RESUMEN

Silver nanoparticles (AgNPs) are a potential antiviral agent due to their ability to disrupt the viral particle or alter the virus metabolism inside the host cell. In vitro, AgNPs exhibit antiviral activity against the most common human respiratory viruses. However, their capacity to modulate immune responses during respiratory viral infections has yet to be explored. This study demonstrates that administering AgNPs directly into the lungs prior to infection can reduce viral loads and therefore virus-induced cytokines in mice infected with influenza virus or murine pneumonia virus. The prophylactic effect was diminished in mice with depleted lymphoid cells. We showed that AgNPs-treatment resulted in the recruitment and activation of lymphocytes in the lungs, particularly natural killer (NK) cells. Mechanistically, AgNPs enhanced the ability of alveolar macrophages to promote both NK cell migration and IFN-γ production. By contrast, following infection, in mice treated with AgNPs, NK cells exhibited decreased activation, indicating that these nanoparticles can regulate the potentially deleterious activation of these cells. Overall, the data suggest that AgNPs may possess prophylactic antiviral properties by recruiting and controlling the activation of lymphoid cells through interaction with alveolar macrophages.

Asunto(s)

Células Asesinas Naturales , Pulmón , Nanopartículas del Metal , Infecciones por Orthomyxoviridae , Plata , Animales , Plata/química , Plata/farmacología , Nanopartículas del Metal/química , Pulmón/virología , Pulmón/patología , Pulmón/efectos de los fármacos , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , Ratones , Células Asesinas Naturales/efectos de los fármacos , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/virología , Ratones Endogámicos C57BL , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Antivirales/farmacología , Antivirales/uso terapéutico , Femenino , Activación de Linfocitos/efectos de los fármacos

RESUMEN

The resurgence of influenza viruses as a significant global threat emphasizes the urgent need for innovative antiviral strategies beyond existing treatments. Here, we present the development and evaluation of a novel super-multivalent sialyllactosylated filamentous phage, termed t-6SLPhage, as a potent entry blocker for influenza A viruses. Structural variations in sialyllactosyl ligands, including linkage type, valency, net charge, and spacer length, were systematically explored to identify optimal binding characteristics against target hemagglutinins and influenza viruses. The selected SLPhage equipped with optimal ligands, exhibited exceptional inhibitory potency in in vitro infection inhibition assays. Furthermore, in vivo studies demonstrated its efficacy as both a preventive and therapeutic intervention, even when administered post-exposure at 2 days post-infection, under 4 lethal dose 50% conditions. Remarkably, co-administration with oseltamivir revealed a synergistic effect, suggesting potential combination therapies to enhance efficacy and mitigate resistance. Our findings highlight the efficacy and safety of sialylated filamentous bacteriophages as promising influenza inhibitors. Moreover, the versatility of M13 phages for surface modifications offers avenues for further engineering to enhance therapeutic and preventive performance.

Asunto(s)

Antivirales , Animales , Antivirales/farmacología , Antivirales/química , Humanos , Perros , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/virología , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/fisiología , Células de Riñón Canino Madin Darby , Inovirus/efectos de los fármacos , Oseltamivir/farmacología , Oseltamivir/química , Ratones , Gripe Humana/virología , Gripe Humana/tratamiento farmacológico , Ratones Endogámicos BALB C , Ácido N-Acetilneuramínico/química , Ácido N-Acetilneuramínico/metabolismo , Femenino

RESUMEN

Luciferase reporter systems are commonly used in scientific research to investigate a variety of biological processes, including antiviral innate immunity. These systems employ the use of luciferase enzymes derived from organisms such as fireflies or renilla reniformis, which emit light upon reaction with a substrate. In the context of antiviral innate immunity, the luciferase reporter systems offer a noninvasive and highly sensitive approach for real-time monitoring of immune responses in vitro and in vivo, enabling researchers to delve into the intricate interactions and signaling pathways involved in host-virus dynamic interactions. Here, we describe the methods of the promoter-luciferase reporter and enhancer-luciferase reporter, which provide insights into the transcriptional and post-transcriptional regulation of antiviral innate immunity. Additionally, we outline the split-luciferase complementary reporter method, which was designed to explore protein-protein interactions associated with antiviral immunity. These methodologies offer invaluable knowledge regarding the molecular mechanisms underlying antiviral immune pathways and have the potential to support the development of effective antiviral therapies.

