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1.
Int J Mol Sci ; 24(2)2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36675232

RESUMO

Despite recent advances in oncology, cancer has remained an enormous global health burden, accounting for about 10 million deaths in 2020. A third of the cancer cases in developing counties are caused by microbial infections such as human papillomavirus (HPV), Epstein-Barr Virus (EBV), and hepatitis B and C viruses. EBV, a member of the human gamma herpesvirus family, is a double-stranded DNA virus and the primary cause of infectious mononucleosis. Most EBV infections cause no long-term complications. However, it was reported that EBV infection is responsible for around 200,000 malignancies worldwide every year. Currently, there are no vaccines or antiviral drugs for the prophylaxis or treatment of EBV infection. Recently, the gut microbiota has been investigated for its pivotal roles in pathogen protection and regulating metabolic, endocrine, and immune functions. Several studies have investigated the efficacy of antiviral agents, gut microbial metabolites, and natural products against EBV infection. In this review, we aim to summarise and analyse the reported molecular mechanistic and clinical studies on the activities of gut microbial metabolites and natural medicines against carcinogenic viruses, with a particular emphasis on EBV. Gut microbial metabolites such as short-chain fatty acids were reported to activate the EBV lytic cycle, while bacteriocins, produced by Enterococcus durans strains, have shown antiviral properties. Furthermore, several natural products and dietary bioactive compounds, such as curcumin, epigallocatechin gallate, resveratrol, moronic acid, and andrographolide, have shown antiviral activity against EBV. In this review, we proposed several exciting future directions for research on carcinogenic viruses.


Assuntos
Infecções por Vírus Epstein-Barr , Microbioma Gastrointestinal , Neoplasias , Humanos , Herpesvirus Humano 4/fisiologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Carcinógenos/metabolismo , Neoplasias/tratamento farmacológico , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/metabolismo , Carcinogênese
2.
Viruses ; 15(1)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36680267

RESUMO

Herpes simplex virus (HSV) has persisted within human populations due to its ability to establish both lytic and latent infection. Given this, human hosts have evolved numerous immune responses to protect against HSV infection. Critical in this defense against HSV, the host protein stimulator of interferon genes (STING) functions as a mediator of the antiviral response by inducing interferon (IFN) as well as IFN-stimulated genes. Emerging evidence suggests that during HSV infection, dsDNA derived from either the virus or the host itself ultimately activates STING signaling. While a complex regulatory circuit is in operation, HSV has evolved several mechanisms to neutralize the STING-mediated antiviral response. Within this review, we highlight recent progress involving HSV interactions with the STING pathway, with a focus on how STING influences HSV replication and pathogenesis.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Humanos , Herpesvirus Humano 1/fisiologia , Interferons/metabolismo , Transdução de Sinais , Antivirais/metabolismo , Imunidade Inata , Replicação Viral/genética
3.
Nat Commun ; 14(1): 471, 2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36709212

RESUMO

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a recent class of anti-HBV antivirals. CAMs disturb proper nucleocapsid assembly, by inducing formation of either aberrant assemblies (CAM-A) or of apparently normal but genome-less empty capsids (CAM-E). Classical structural approaches have revealed the CAM binding sites on the capsid protein (Cp), but conformational information on the CAM-induced off-path aberrant assemblies is lacking. Here we show that solid-state NMR can provide such information, including for wild-type full-length Cp183, and we find that in these assemblies, the asymmetric unit comprises a single Cp molecule rather than the four quasi-equivalent conformers typical for the icosahedral T = 4 symmetry of the normal HBV capsids. Furthermore, while in contrast to truncated Cp149, full-length Cp183 assemblies appear, on the mesoscopic level, unaffected by CAM-A, NMR reveals that on the molecular level, Cp183 assemblies are equally aberrant. Finally, we use a eukaryotic cell-free system to reveal how CAMs modulate capsid-RNA interactions and capsid phosphorylation. Our results establish a structural view on assembly modulation of the HBV capsid, and they provide a rationale for recently observed differences between in-cell versus in vitro capsid assembly modulation.


