RESUMO
Influenza A (IAV) is a major human respiratory pathogen that contributes to a significant threat to health security, worldwide. Despite vaccinations and previous immunisations through infections, humans can still be infected with influenza several times throughout their lives. This phenomenon is attributed to the antigenic changes of hemagglutinin (HA) and neuraminidase (NA) proteins in IAV via genetic mutation and reassortment, conferring antigenic drift and antigenic shift, respectively. Numerous findings indicate that slow antigenic drift and reassortment-derived antigenic shift exhibited by IAV are key processes that allow IAVs to overcome the previously acquired host immunity, which eventually leads to the annual re-emergence of seasonal influenza and even pandemic influenza, in rare occasions. As a result, current therapeutic options hit a brick wall quickly. As IAV remains a constant threat for new outbreaks worldwide, the underlying processes of genetic changes and alternative antiviral approaches for IAV should be further explored to improve disease management. In the light of the above, this review discusses the characteristics and mechanisms of mutations and reassortments that contribute to IAV's evolution. We also discuss several alternative RNA-targeting antiviral approaches, namely the CRISPR/Cas13 systems, RNA interference (RNAi), and antisense oligonucleotides (ASO) as potential antiviral approaches against IAV.
Assuntos
Antivirais , Vírus da Influenza A , Influenza Humana , Humanos , Antivirais/farmacologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , MutaçãoRESUMO
The family of Suppressor of Cytokine Signalling (SOCS) proteins plays pivotal roles in cytokine and immune regulation. Despite their key roles, little attention has been given to the SOCS family as compared to other feedback regulators. To date, SOCS proteins have been found to be exploited by viruses such as herpes simplex virus (HSV), hepatitis B virus (HBV), hepatitis C virus (HCV), Zika virus, respiratory syncytial virus (RSV), Ebola virus, influenza A virus (IAV) and SARS-CoV, just to name a few. The hijacking and subsequent upregulation of the SOCS proteins upon viral infection, suppress the associated JAK-STAT signalling activities, thereby reducing the host antiviral response and promoting viral replication. Two SOCS protein family members, SOCS1 and SOCS3 are well-studied and their roles in the JAK-STAT signalling pathway are defined as attenuating interferon (IFN) signalling upon viral infection. The upregulation of SOCS protein by SARS-CoV during the early stages of infection implies strong similarity with SARS-CoV-2, given their closely related genomic organisation. Thus, this review aims to outline the plausibility of SOCS protein inhibitors as a potential therapeutic regimen for COVID-19 patients. We also discuss the antagonists against SOCS protein to offer an overview on the previous 'successes' of SOCS protein inhibition in various viral infections that may portray possible clues for COVID-19 disease management.
Assuntos
COVID-19 , Progressão da Doença , Proteínas Supressoras da Sinalização de Citocina , Citocinas/metabolismo , Humanos , SARS-CoV-2 , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
The Coronavirus Disease 2019 (COVID-19), a pneumonic disease caused by the SARS Coronavirus 2 (SARS-CoV-2), is the 7th Coronavirus to have successfully infected and caused an outbreak in humans. Genome comparisons have shown that previous isolates, the SARS-related coronavirus (SARSr-CoV), including the SARS-CoV are closely related, yet different in disease manifestation. Several explanations were suggested for the undetermined origin of SARS-CoV-2, in particular, bats, avian and Malayan pangolins as reservoir hosts, owing to the high genetic similarity. The general morphology and structure of all these viral isolates overlap with analogous disease symptoms such as fever, dry cough, fatigue, dyspnoea and headache, very similar to the current SARS-CoV-2. Chest CT scans for SARS-CoV-2, SARS-CoV and MERS-CoV reveal pulmonary lesions, bilateral ground-glass opacities, and segmental consolidation in the lungs, a common pathological trait. With greatly overlapping similarities among the previous coronavirus, the SARS-CoV, it becomes interesting to observe marked differences in disease severity of the SARS-CoV-2 thereby imparting it the ability to rapidly transmit, exhibit greater stability, bypass innate host defences, and increasingly adapt to their new host thereby resulting in the current pandemic. The most recent B.1.1.7, B.1.351 and P.1 variants of SARS-CoV-2, highlight the fact that changes in amino acids in the Spike protein can contribute to enhanced infection and transmission efficiency. This review covers a comparative analysis of previous coronavirus outbreaks and highlights the differences and similarities among different coronaviruses, including the most recent isolates that have evolved to become easily transmissible with higher replication efficiency in humans.