Asunto(s)

Genes Reporteros , Inmunidad Innata , Luciferasas , Humanos , Luciferasas/metabolismo , Luciferasas/genética , Animales , Interferones/metabolismo , Interferones/inmunología , Regiones Promotoras Genéticas , Antivirales/farmacología , Células HEK293 , Interacciones Huésped-Patógeno/inmunología , Interacciones Huésped-Patógeno/genética

RESUMEN

This chapter summarizes the epidemiological study design of natural immune epidemiology studies based on recent COVID-19-related research. The epidemiological studies on antiviral innate immunity have mainly included randomized controlled trials (RCTs) and observational studies. Importantly, this chapter will discuss how to use these methodologies to answer an epidemiological question of natural immunity in the viral infection process based on previous studies. An observational case- or cohort-based study of antiviral innate immunity may support this theoretical hypothesis but is not appropriate for clinical practice or treatment. RCTs are the gold standard for epidemiological studies and occupy a greater role in the hierarchy of evidence.

Asunto(s)

COVID-19 , Inmunidad Innata , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/epidemiología , COVID-19/virología , SARS-CoV-2/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Epidemiológicos , Antivirales/uso terapéutico , Estudios Observacionales como Asunto

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Morus alba L. are widely used as ethnomedicine and functional food in China, Japan, Korea and other Asian countries. Morus alba L. have a variety of pharmacological activity such as antiviral, antioxidation, anti-cholesterol, anticancer, hypoglycemia, and neuroprotection. Morus alba L. has demonstrated antiviral efficacy against influenza viruses, SARS-CoV-2 and so on, but its potential activity against pseudorabies virus (PRV) remains uncertain. AIM OF THE STUDY: This study endeavors to delve into the anti-pseudorabies virus (PRV) potential of the ethanol extract of Morus alba L. leaves (MLE), while simultaneously elucidating its underlying mechanism of action. MATERIALS AND METHODS: The anti-PRV activities of Morus alba L. extracts at different concentrations were evaluated by qPCR and immunoblotting. The inhibitory effects of MLE on PRV replication in three distinct treatment modes (pretreatment, co-treatment, and post-treatment) were detected by qPCR and indirect immunofluorescence assays. qPCR was used to investigate the effects of MLE on PRV attachment, entrance, and cytokine expression in PRV-infected cells. The chemical components in MLE were analyzed by UPLC-MS/MS. RESULTS: MLE significantly inhibits PRV replication and protein expression in a dose-dependent manner. MLE displays inhibitory effects against PRV at three different modes of treatment. The most significant inhibitory effect of MLE was observed when used in co-treatment mode, resulting in an inhibition rate of 99.42%. MLE inhibits PRV infection in the early stage. MLE inhibits PRV infection by affecting viral attachment and viral entry. Furthermore, MLE exerts its inhibition on PRV replication by mitigating the heightened expression of cytokines (TNF-α and IFN-α) triggered by PRV. Analysis of its chemical composition highlights phenolic acids and flavonoids as the principal constituents of MLE. CONCLUSION: The results illustrate that MLE effectively impedes PRV infection by suppressing viral adsorption and entry, while also curbing the expression of antiviral cytokines. Therefore, MLE may be a potential resource for creating new medications to treat human and animal PRV infections.