Assuntos
Proteínas do Capsídeo , Vírus da Hepatite B , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Montagem de Vírus , Capsídeo/metabolismo , Nucleocapsídeo/metabolismo , Antivirais/farmacologia , Antivirais/metabolismo
4.
Antiviral Res ; 210: 105487, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36657882

RESUMO

Chikungunya virus (CHIKV) is an enveloped RNA virus that causes Chikungunya fever (CHIKF), which is transmitted to humans through the bite of infected Aedes mosquitos. Although CHIKVF had been regarded as an endemic disease in limited regions of Africa and Asia, the recent global reemergence of CHIKV heightened awareness of this infectious disease, and CHIKV infection is currently considered an increasing threat to public health. However, no specific drug or licensed vaccine is available for CHIKV infection. As seen in other RNA virus infections, CHIKV triggers the interferon (IFN) response that plays a central role in host defense against pathogens. Experimental evidence has demonstrated that control of CHIVK replication by the IFN response is achieved by antiviral effector molecules called interferon-stimulated genes (ISGs), whose expressions are upregulated by IFN stimulation. This review details the molecular basis of the IFN-mediated suppression of CHIKV, particularly the ISGs restricting CHIKV replication.


Assuntos
Febre de Chikungunya , Vírus Chikungunya , Interferon Tipo I , Animais , Humanos , Vírus Chikungunya/genética , Antivirais/farmacologia , Antivirais/metabolismo , Replicação Viral
5.
Int J Mol Sci ; 24(2)2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36674550

RESUMO

Viruses share many attributes in common with extracellular vesicles (EVs). The cellular machinery that is used for EV production, packaging of substrates and secretion is also commonly manipulated by viruses for replication, assembly and egress. Viruses can increase EV production or manipulate EVs to spread their own genetic material or proteins, while EVs can play a key role in regulating viral infections by transporting immunomodulatory molecules and viral antigens to initiate antiviral immune responses. Ultimately, the interactions between EVs and viruses are highly interconnected, which has led to interesting discoveries in their associated roles in the progression of different diseases, as well as the new promise of combinational therapeutics. In this review, we summarize the relationships between viruses and EVs and discuss major developments from the past five years in the engineering of virus-EV therapies.


Assuntos
Vesículas Extracelulares , Viroses , Vírus , Humanos , Vesículas Extracelulares/metabolismo , Viroses/metabolismo , Antivirais/metabolismo
6.
Function (Oxf) ; 4(1): zqac065, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36654930

RESUMO

Nephrotoxicity is a major cause of kidney disease and failure in drug development, but understanding of cellular mechanisms is limited, highlighting the need for better experimental models and methodological approaches. Most nephrotoxins damage the proximal tubule (PT), causing functional impairment of solute reabsorption and systemic metabolic complications. The antiviral drug tenofovir disoproxil fumarate (TDF) is an archetypal nephrotoxin, inducing mitochondrial abnormalities and urinary solute wasting, for reasons that were previously unclear. Here, we developed an automated, high-throughput imaging pipeline to screen the effects of TDF on solute transport and mitochondrial morphology in human-derived RPTEC/TERT1 cells, and leveraged this to generate realistic models of functional toxicity. By applying multiparametric metabolic profiling-including oxygen consumption measurements, metabolomics, and transcriptomics-we elucidated a highly robust molecular fingerprint of TDF exposure. Crucially, we identified that the active metabolite inhibits complex V (ATP synthase), and that TDF treatment causes rapid, dose-dependent loss of complex V activity and expression. Moreover, we found evidence of complex V suppression in kidney biopsies from humans with TDF toxicity. Thus, we demonstrate an effective and convenient experimental approach to screen for disease relevant functional defects in kidney cells in vitro, and reveal a new paradigm for understanding the pathogenesis of a substantial cause of nephrotoxicity.