Assuntos
COVID-19/epidemiologia , Infecções por Coronavirus/epidemiologia , SARS-CoV-2/genética , Animais , COVID-19/imunologia , COVID-19/virologia , Infecções por Coronavirus/virologia , Surtos de Doenças , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , SARS-CoV-2/imunologiaRESUMO
Viruses are obligate parasites known to interact with a wide variety of host proteins at different stages of infection. Current antiviral treatments target viral proteins and may be compromised due to the emergence of drug resistant viral strains. Targeting viral-host interactions is now gaining recognition as an alternative approach against viral infections. Recent research has revealed that heterogeneous ribonucleoprotein A1, an RNA-binding protein, plays an essential functional and regulatory role in the life cycle of many viruses. In this review, we summarize the interactions between heterogeneous ribonucleoprotein A1 (hnRNPA1) and multiple viral proteins during the life cycle of RNA and DNA viruses. hnRNPA1 protein levels are modulated differently, in different viruses, which further dictates its stability, function, and intracellular localization. Multiple reports have emphasized that in Sindbis virus, enteroviruses, porcine endemic diarrhea virus, and rhinovirus infection, hnRNPA1 enhances viral replication and survival. However, in others like hepatitis C virus and human T-cell lymphotropic virus, it exerts a protective response. The involvement of hnRNPA1 in viral infections highlights its importance as a central regulator of host and viral gene expression. Understanding the nature of these interactions will increase our understanding of specific viral infections and pathogenesis and eventually aid in the development of novel and robust antiviral intervention strategies.
Assuntos
Suscetibilidade a Doenças , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Interações Hospedeiro-Patógeno , Viroses/metabolismo , Viroses/virologia , Animais , Regulação da Expressão Gênica , Ribonucleoproteína Nuclear Heterogênea A1/genética , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ligação Proteica , Transporte Proteico , RNA Viral , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Viroses/genética , Replicação ViralRESUMO
Tetherin, an interferon-inducible gene was first discovered to be an antiviral factor in 2008. A vast range of viruses, such as influenza A virus (IAV), dengue virus, Ebola virus, HIV, and RSV, have been reported to be susceptible to the antiviral activity of tetherin. Multiple reports have been published encompassing the role of tetherin in the IAV life cycle. To date, nine reports have been published regarding the role of tetherin in the IAV life cycle, with four reports supporting tetherin as an antiviral factor while five other reports suggesting no effect. To this end, this review summarizes the list of viruses currently known to be inhibited by tetherin and describes mechanisms used by viruses to overcome the antiviral potential of tetherin. Further, using IAV as disease model, we provide existing evidence in favor and against tetherin being considered as an antiviral candidate. Subsequent analysis of the experimental procedures across IAV-tetherin published reports revealed that the experimental setup (ie, cell lines, transfection reagents, and multiplicity of infection), strain-specific activity of NS1, and differing roles of NS1 in different cell lines may add up to the contributing factors leading to the discrepancies observed.
Assuntos
Antígeno 2 do Estroma da Médula Óssea/metabolismo , Interações Hospedeiro-Patógeno , Fatores Imunológicos/metabolismo , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Vírus da Dengue/imunologia , Ebolavirus/imunologia , HIV/imunologia , Humanos , Evasão da Resposta Imune , Vírus Sinciciais Respiratórios/imunologiaRESUMO
Neuraminidase protein (NA) of influenza A virus (IAV) is popularly known for its sialidase function to assist in the release of progeny virus. However, involvement of NA in other stages of the IAV life cycle also indicates its multifunctional nature and necessity to interact with other host proteins. Here, we report a host protein-heat shock protein 90 (Hsp90), as a novel interacting partner of IAV NA. A classical yeast two-hybrid screen was conducted to identify a new host interacting partner for NA and the interaction was further validated by coimmunoprecipitation from cells, transiently expressing both proteins and also from IAV-infected cells. Confocal imaging showed that both proteins colocalized in the cytoplasm in transfected host cells. Interestingly, increased levels of NA in the presence of Hsp90 was observed, which tends to decrease if adenosine triphosphatase activity of Hsp90 is inhibited using 17-N-allylamino-17-demethoxygeldanamycin (17AAG). This establishes viral NA as a client protein of host chaperone Hsp90 contributing toward NA's stability via the NA-Hsp90 interaction. This is the first report showing the interaction of NA with Hsp90 and its role in stabilizing viral NA thus preventing it from degradation. Enhanced cell survival in the presence of this interaction was also observed, thus suggesting the requirement of stable viral NA, post-IAV infection, for efficient virus production in infected mammalian cells.
Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Vírus da Influenza A/fisiologia , Influenza Humana/virologia , Neuraminidase/química , Neuraminidase/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo , Replicação Viral , Células A549 , Sobrevivência Celular , Interações Hospedeiro-Patógeno , Humanos , Influenza Humana/metabolismo , Influenza Humana/patologia , Estabilidade ProteicaRESUMO
The infectious salmon anaemia virus (ISAV) is a piscine virus, a member of Orthomyxoviridae family. It encodes at least 10 proteins from eight negative-strand RNA segments. Since ISAV belongs to the same virus family as Influenza A virus, with similarities in protein functions, they may hence be characterised by analogy. Like NS1 protein of Influenza A virus, s8ORF2 of ISAV is implicated in interferon antagonism and RNA-binding functions. In this study, we investigated the role of s8ORF2 in RNAi suppression in a well-established Agrobacterium transient suppression assay in stably silenced transgenic Nicotiana xanthi. In addition, s8ORF2 was identified as a novel interactor with SsMov10, a key molecule responsible for RISC assembly and maturation in the RNAi pathway. This study thus sheds light on a novel route undertaken by viral proteins in promoting viral growth, using the host RNAi machinery.
Assuntos
Proteínas de Peixes/metabolismo , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , Isavirus/fisiologia , Proteínas de Ligação a RNA/metabolismo , Salmão , Proteínas não Estruturais Virais/metabolismo , Animais , Isavirus/imunologia , Ligação Proteica , Interferência de RNARESUMO
The matrix protein 2 (M2) is a spliced product of segment 7 genome of influenza A virus. Previous studies indicate its role in uncoating of the viral ribonucleoprotein complex during viral entry and in membrane scission while budding. Despite its crucial role in the viral life cycle, little is known about its subcellular distribution and dynamics. In this study, we have shown that the M2 protein is translocated from the membrane to the cytoplasm by a retrograde route via endosomes and the Golgi network. It utilizes retromer cargo while moving from the endosome to the trans-Golgi network and prevents endosome fusion with the lysosome. Further, M2 interacts with the endoplasmic-reticulum-resident AAA-ATPase p97 for its release into the cytoplasm. Our study also revealed that the M2 protein in the cellular milieu does not undergo ubiquitin-mediated proteasomal degradation. The migration of M2 through this pathway inside the infected cell suggests possible new roles that the M2 protein may have in the host cytoplasm, apart from its previously described functions.
Assuntos
Citoplasma/metabolismo , Retículo Endoplasmático/metabolismo , Vírus da Influenza A Subtipo H1N1/metabolismo , Influenza Humana/virologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas da Matriz Viral/metabolismo , Endossomos/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/metabolismo , Transporte Proteico , Proteólise , Proteínas da Matriz Viral/genética , Rede trans-Golgi/metabolismoRESUMO
Influenza A viruses (IAVs) pose a major public health threat worldwide. Recent experience with the 2013 H7N9 outbreak in China and the 2009 "swine flu" pandemic have shown that antiviral vaccines and drugs fall short of controlling the spread of disease in a timely and effective manner. Major problems include rapid emergence of drug-resistant influenza virus strains and the slow process of vaccine production. With the threat of a highly pathogenic H5N1 bird-flu pandemic looming large, it is crucial to develop novel ways of combating influenza A viruses. Targeting the host factors critical for influenza A virus replication has shown promise as a strategy to develop novel antiviral molecules with broad-spectrum protection. In this review, we summarize the role of currently identified host factors that play a critical role in the influenza A virus life cycle and discuss the most promising candidates for anti-influenza therapeutics.