Asunto(s)

Antivirales , Herpesvirus Suido 1 , Morus , Extractos Vegetales , Hojas de la Planta , Replicación Viral , Herpesvirus Suido 1/efectos de los fármacos , Morus/química , Antivirales/farmacología , Antivirales/aislamiento & purificación , Extractos Vegetales/farmacología , Animales , Replicación Viral/efectos de los fármacos , Hojas de la Planta/química , Citocinas/metabolismo , Perros , Células de Riñón Canino Madin Darby , Internalización del Virus/efectos de los fármacos , Acoplamiento Viral/efectos de los fármacos

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Viral pneumonia is the leading cause of death after SARS-CoV-2 infection. Despite effective at early stage, long-term treatment with glucocorticoids can lead to a variety of adverse effects and limited benefits. The Chinese traditional herb Pogostemonis Herba is the aerial part of Pogostemon Cablin (Blanco) Benth., which has potent antiviral, antibacterial, anti-inflammatory, and anticancer effects. It was used widely for treating various throat and respiratory diseases, including COVID-19, viral infection, cough, allergic asthma, acute lung injury and lung cancer. AIM OF THE STUDY: To investigate the antiviral and anti-inflammatory effects of chemical compounds from Pogostemonis Herba in SARS-CoV-2-infected hACE2-overexpressing mouse macrophage RAW264.7 cells and hACE2 transgenic mice. MATERIALS AND METHODS: The hACE2-overexpressing RAW264.7 cells were exposed with SARS-CoV-2. The cell viability was detected by CCK8 assay and cell apoptotic rate was by flow cytometric assay. The expressions of macrophage M1 phenotype markers (TNF-α and IL-6) and M2 markers (IL-10 and Arg-1) as well as the viral loads were detected by qPCR. The mice were inoculated intranasally with SARS-CoV-2 omicron variant to induce viral pneumonia. The levels of macrophages, neutrophils, and T cells in the lung tissues of infected mice were analyzed by full spectrum flow cytometry. The expressions of key proteins were detected by Western blot assay. RESULTS: Diosmetin-7-O-ß-D-glucopyranoside (DG) presented the strongest anti-SARS-CoV-2 activity. Intervention with DG at the concentrations of 0.625-2.5 µM not only reduced the viral replication, cell apoptosis, and the productions of inflammatory cytokines (IL-6 and TNF-α) in SARS-CoV-2-infected RAW264.7 cells, but also reversed macrophage polarity from M1 to M2 phenotype. Furthermore, treatment with DG (25-100 mg/kg) alleviated acute lung injury, and reduced macrophage infiltration in SARS-COV-2-infected mice. Mechanistically, DG inhibited SARS-COV-2 gene expression and HK3 translation via targeting YTHDF1, resulting in the inactivation of glycolysis-mediated NF-κB pathway. CONCLUSIONS: DG exerted the potent antiviral and anti-inflammatory activities. It reduced pneumonia in SARS-COV-2-infected mice via inhibiting the viral replication and accelerating M2 macrophage polarization via targeting YTHDF1, indicating its potential for COVID-19 treatment.

Asunto(s)

Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Macrófagos , SARS-CoV-2 , Replicación Viral , Animales , Ratones , Células RAW 264.7 , Replicación Viral/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/virología , SARS-CoV-2/efectos de los fármacos , Antivirales/farmacología , Ratones Transgénicos , Pogostemon/química , Citocinas/metabolismo , Apoptosis/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/virología , Pulmón/patología , Glucósidos/farmacología , Glucósidos/aislamiento & purificación , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/uso terapéutico , Enzima Convertidora de Angiotensina 2/metabolismo , Antiinflamatorios/farmacología , Masculino , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Humanos