Assuntos
Antivirais , Insuficiência Renal , Humanos , Tenofovir/efeitos adversos , Antivirais/metabolismo , Rim , Mitocôndrias , Insuficiência Renal/tratamento farmacológico , Metabolômica
7.
Gene ; 851: 146981, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36270458

RESUMO

Andrographolide and related compounds are effective against several viral diseases, including dengue, COVID-19, influenza, and chikungunya. Andrographis paniculata is the primary source for these compounds, but its availability is limited. A. alata is a potential alternative source, and neoandrographolide (NAG) is the major antiviral compound in this species. Since molecular studies in A. alata are scarce, we sequenced its leaf transcriptome to identify the full-length genes involved in neoandrographolide biosynthesis. We assembled 13.6 Gb RNA-Seq data and generated 81,361 transcripts with 1007 bp average length and 1,810 bp N50. The transcripts were categorized under biological processes (2,707), cellular components (678), and molecular functions (2,036). KEGG analysis mapped 975 transcripts to the secondary metabolite pathways. Among the 420 transcripts mapped to terpenoids and polyketides pathways, 142 transcripts were related to the biosynthesis of andrographolide and its derivatives. After a detailed analysis of these transcripts, we identified 32 full-length genes coding for all the 22 enzymes needed for andrographolide biosynthesis. Among them, 15 full-length genes were identified for the first time from Andrographis species. These full-length genes and the transcripts shall serve as an invaluable resource for the metabolic engineering of andrographolides and neoandrographolide in Andrographis and other species.


Assuntos
Andrographis , COVID-19 , Diterpenos , Andrographis/genética , Andrographis/metabolismo , Antivirais/metabolismo , Diterpenos/metabolismo , Perfilação da Expressão Gênica
8.
J Med Chem ; 66(1): 188-219, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36521178

RESUMO

Influenza PAN inhibitors are of particular importance in current efforts to develop a new generation of antiviral drugs due to the growing emergence of highly pathogenic influenza viruses and the resistance to existing antiviral inhibitors. Herein, we design and synthesize a set of 1,3-cis-N-substituted-1,2,3,4-tetrahydroisoquinoline derivatives to enhance their potency by further exploiting the pockets 3 and 4 in the PAN endonuclease based on the hit d,l-laudanosoline. Particularly, the lead compound 35 exhibited potent and broad anti-influenza virus effects with EC50 values ranging from 0.43 to 1.12 µM in vitro and good inhibitory activity in a mouse model. Mechanistic studies demonstrated that 35 could bind tightly to the PAN endonuclease of RNA-dependent RNA polymerase, thus blocking the viral replication to exert antiviral activity. Overall, our study might establish the importance of 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based derivatives for the development of novel PAN inhibitors of influenza viruses.


Assuntos
Influenza Humana , Orthomyxoviridae , Tetra-Hidroisoquinolinas , Animais , Camundongos , Humanos , Tetra-Hidroisoquinolinas/farmacologia , Antivirais/farmacologia , Antivirais/metabolismo , Endonucleases
9.
Antiviral Res ; 210: 105494, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36574906

RESUMO

Many alphaviruses, including chikungunya virus (CHIKV) are known human pathogens that lack specific and effective antivirals or vaccines available. The upstream portion of the positive-sense single-stranded RNA genome of alphaviruses encodes four nonstructural proteins: nsP1 to nsP4. They are expressed and autoprocessed to nonstructural proteins which assemble into a replication complex (RC) playing multiple essential roles on viral RNA replication and communication with the host components. The assembly of alphavirus RC and its RNA genome initiates the membrane-derived ultrastructure known as spherule which facilitates viral RNA synthesis protected from host immune responses. Recent advances in the molecular understanding of the high-resolution CHIKV RC heteromeric ultrastructure have provided new insights into the viral replication process. Hence, alphavirus RC presents as an ideal multi-enzyme target for the development of structure-based antiviral drugs. Moreover, the alphavirus RC has therapeutic potential in the form of self-amplifying RNA technology against both infectious and non-infectious diseases.


