggesting MAGED2 cleavage by Mpro is an evolutionarily conserved mechanism of coronavirus infection in mammals. Intriguingly, Mpro from Beta variant cleaves MAGED2 more efficiently than wild type, but Omicron Mpro is opposite. Further studies show that MAGED2 inhibits SARS-CoV-2 infection at viral replication step. Mechanistically, MAGED2 is associated with SARS-CoV-2 nucleocapsid protein through its N-terminal region in an RNA-dependent manner, and this disrupts the interaction between SARS-CoV-2 nucleocapsid protein and viral genome, thus inhibiting viral replication. When MAGED2 is cleaved by Mpro, the N-terminal of MAGED2 will translocate into the nucleus, and the truncated MAGED2 is unable to suppress SARS-CoV-2 replication. This work not only discovers the antiviral function of MAGED2 but also provides new insights into how SARS-CoV-2 Mpro antagonizes host antiviral response. IMPORTANCE Host factors that restrict severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain elusive. Here, we found that MAGED2 can be cleaved by SARS-CoV-2 main protease (Mpro) at Gln-263. SARS-CoV and MERS-CoV Mpro can also cleave MAGED2, and MAGED2 from multiple species can be cleaved by SARS-CoV-2 Mpro. Mpro from Beta variant cleaves MAGED2 more efficiently efficiently than wild type, but Omicron is the opposite. MAGED2 depletion enhances SARS-CoV-2 infection, suggesting its inhibitory role in SARS-CoV-2 infection. Mechanistically, MAGED2 restricts SARS-CoV-2 replication by disrupting the interaction between nucleocapsid and viral genomes. When MAGED2 is cleaved, its N-terminal will translocate into the nucleus. In this way, Mpro relieves MAGED2' inhibition on viral replication. This study improves our understanding of complex viral-host interaction and provides novel targets to treat SARS-CoV-2 infection.
Topics: Animals; Humans; Antiviral Agents; SARS-CoV-2; COVID-19; Coronavirus 3C Proteases; Middle East Respiratory Syndrome Coronavirus; Nucleocapsid Proteins; Mammals; Antigens, Neoplasm; Adaptor Proteins, Signal Transducing
PubMed: 37439567
DOI: 10.1128/mbio.01373-23 -
Nature Communications Feb 2024Human cytomegalovirus (HCMV) is a widespread pathogen that in immunocompromised hosts can cause life-threatening disease. Studying HCMV-exposed monocyte-derived...
Human cytomegalovirus (HCMV) is a widespread pathogen that in immunocompromised hosts can cause life-threatening disease. Studying HCMV-exposed monocyte-derived dendritic cells by single-cell RNA sequencing, we observe that most cells are entered by the virus, whereas less than 30% of them initiate viral gene expression. Increased viral gene expression is associated with activation of the stimulator of interferon genes (STING) that usually induces anti-viral interferon responses, and with the induction of several pro- (RHOB, HSP1A1, DNAJB1) and anti-viral (RNF213, TNFSF10, IFI16) genes. Upon progression of infection, interferon-beta but not interferon-lambda transcription is inhibited. Similarly, interferon-stimulated gene expression is initially induced and then shut off, thus further promoting productive infection. Monocyte-derived dendritic cells are composed of 3 subsets, with one being especially susceptible to HCMV. In conclusion, HCMV permissiveness of monocyte-derived dendritic cells depends on complex interactions between virus sensing, regulation of the interferon response, and viral gene expression.
Topics: Humans; Cytomegalovirus; Interferons; Signal Transduction; Antiviral Agents; Dendritic Cells; HSP40 Heat-Shock Proteins; Adenosine Triphosphatases; Ubiquitin-Protein Ligases
PubMed: 38409141
DOI: 10.1038/s41467-024-45614-3 -
Viruses Sep 2023(1) Background: Epigallocatechin gallate (EGCG) has been recognized as a flavonoid showing antiviral activity against various types of DNA and RNA viruses. In this work,...
(1) Background: Epigallocatechin gallate (EGCG) has been recognized as a flavonoid showing antiviral activity against various types of DNA and RNA viruses. In this work, we tested if EGCG-modified silver nanoparticles (EGCG-AgNPs) can become novel microbicides with additional adjuvant properties to treat herpes infections. (2) Methods: The anti-HSV and cytotoxic activities of EGCG-AgNPs were tested in human HaCaT and VK-2-E6/E7 keratinocytes. HSV-1/2 titers and immune responses after treatment with EGCG-AgNPs were tested in murine models of intranasal HSV-1 infection and genital HSV-2 infection. (3) Results: EGCG-AgNPs inhibited attachment and entry of HSV-1 and HSV-2 in human HaCaT and VK-2-E6/E7 keratinocytes much better than EGCG at the same concentration. Infected mice treated intranasally (HSV-1) or intravaginally (HSV-2) with EGCG-AgNPs showed lower virus titers in comparison to treatment with EGCG alone. After EGCG-AgNPs treatment, mucosal tissues showed a significant infiltration in dendritic cells and monocytes in comparison to NaCl-treated group, followed by significantly better infiltration of CD8+ T cells, NK cells and increased expression of IFN-α, IFN-γ, CXCL9 and CXCL10. (4) Conclusions: Our findings show that EGCG-AgNPs can become an effective novel antiviral microbicide with adjuvant properties to be applied upon the mucosal tissues.
Topics: Animals; Humans; Mice; Silver; Metal Nanoparticles; Herpes Simplex; Herpes Genitalis; Herpesvirus 2, Human; Herpesvirus 1, Human; Antiviral Agents
PubMed: 37896801
DOI: 10.3390/v15102024