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Jinye Baidu granules (JYBD) have been used to treat acute respiratory tract infections and demonstrated clinical efficacy for the treatment of emerging or epidemic respiratory viruses such as SARS-CoV-2 and influenza virus. AIM OF THE STUDY: This study is to investigate the antiviral effect of JYBD against influenza A viruses (IAV) in vitro and in vivo and elucidate its underlying mechanism. MATERIALS AND METHODS: Ultra-high-performance liquid chromatography connected with Orbitrap mass spectrometer (UHPLC-Orbitrap MS) was employed to describe the chemical profile of JYBD. The potential pathways and targets involved in JYBD against IAV infection were predicted by network pharmacology. The efficacy and mechanism of JYBD were validated through both in vivo and in vitro experiments. Moreover, combination therapy with JYBD and the classic anti-influenza drugs was also investigated. RESULTS: A total of 126 compounds were identified by UHPLC-Orbitrap MS, of which 9 compounds were unambiguously confirmed with reference standards. JYBD could significantly inhibit the replication of multiple strains of IAV, especially oseltamivir-resistant strains. The results of qRT-PCR and WB demonstrated that JYBD could inhibit the excessive induction of pro-inflammatory cytokines induced by IAV infection and regulate inflammatory response through inhibiting JAK/STAT, NF-κB and MAPK pathways. Moreover, both JYBD monotherapy or in combination with oseltamivir could alleviate IAV-induced severe lung injury in mice. CONCLUSIONS: JYBD could inhibit IAV replication and mitigate virus-induced excessive inflammatory response. Combinations of JYBD and neuraminidase inhibitors conferred synergistic suppression of IAV both in vitro and in vivo. It might provide a scientific basis for clinical applications of JYBD against influenza virus infected diseases.

Asunto(s)

Antivirales , Medicamentos Herbarios Chinos , Virus de la Influenza A , Farmacología en Red , Infecciones por Orthomyxoviridae , Antivirales/farmacología , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Virus de la Influenza A/efectos de los fármacos , Perros , Ratones , Humanos , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , Células de Riñón Canino Madin Darby , Replicación Viral/efectos de los fármacos , Células A549 , Ratones Endogámicos BALB C , Masculino , Femenino , Cromatografía Líquida de Alta Presión

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Chaihu Guizhi Decoction (CGD) has a long history of use in China for the treatment of influenza, which involves the use of a variety of aromatic herbs. Our previous studies have found that the contents of aromatic constituents in CGD affected the efficacy of treatment of influenza-infected mice, suggesting a clue that essential oil from CGD may play a relatively important role in ameliorating influenza induced pneumonia. AIM OF THE STUDY: To evaluate the anti-influenza potential of essential oil derived from Chaihu Guizhi Decoction (CGD-EO), to characterize and predict the key active components in CGD-EO, and to explore the mechanism of action of CGD-EO. MATERIALS AND METHODS: CGD-EO was obtained by steam distillation, and the components of the essential oil were characterized by gas chromatography-mass spectrometry (GC-MS) in conjunction with the retention index. The constituents absorbed into the blood of mice treated with CGD-EO were analyzed by headspace solid phase microextraction gas chromatography/mass spectrometry (HS-SPME-GC/MS). The potential anti-influenza active constituents and their possible action pathway were predicted by simulation using a network pharmacology approach. The protective effect of CGD-EO and its major components on H1N1/PR8-infected cells was determined using the CCK8 assay kit. Mice infected with influenza A virus H1N1/PR8 were administered different doses of CGD-EO orally and the body weights and lung weights were recorded. Mice with varying degrees of H1N1/PR8 infection were administered CGD-EO orally, and their daily weight, water consumption, and clinical indicators were recorded. Necropsies were conducted on days 3 and 5, during which lung weights were measured and lung tissues were preserved. Furthermore, the mRNA expression of the H1N1/PR8 virus and inflammatory factors in lung tissue was analyzed using RT-qPCR. RESULTS: (E)-cinnamaldehyde was the most abundant compound in the CGD-EO. The results of serum medicinal chemistry combined with network pharmacological analysis indicated that (E)-cinnamaldehyde and 3-phenyl-2-propenal may be potential active components of the CGD-EO anti-influenza, and may be involved in the NF-κB signalling pathway. In vitro studies have demonstrated that both CGD-EO and cinnamaldehyde exert a protective effect on MDCK cells infected with H1N1/PR8. In a 0.5 TCID50 H1N1/PR8-induced influenza model, mice treated with CGD-EO at a dose of 63.50 µg/kg exhibited a reduction in lung index, pathological lung lesions, and H1N1/PR8 viral gene levels. In addition, CGD-EO treatment was found to regulate the levels of inflammatory cytokines, including IL-6, TNF-α, and IFN-γ. Moreover, following three days of administration, an upregulation of NF-κB mRNA levels in mouse lung tissue was observed in response to CGD-EO treatment. CONCLUSIONS: The findings of our study indicate CGD-EO exerts a protective effect against H1N1-induced cytopathic lesions in vitro and is capable of alleviating H1N1-induced pneumonitis in mice. Moreover, it appears to be more efficacious in the treatment of mild symptoms of H1N1 infection. Studies have demonstrated that CGD-EO has antiviral potential to attenuate influenza-induced lung injury by modulating inflammatory cytokines and NF-κB signalling pathways during the early stages of influenza infection. It is possible that (E)-cinnamaldehyde is a potential active ingredient in the anti-influenza efficacy of CGD-EO.