Assuntos
Alphavirus , Febre de Chikungunya , Vírus Chikungunya , Humanos , Alphavirus/genética , Antivirais/farmacologia , Antivirais/metabolismo , Replicação Viral/genética , Vírus Chikungunya/genética , RNA/metabolismo , Proteínas não Estruturais Virais/genética , RNA Viral/metabolismo
10.
Aliment Pharmacol Ther ; 57(4): 387-398, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36585909

RESUMO

BACKGROUND: Natural killer (NK) cells exhibit a selective deficiency of IFN-γ production in chronic hepatitis B (CHB). Toll-like receptor 8 (TLR8) agonists could induce IFN-γ production in immune cells, although their effects on the deficiency in NK cells remain unclear. AIMS: To investigate TLR8 expression in NK cells and the effect of TLR8 agonists in patients with CHB METHODS: We enrolled 32 patients with CHB and 19 healthy controls to assess TLR8 expression and IFN-γ production in NK cells. The sorted NK cells and monocytes were co-cultured to compare the extent of IFN-γ and IL-10 production after TLR8 agonist ssRNA40 stimulation. The synergic effect of NK cells and monocytes was assessed by blocking IL-12 and IL-18. We recruited another 22 patients with CHB undergoing nucleotide analogue (NA) therapy to explore the impact of antiviral treatment on the ssRNA40-mediated response of NK cells. RESULTS: In patients with CHB, TLR8 expression in NK cells was up-regulated, accompanied by insufficient IFN-γ production. The enhanced IFN-γ secretion by ssRNA40 in NK cells depended on monocyte-derived IL-12 and IL-18. NK cells displayed an imbalanced response to ssRNA40 in patients with CHB with a weak increase in IFN-γ despite a higher IL-10 production. The response was improved in patients with CHB undergoing NA therapy. CONCLUSIONS: In patients with CHB, targeting TLR8 partially rescues the IFN-γ insufficiency in NK cells. However, NK cells show an inhibitory response to TLR8 agonist stimulation. TLR8 agonist combined with NA may enhance the antiviral effect of NK cells.


Assuntos
Hepatite B Crônica , Monócitos , Humanos , Monócitos/metabolismo , Interleucina-18 , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/metabolismo , Receptor 8 Toll-Like/uso terapêutico , Interleucina-10 , Interferon gama/metabolismo , Interferon gama/farmacologia , Células Matadoras Naturais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/metabolismo , Interleucina-12/metabolismo , Interleucina-12/farmacologia , Interleucina-12/uso terapêutico
11.
Antiviral Res ; 210: 105506, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36565756

RESUMO

Massive efforts on both vaccine development and antiviral research were launched to combat the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We contributed, amongst others, by the development of a high-throughput screening (HTS) antiviral assay against SARS-CoV-2 using a fully automated, high-containment robot system. Here, we describe the development of this novel, convenient and phenotypic dual-reporter virus-cell-based high-content imaging assay using the A549+hACE2+TMPRSS2_mCherry reporter lung carcinoma cell line and an ancestral SARS-CoV-2_Wuhan_mNeonGreen reporter virus. Briefly, by means of clonal selection, a host cell subclone was selected that (i) efficiently supports replication of the reporter virus with high expression, upon infection, of the NeonGreen fluorescent reporter protein, (ii) that is not affected by virus-induced cytopathogenic effects and, (iii) that expresses a strong fluorescent mCherry signal in the nucleus. The selected clone matched these criteria with an infection rate on average of 75% with limited cell death. The average (R)Z'-factors of the assay plates were all >0.8, which indicates a robust assay suitable for HTS purposes. A selection of reference compounds that inhibits SARS-CoV-2 replication in vitro were used to validate this novel dual-reporter assay and confirms the data reported in the literature. This assay is a convenient and powerful tool for HTS of large compound libraries against SARS-CoV-2.