Assuntos
Vírus da Influenza A/fisiologia , Influenza Humana/imunologia , Animais , Interações Hospedeiro-Patógeno , Humanos , Vírus da Influenza A/genética , Influenza Humana/genética , Influenza Humana/virologiaRESUMO
Tumour suppressor genes restrain inappropriate cell growth and division, as well as stimulate cell death to maintain tissue homeostasis. Loss of function leads to abnormal cellular behaviour, including hyperproliferation of cell and perturbation of cell cycle regulation. LIMD1 is a tumour suppressor gene located at chromosome 3p21.3, a region commonly deleted in many solid malignancies. LIMD1 interacts with retinoblastoma (Rb) and is involved in Rb-mediated downregulation of E2F1-target genes. However, the role of LIMD1 in cell cycle regulation remains unclear. We propose that LIMD1 induces cell cycle arrest, utilising Rb-E2F1 axis, and show that ectopic expression of LIMD1 in A549 cells results in hypo-phosphorylation that potentiates Rb function, which correlates with downregulation of E2F1. In agreement with these observations, LIMD1 overexpression retards cell cycle progression and blocks S-phase entry, as cells accumulate in G0/G1 phase and have reduced incorporation of BrdU. Most significantly, LIMD1-dependent effects on Rb function and cell cycle are reversed on depletion of endogenous LIMD1, underscoring its centrality in Rb-mediated cell cycle regulation. Hence, our findings provide new insight into cell cycle control by Rb-LIMD1 nexus.
Assuntos
Fator de Transcrição E2F1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Proteína do Retinoblastoma/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Fator de Transcrição E2F1/antagonistas & inibidores , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Fosforilação , Ligação ProteicaRESUMO
Influenza virus remains one of the most important disease-causing viruses owing to its high adaptability and even higher contagious nature. Thus, it poses a constant threat of pandemic, engulfing a large population within the smallest possible time interval. A similar threat was anticipated with the identification of the novel H7N9 virus in China on 30 March 2013. Detection of transmission of the virus between humans has caused a stir with the identification of family clusters along with sporadic infections all across China. In this review we analyze the potential of the novel H7N9 virus as a probable cause of a pandemic and the possible consequences thereof.
Assuntos
Surtos de Doenças , Subtipo H7N9 do Vírus da Influenza A , Influenza Humana/epidemiologia , Animais , Aves , China/epidemiologia , Humanos , Subtipo H7N9 do Vírus da Influenza A/metabolismo , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Influenza Aviária/epidemiologia , Influenza Aviária/transmissão , Influenza Aviária/virologia , Influenza Humana/transmissão , Influenza Humana/virologia , Receptores Virais/metabolismo , Especificidade da Espécie , Virulência , Replicação ViralRESUMO
The influenza virus neuraminidase (NA) protein primarily aids in the release of progeny virions from infected cells. Here, we demonstrate a novel role for NA in enhancing host cell survival by activating the Src/Akt signaling axis via an interaction with carcinoembryonic antigen-related cell adhesion molecule 6/cluster of differentiation 66c (C6). NA/C6 interaction leads to increased tyrosyl phosphorylation of Src, FAK, Akt, GSK3ß, and Bcl-2, which affects cell survival, proliferation, migration, differentiation, and apoptosis. siRNA-mediated suppression of C6 resulted in a down-regulation of activated Src, FAK, and Akt, increased apoptosis, and reduced expression of viral proteins and viral titers in influenza virus-infected human lung adenocarcinoma epithelial and normal human bronchial epithelial cells. These findings indicate that influenza NA not only aids in the release of progeny virions, but also cell survival during viral replication.