Asunto(s)

Antivirales , Medicamentos Herbarios Chinos , Aceites Volátiles , Infecciones por Orthomyxoviridae , Animales , Aceites Volátiles/farmacología , Medicamentos Herbarios Chinos/farmacología , Ratones , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Antivirales/farmacología , Ratones Endogámicos BALB C , Neumonía Viral/tratamiento farmacológico , Masculino , Células de Riñón Canino Madin Darby , Perros , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Pulmón/metabolismo , Humanos , Femenino , Neumonía/tratamiento farmacológico , Neumonía/virología , Neumonía/metabolismo

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Yupingfeng powder (YPF) is a classic traditional Chinese medicine prescription with a long history of clinical application. However, there is a consensus on the clinical efficacy of YPF in the prevention and treatment of influenza, the underlying pharmacological mechanisms and functional substances have not been thoroughly investigated. AIM OF THE STUDY: This study aimed to elucidate the functional substances and potential mechanisms of YPF against influenza infections by integrating network analysis, metabolomics, computational system pharmacology, and in vitro experiments. MATERIALS AND METHODS: In this study, the active ingredients, related targets, and potential mechanisms of YPF against influenza were identified through network pharmacology and GEO database mining. Combined with metabolomics to corroborate the results of network pharmacology analysis and construct C-T-P-D-M network. Based on this, the key network motifs (KNM) with significance were predicted by system pharmacology algorithm. Finally, the key components as functional substances in the KNM were validated by the coverage of influenza-causing genes and functional pathways, and in vitro experiments. RESULTS: A total of 238 active components and 158 potential target genes intersecting with influenza infection differential genes were screened from YPF. KEGG enrichment analysis indicated that metabolism participated in YPF-provided prevention and treatment on influenza, and metabolomic results further corroborated the significance of the metabolic pathways intervened by YPF included pyruvate metabolism, Valine, leucine and isoleucine degradation, etc. The KNM prediction strategy was computed to include wogonin and isoimperaporin, a group of 48 potential functional components. This functional component group maintained a high degree of consistency with the corresponding C-T network in terms of the coverage of influenza pathogenic genes, and the coverage of functional pathways. Meanwhile, the in vitro results showed that wogonin and isoimperaporin had significant inhibitory effects on inflammation induced by influenza infection, confirming the reliability and accuracy of the KNM prediction strategy. CONCLUSION: YPF against influenza has multi-target and multi-pathway effects, and the underlying mechanisms may be related to metabolism. The pharmacodynamic effects of core components such as wogonin and isoimperaporin on influenza prevention and treatment were confirmed, which represent promising functional candidates for subsequent influenza prevention and treatment, and provide references for the pharmacological and mechanistic analyses of subsequent formulas.

Asunto(s)

Medicamentos Herbarios Chinos , Gripe Humana , Metabolómica , Farmacología en Red , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Metabolómica/métodos , Gripe Humana/tratamiento farmacológico , Humanos , Antivirales/farmacología , Animales , Polvos , Células de Riñón Canino Madin Darby , Perros , Medicina Tradicional China/métodos

RESUMEN

The coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents the most disastrous infectious disease pandemic of the past century. As a member of the Betacoronavirus genus, the SARS-CoV-2 genome encodes a total of 29 proteins. The spike protein, RNA-dependent RNA polymerase, and proteases play crucial roles in the virus replication process and are promising targets for drug development. In recent years, structural studies of these viral proteins and of their complexes with antibodies and inhibitors have provided valuable insights into their functions and laid a solid foundation for drug development. In this review, we summarize the structural features of these proteins and discuss recent progress in research regarding therapeutic development, highlighting mechanistically representative molecules and those that have already been approved or are under clinical investigation.