Assuntos
Antivirais , COVID-19 , Humanos , Antivirais/farmacologia , Antivirais/metabolismo , Ensaios de Triagem em Larga Escala/métodos , SARS-CoV-2 , Descoberta de Drogas , Replicação Viral
12.
Fish Shellfish Immunol ; 132: 108490, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36509415

RESUMO

Beclin-1, the mammalian ortholog of the yeast autophagy-related gene 6 (Atg 6), is a key regulator of autophagy. A variety of health and disease conditions in mammals are intricately related to the broad spectrum of beclin-1 functions. Nevertheless, few studies have investigated the role of beclin-1 in fish. In this study, we identified and cloned the beclin-1 cDNA (EaBECN-1) of Epinephelus akaara (red-spotted grouper) and carried out in silico analysis, tissue-specific expression analysis, immune challenge experiment, and in vitro analysis of its roles against viral infection and oxidative stress. The open reading frame was 1344 bp long and encoded 447 amino acids with a molecular weight of 51.2 kDa. Beclin-1 consisted of a conserved N-terminal BH3 and APG6 domains, and shared more than 88% identity with other vertebrates, according to a pairwise sequence alignment. EaBECN-1 expression profile analysis in E. akaara revealed that it is mostly expressed in the blood. Moreover, transcriptional modulation of EaBECN-1 was observed following stimulation with lipopolysaccharide (LPS), polyinosinic-polycytidylic acid (poly (I:C)), and nervous necrosis virus. During the viral hemorrhagic septicemia virus challenge, increased viral gene expression was observed at 12 h post-infection in FHM cells ectopically expressing EaBECN-1, and decreased thereafter at 24 h post-infection compared to control cells. However, increased antiviral gene expression at 12 and 24 h confirmed the antiviral function of EaBECN-1. Furthermore, EaBECN-1 overexpression protected the cells against H2O2-mediated apoptosis, as evidenced by the MTT assay, analysis of mRNA expression levels of apoptotic genes, and AO-EtBr staining. Overall, our study demonstrated the protective role of EaBECN-1 against viral pathogenesis and oxidative stress through autophagy, increasing our understanding of the role of beclin-1 in fish.


Assuntos
Bass , Doenças dos Peixes , Nodaviridae , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/química , Sequência de Aminoácidos , Sequência de Bases , Peróxido de Hidrogênio/metabolismo , Antivirais/metabolismo , Estresse Oxidativo , Proteínas de Peixes/química , Filogenia , Nodaviridae/fisiologia , Mamíferos/metabolismo
13.
Nat Commun ; 13(1): 7498, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36470880

RESUMO

An essential step in restricting HIV infectivity by the antiviral factor APOBEC3G is its incorporation into progeny virions via binding to HIV RNA. However, the mechanism of APOBEC3G capturing viral RNA is unknown. Here, we report crystal structures of a primate APOBEC3G bound to different types of RNAs, revealing that APOBEC3G specifically recognizes unpaired 5'-AA-3' dinucleotides, and to a lesser extent, 5'-GA-3' dinucleotides. APOBEC3G binds to the common 3'A in the AA/GA motifs using an aromatic/hydrophobic pocket in the non-catalytic domain. It binds to the 5'A or 5'G in the AA/GA motifs using an aromatic/hydrophobic groove conformed between the non-catalytic and catalytic domains. APOBEC3G RNA binding property is distinct from that of the HIV nucleocapsid protein recognizing unpaired guanosines. Our findings suggest that the sequence-specific RNA recognition is critical for APOBEC3G virion packaging and restricting HIV infectivity.


Assuntos
Infecções por HIV , HIV-1 , Nucleosídeo Desaminases , Animais , Desaminase APOBEC-3G/metabolismo , Citidina Desaminase/genética , HIV-1/genética , Antivirais/metabolismo , Nucleosídeo Desaminases/metabolismo , Vírion/metabolismo , RNA Viral/metabolismo , Infecções por HIV/metabolismo
14.
Virol J ; 19(1): 226, 2022 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-36578037