Assuntos
Antígenos CD/metabolismo , Brônquios/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Epiteliais/metabolismo , Vírus da Influenza A/fisiologia , Influenza Humana/metabolismo , Neuraminidase/metabolismo , Mucosa Respiratória/metabolismo , Proteínas Virais/metabolismo , Antígenos CD/genética , Apoptose/genética , Brônquios/patologia , Brônquios/virologia , Moléculas de Adesão Celular/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Sobrevivência Celular/genética , Células Epiteliais/patologia , Células Epiteliais/virologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células HEK293 , Humanos , Influenza Humana/patologia , Influenza Humana/virologia , Neuraminidase/genética , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia , Transdução de Sinais/genética , Proteínas Virais/genética , Replicação Viral/genética , Quinases da Família src/genética , Quinases da Família src/metabolismoRESUMO
The COVID-19 pandemic caused by SARS-CoV-2 is associated with a lower fatality rate than its SARS and MERS counterparts. However, the rapid evolution of SARS-CoV-2 has given rise to multiple variants with varying pathogenicity and transmissibility, such as the Delta and Omicron variants. Individuals with advanced age or underlying comorbidities, including hypertension, diabetes and cardiovascular diseases, are at a higher risk of increased disease severity. Hence, this has resulted in an urgent need for the development of better therapeutic and preventive approaches. This review describes the origin and evolution of human coronaviruses, particularly SARS-CoV-2 and its variants as well as sub-variants. Risk factors that contribute to disease severity and the implications of co-infections are also considered. In addition, various antiviral strategies against COVID-19, including novel and repurposed antiviral drugs targeting viral and host proteins, as well as immunotherapeutic strategies, are discussed. We critically evaluate strategies of current and emerging vaccines against SARS-CoV-2 and their efficacy, including immune evasion by new variants and sub-variants. The impact of SARS-CoV-2 evolution on COVID-19 diagnostic testing is also examined. Collectively, global research and public health authorities, along with all sectors of society, need to better prepare against upcoming variants and future coronavirus outbreaks.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , COVID-19/prevenção & controle , Teste para COVID-19 , Vacinas contra COVID-19 , Pandemias/prevenção & controle , Vacinação , Antivirais/uso terapêuticoRESUMO
BACKGROUND: Nuclear factor kappa B (NF-κB) is a key transcription factor that plays a crucial role in host survival during infection by pathogens. Therefore, it has been a priority of many pathogens to manipulate the cellular NF-κB activity in order to create a favorable environment for their survival inside the host. RESULTS: We observed that heterologous expression of the open reading frame 2 (ORF2) protein in human hepatoma cells led to stabilization of the cellular I kappa B alpha (IκBα) pool, with a concomitant reduction in the nuclear localization of the p65 subunit of NF-κB and inhibition of NF-κB activity. Although basal or TPA induced phosphorylation of IκBα was not altered, its ubiquitination was markedly reduced in ORF2 expressing cells. Further analysis revealed that ORF2 protein could directly associate with the F-box protein, beta transducin repeat containing protein (ßTRCP) and ORF2 over expression resulted in reduced association of IκBα with the SKP1 and CUL1 components of the SCFßTRCP complex. Chromatin immunoprecipitation (ChIP) assay of the proximal promoter regions of MHC-I heavy chain and IL-8 genes using p65 antibody and LPS stimulated ORF2 expressing cell extract revealed decreased association of p65 with the above regions, indicating that ORF2 inhibited p65 binding at endogenous promoters. CONCLUSIONS: In this report we suggest a mechanism by which ORF2 protein of HEV may inhibit host cell NF-κB activity during the course of a viral infection.
Assuntos
Vírus da Hepatite E/metabolismo , Proteínas I-kappa B/metabolismo , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Virais/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Proteínas F-Box/metabolismo , Glicoproteínas , Humanos , Proteínas I-kappa B/genética , Interleucina-8/genética , Interleucina-8/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Fator de Transcrição RelA/metabolismo , Transfecção , Ubiquitinação , Proteínas Contendo Repetições de beta-Transducina/metabolismoRESUMO
Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but have also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/ß1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein, disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.
Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Reposicionamento de Medicamentos , Ivermectina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Antivirais/farmacologia , COVID-19/metabolismo , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/metabolismo , Humanos , Ivermectina/farmacologia , Carioferinas/metabolismo , SARS-CoV-2/fisiologiaRESUMO
Molnupiravir is a ß-d-N4-hydroxycytidine-5'-isopropyl ester (NHC) compound that exerts antiviral activity against various RNA viruses such as influenza, SARS, and Ebola viruses. Thus, the repurposing of Molnupiravir has gained significant attention for combatting infection with SARS-CoV-2, the etiological agent of COVID-19. Recently, Molnupiravir was granted authorization for the treatment of mild-to-moderate COVID-19 in adults. Findings from in vitro experiments, in vivo studies and clinical trials reveal that Molnupiravir is effective against SARS-CoV-2 by inducing viral RNA mutagenesis, thereby giving rise to mutated complementary RNA strands that generate non-functional viruses. To date, the data collectively suggest that Molnupiravir possesses promising antiviral activity as well as favorable prophylactic efficacy, attributed to its effective mutagenic property of disrupting viral replication. This review discusses the mechanisms of action of Molnupiravir and highlights its clinical utility by disabling SARS-CoV-2 replication, thereby ameliorating COVID-19 severity. Despite relatively few short-term adverse effects thus far, further detailed clinical studies and long-term pharmacovigilance are needed in view of its mutagenic effects.