RESUMO

BACKGROUND: Porcine hemagglutinating encephalomyelitis virus (PHEV), a member of the genus Betacoronavirus, is the causative agent of neurological disease in pigs. No effective therapeutics are currently available for PHEV infection. Resveratrol has been shown to exert neuroprotective and antiviral effects. Here resveratrol was investigated for its ability to inhibit PHEV replication in nerve cells and central nervous system tissues. METHODS: Anti-PHEV effect of resveratrol was evaluated using an in vitro cell-based PHEV infection model and employing a mouse PHEV infection model. The collected cells or tissues were used for quantitative PCR analysis, western blot analysis, or indirect immunofluorescence assay. The supernatants were collected to quantify viral loads by TCID50 assay in vitro. EC50 and CC50 were determined by dose-response experiments, and the ratio (EC50/CC50) was used as a selectivity index (SI) to measure the antiviral versus cytotoxic activity. RESULTS: Our results showed that resveratrol treatment reduced PHEV titer in a dose-dependent manner, with a 50% inhibition concentration of 6.24 µM. A reduction of > 70% of viral protein expression and mRNA copy number and a 19-fold reduction of virus titer were achieved when infected cells were treated with 10 µM resveratrol in a pre-treatment assay. Quantitative PCR analysis and TCID50 assay results revealed that the addition of 10 µM resveratrol to cells after adsorption of PHEV significantly reduced 56% PHEV mRNA copy number and eightfold virus titer. 10 µM resveratrol treatment reduced 46% PHEV mRNA copy number and fourfold virus titer in virus inactivation assay. Moreover, the in vivo data obtained in this work also demonstrated that resveratrol inhibited PHEV replication, and anti-PHEV activities of resveratrol treatment via intranasal installation displayed better than oral gavage. CONCLUSION: These results indicated that resveratrol exerted antiviral effects under various drug treatment and virus infection conditions in vitro and holds promise as a treatment for PHEV infection in vivo.


Assuntos
Betacoronavirus 1 , Camundongos , Suínos , Animais , Resveratrol/farmacologia , Resveratrol/metabolismo , Betacoronavirus 1/genética , Betacoronavirus 1/metabolismo , Neurônios , Antivirais/farmacologia , Antivirais/metabolismo , Replicação Viral
15.
Viruses ; 14(12)2022 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-36560708

RESUMO

Human Immunodeficiency virus (HIV-1) fusion is mediated by glycoprotein-41, a protein that has not been widely exploited as a drug target. Small molecules directed at the gp41 ectodomain have proved to be poorly drug-like, having moderate efficacy, high hydrophobicity and/or high molecular weight. We recently investigated conversion of a fairly potent hydrophobic inhibitor into a covalent binder, by modifying it to react with a lysine residue on the protein. We demonstrated a 10-fold improvement in antiviral efficacy. Here, we continue this study, utilizing instead molecules with better inherent drug-like properties. Molecules possessing low to no antiviral activity as equilibrium binders were converted into µM inhibitors upon addition of an electrophilic warhead in the form of a sulfotetrafluorophenyl (STP) activated ester. We confirmed specificity for gp41 and for entry. The small size of the inhibitors described here offers an opportunity to expand their reach into neighboring pockets while retaining drug-likeness. STP esterification of equilibrium binders is a promising avenue to explore for inhibiting HIV-1 entry. Many gp41 targeting molecules studied over the years possess carboxylic acid groups which can be easily converted into the corresponding STP ester. It may be worth the effort to evaluate a library of such inhibitors as a way forward to small molecule inhibition of fusion of HIV and possibly other enveloped viruses.


Assuntos
Inibidores da Fusão de HIV , HIV-1 , Humanos , Inibidores da Fusão de HIV/farmacologia , Inibidores da Fusão de HIV/química , HIV-1/metabolismo , Antivirais/farmacologia , Antivirais/metabolismo , Lisina/metabolismo , Proteína gp41 do Envelope de HIV/química , Interações Hidrofóbicas e Hidrofílicas
16.
Front Immunol ; 13: 1007718, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36532074

RESUMO

Background: Type I interferon (IFN) inhibits virus infection through multiple processes. Recent evidence indicates that IFN carries out its antiviral activity through readjusting of the cellular metabolism. The sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1), as an interferon-stimulated gene (ISG), has been reported to inhibit a number of retroviruses and DNA viruses, by depleting dNTPs indispensable for viral DNA replication. Here we report a new antiviral activity of SAMHD1 against RNA viruses including HCV and some other flaviviruses infection. Methods: Multiple cellular and molecular biological technologies have been used to detect virus infection, replication and variation of intracellular proteins, including western blotting, qRT-PCR, Gene silencing, immunofluorescence, etc. Besides, microarray gene chip technology was applied to analyze the effects of SAMHD1 overexpression on total expressed genes. Results: Our data show that SAMHD1 down-regulates the expression of genes related to lipid bio-metabolic pathway, accompanied with impaired lipid droplets (LDs) formation, two events important for flaviviruses infection. Mechanic study reveals that SAMHD1 mainly targets on HCV RNA replication, resulting in a broad inhibitory effect on the infectivity of flaviviruses. The C-terminal domain of SAMHD1 is showed to determine its antiviral function, which is regulated by the phosphorylation of T592. Restored lipid level by overexpression of SREBP1 or supplement with LDs counteracts with the antiviral activity of SAMHD1, providing evidence supporting the role of SAMHD1-mediated down-regulation of lipid synthesis in its function to inhibit viral infection. Conclusion: SAMHD1 plays an important role in IFN-mediated blockade of flaviviruses infection through targeting lipid bio-metabolic pathway.


Assuntos
Hepatite C , Interferon Tipo I , Viroses , Humanos , Proteína 1 com Domínio SAM e Domínio HD/genética , Proteína 1 com Domínio SAM e Domínio HD/metabolismo , Replicação Viral/fisiologia , Regulação para Baixo , Replicação do DNA , DNA Viral , Antivirais/farmacologia , Antivirais/metabolismo , Interferon Tipo I/metabolismo , Lipídeos
17.
Virol J ; 19(1): 195, 2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36419065

RESUMO

BACKGROUND: Foamy viruses (FVs) are retroviruses with unique replication strategies that cause lifelong latent infections in their hosts. FVs can also produce foam-like cytopathic effects in vitro. However, the effect of host cytokines on FV replication requires further investigation. Although interferon induced transmembrane (IFITMs) proteins have become the focus of antiviral immune response research due to their broad-spectrum antiviral ability, it remains unclear whether IFITMs can affect FV replication. METHOD: In this study, the PFV virus titer was characterized by measuring luciferase activity after co-incubation of PFVL cell lines with the cell culture supernatants (cell-free PFV) or the cells transfected with pcPFV plasmid/infected with PFV (cell-associated PFV). The foam-like cytopathic effects of PFV infected cells was observed to reflect the virus replication. The total RNA of PFV infected cells was extracted, and the viral genome was quantified by Quantitative reverse transcription PCR to detect the PFV entry into target cells. RESULTS: In the present study, we demonstrated that IFITM1-3 overexpression inhibited prototype foamy virus (PFV) replication. In addition, an IFITM3 knockdown by small interfering RNA increased PFV replication. We further demonstrated that IFITM3 inhibited PFV entry into host cells. Moreover, IFITM3 also reduced the number of PFV envelope proteins, which was related to IFITM3 promoted envelope degradation through the lysosomal pathway. CONCLUSIONS: Taken together, these results demonstrate that IFITM3 inhibits PFV replication by inhibiting PFV entry into target cells and reducing the number of PFV envelope.


Assuntos
Spumavirus , Viroses , Humanos , Antivirais/metabolismo , Spumavirus/genética , Replicação Viral , Linhagem Celular , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
18.
Nat Commun ; 13(1): 6920, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376330

RESUMO

Plant viruses adopt diverse virulence strategies to inhibit host antiviral defense. However, general antiviral defense directly targeted by different types of plant viruses have rarely been studied. Here, we show that the single rice DELLA protein, SLENDER RICE 1 (SLR1), a master negative regulator in Gibberellin (GA) signaling pathway, is targeted by several different viral effectors for facilitating viral infection. Viral proteins encoded by different types of rice viruses all directly trigger the rapid degradation of SLR1 by promoting association with the GA receptor OsGID1. SLR1-mediated broad-spectrum resistance was subverted by these independently evolved viral proteins, which all interrupted the functional crosstalk between SLR1 and jasmonic acid (JA) signaling. This decline of JA antiviral further created the advantage of viral infection. Our study reveals a common viral counter-defense strategy in which different types of viruses convergently target SLR1-mediated broad-spectrum resistance to benefit viral infection in the monocotyledonous crop rice.