Assuntos
Tratamento Farmacológico da COVID-19 , Antivirais/farmacologia , Antivirais/uso terapêutico , Citidina/análogos & derivados , Humanos , Hidroxilaminas , SARS-CoV-2RESUMO
The human gut contains a complex microbiota dominated by bacteriophages but also containing other viruses and bacteria and fungi. There are a growing number of techniques for the extraction, sequencing, and analysis of the virome but currently no standardized protocols. This study established an effective workflow for virome analysis to investigate the virome of stool samples from two understudied ethnic groups from Malaysia: the Jakun and Jehai Orang Asli. By using the virome extraction and analysis workflow with the Oxford Nanopore Technology, long-read sequencing successfully captured close to full-length viral genomes. The virome composition of the two indigenous Malaysian communities were remarkably different from those found in other parts of the world. Additionally, plant viruses found in the viromes of these individuals were attributed to traditional food-seeking methods. This study establishes a human gut virome workflow and extends insights into the healthy human gut virome, laying the groundwork for comparative studies.
Assuntos
Microbioma Gastrointestinal/genética , Genoma Viral , Povos Indígenas , Vírus/genética , Fezes/virologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Malásia , Metagenômica/métodos , Filogenia , Viroma/genética , Vírus/classificaçãoRESUMO
Coronavirus disease 2019 (COVID-19) has caused an unprecedented global crisis and continues to threaten public health. The etiological agent of this devastating pandemic outbreak is the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). COVID-19 is characterized by delayed immune responses, followed by exaggerated inflammatory responses. It is well-established that the interferon (IFN) and JAK/STAT signaling pathways constitute the first line of defense against viral and bacterial infections. To achieve viral replication, numerous viruses are able to antagonize or hijack these signaling pathways to attain productive infection, including SARS-CoV-2. Multiple studies document the roles of several non-structural proteins (NSPs) of SARS-CoV-2 that facilitate the establishment of viral replication in host cells via immune escape. In this review, we summarize and highlight the functions and characteristics of SARS-CoV-2 NSPs that confer host immune evasion. The molecular mechanisms mediating immune evasion and the related potential therapeutic strategies for controlling the COVID-19 pandemic are also discussed.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Evasão da Resposta Imune , Imunidade Inata , Interferons , PandemiasRESUMO
The outbreak of severe acute respiratory syndrome (SARS) in 2003 in China, characterized by atypical pneumonia, was associated with the emergence of a novel coronavirus named severe acute respiratory syndrome coronavirus (SARS-CoV). Eight accessory proteins of SARS coronavirus were the suspected players in the pathogenesis of the virus. Among them, protein 3b localizes to the nucleus and behaves as an interferon antagonist by inhibiting IRF3 activation. However, the effect of 3b on the activity of other common host transcription factors remains unexplored. In this work, we studied the effect of 3b on the transcriptional activity of AP-1. Our findings elucidate augmentation of AP-1-dependent gene expression in 3b-transfected Huh7 cells. Reporter gene and mobility shift assays depict an increase in the AP-1 transcriptional and DNA binding activity in the presence of 3b. This increase in activity correlates with the activation of ERK and JNK pathways. Furthermore, 3b expression potentiates AP-1-driven promoter activity of proinflammatory cytokine MCP-1, suggesting a plausible role for 3b as a virulence factor that might function by upregulating AP-1-dependent cytokine levels in SARS-CoV infection.
Assuntos
Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/metabolismo , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/patogenicidade , Fator de Transcrição AP-1/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Quimiocina CCL2/genética , Chlorocebus aethiops , Sondas de DNA/genética , Humanos , Fator Regulador 3 de Interferon/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Transdução de Sinais , Ativação Transcricional , Transfecção , Células Vero , Proteínas Virais Reguladoras e Acessórias/genética , VirulênciaRESUMO
RNA silencing suppressors (RSSs) are well studied for plant viruses but are not well defined to date for animal viruses. Here, we have identified an RSS from a medically important positive-sense mammalian virus, Severe acute respiratory syndrome coronavirus. The viral 7a accessory protein suppressed both transgene and virus-induced gene silencing by reducing the levels of small interfering RNA (siRNA). The suppression of silencing was analyzed by two independent assays, and the middle region (amino acids [aa] 32 to 89) of 7a was responsible for suppression. Finally, the RNA suppression property and the enhancement of heterologous replicon activity by the 7a protein were confirmed for animal cell lines.