Assuntos
Oryza , Oryza/genética , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Antivirais/metabolismo , Giberelinas/metabolismo , Proteínas Virais/metabolismo , Regulação da Expressão Gênica de Plantas
19.
Front Immunol ; 13: 1025796, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341332

RESUMO

Dysregulated innate and adaptive immune response to rhinoviral infection plays an important role in the exacerbation or progressive course of chronic rhinosinusitis (CRS). However, few studies have evaluated whether rhinovirus-induced production of anti-viral interferon is deficient or delayed in inflammatory epithelial cells of patients with CRS with nasal polyps. The aim of the present study is to investigate the replication rates of rhinovirus 16 (RV 16), RV16-induced antiviral interferon secretion, and the expression levels of pattern recognition receptors after RV 16 infection or TLR3 stimulation with poly (I: C) in normal and inflammatory epithelial cells. Inflammatory epithelial cells were obtained from CRS patients with nasal polyps and normal epithelial cells were derived from ethmoid sinus mucosa during endoscopic reduction of blowout fracture or uncinate process mucosa of patients with septal deviation. Cultured cells were infected with RV 16 or treated with poly (I: C) for 24, 48, and 72 h. Cells and media were harvested at each time point and used to evaluate RV16 replication rates, the secretion of IFN-ß, -λ1, -λ2, viperin, Mx, and OAS, and the expression levels of TRL3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3. RV replication rates reached peak levels 48 h after inoculation in both normal and inflammatory epithelial cells and showed no difference between both groups of epithelial cells at any time point. The release of IFN-ß, -λ1, and -λ2 in normal and inflammatory epithelial cells was also strongly induced 48 h after RV16 inoculation but reached peak levels 24 h after poly (I: C) treatment. The expression levels of viperin, Mx, OAS, TLR3, RIG-I, MDA5, phospho-NFκB, and phospho-IRF3 showed similar patterns in both groups of epithelial cells. These results suggest that the production of RV16-induced antiviral interferons is not deficient or delayed in inflammatory epithelial cells from CRS patients with nasal polyps.


Assuntos
Pólipos Nasais , Sinusite , Humanos , Rhinovirus , Pólipos Nasais/metabolismo , Receptor 3 Toll-Like/metabolismo , Antivirais/metabolismo , Sinusite/metabolismo , Células Epiteliais , Interferons/metabolismo , Interferon beta/metabolismo , Doença Crônica
20.
Front Immunol ; 13: 900624, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341337

RESUMO

Influenza A virus (IAV) infections are a significant recurrent threat to public health and a significant burden on global economy, highlighting the need for developing more effective therapies. Natural killer (NK) cells play a pivotal role in the control of pulmonary IAV infection, however, little is known about the therapeutic potential of adoptively transferred NK cells for viral infections. Here, we investigated the antiviral activity of CYNK, human placental hematopoietic stem cell-derived NK cells, against IAV infection in vitro. Virus infection induced the expression of NK cell activating ligands on respiratory epithelial cells, resulting in enhanced recognition by CYNK cells. Upon co-culture with IAV-infected epithelial cells, CYNK exhibited elevated degranulation and increased production of IFN-γ, TNF-α and GM-CSF in a virus dose-dependent manner. Furthermore, CYNK showed virus dose-dependent cytotoxicity against IAV-infected cells. The antiviral activity of CYNK was mediated by NKp46 and NKG2D. Together, these data demonstrate that CYNK possesses potent antiviral function against IAV and warrant clinical investigations for adoptive NK cell therapies against viral infections.


Assuntos
Vírus da Influenza A , Influenza Humana , Gravidez , Humanos , Feminino , Placenta , Células Matadoras Naturais/metabolismo , Influenza Humana/metabolismo , Células-Tronco Hematopoéticas , Antivirais/metabolismo
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