Asunto(s)

Antivirales , SARS-CoV-2 , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/metabolismo , Antivirales/farmacología , Antivirales/química , Humanos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , Tratamiento Farmacológico de COVID-19 , ARN Polimerasa Dependiente de ARN de Coronavirus/metabolismo , ARN Polimerasa Dependiente de ARN de Coronavirus/química , ARN Polimerasa Dependiente de ARN de Coronavirus/antagonistas & inhibidores , Modelos Moleculares , COVID-19/virología , COVID-19/metabolismo , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/metabolismo

RESUMEN

Enterovirus 71 (EV71) is recognized as a major causative agent of hand, foot, and mouth disease (HFMD), posing a significant global public health concern due to its widespread impact and resulting in a major public health issue worldwide. Despite its prevalence, current clinical therapy lacks effective antiviral agents. Fucosylated chondroitin sulfates (FCS) derived from sea cucumber exhibits a range of biological activities including potent antiviral effects. This study provides compelling evidence of the potent antiviral efficacy of FCS against EV71. To further elucidate the impact of structural variations on the anti-EV71 activity, native FCSs with diverse sulfation patterns and a varity of FCS derivatives were prepared and analyzed. Notably, this study presents the detailed structural characterization of FCSs from the sea cucumbers Holothuria scabra Jaege and Holothuria fuscopunctata. Analysis of the structure-activity relationships revealed that molecular weight, sulfated fucose branches, and sulfation pattern were all crucial factors contributing to the potent inhibitory effects of FCS against EV71. Interestingly, molecular weight emerged as the most significant structural determinant of the antiviral potency. These findings suggest the promising potential of utilizing FCS as an innovative EV71 entry inhibitor for the treatment of HFMD.

Asunto(s)

Antivirales , Sulfatos de Condroitina , Enterovirus Humano A , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacología , Antivirales/farmacología , Antivirales/química , Animales , Enterovirus Humano A/efectos de los fármacos , Relación Estructura-Actividad , Humanos , Pepinos de Mar/química , Chlorocebus aethiops , Peso Molecular , Células Vero

RESUMEN

Mitochondria are vital for most cells' functions. Viruses hijack mitochondria machinery for misappropriation of energy supply or to bypass defense mechanisms. Many of these mitochondrial dysfunctions persist after recovery from treated or untreated viral infections, particularly when mitochondrial DNA is permanently damaged. Quantitative defects and structural rearrangements of mitochondrial DNA accumulate in post-mitotic tissues as recently reported long after SARS-CoV-2 or HIV infection, or following antiviral therapy. These observations are consistent with the "hit-and-run" concept proposed decades ago to explain viro-induced cell transformation and it could apply to delayed post-viral onsets of symptoms and advocate for complementary supportive care. Thus, according to this concept, following exposure to viruses or antiviral agents, mitochondrial damage could evolve into an autonomous clinical condition. It also establishes a pathogenic link between communicable and non-communicable chronic diseases.

Asunto(s)

Antivirales , COVID-19 , ADN Mitocondrial , Mitocondrias , Virosis , Humanos , Antivirales/uso terapéutico , Mitocondrias/efectos de los fármacos , ADN Mitocondrial/genética , COVID-19/virología , Virosis/tratamiento farmacológico , Virosis/virología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19

Asunto(s)

Productos Biológicos , Tratamiento Farmacológico de COVID-19 , Humanos , Productos Biológicos/uso terapéutico , Antivirales/uso terapéutico , COVID-19

RESUMEN

OBJECTIVE: There is early evidence about Valproic acid (VPA) antiviral effect. Our aim was to investigate the incidence and severity of SARS-CoV-2 infection in VPA users as compared with the general population. MATERIAL AND METHODS: A case-control study nested within a cohort, carried out between March 1 and December 17, 2020. Retrospectively, we identified confirmed SARS-CoV-2 infection patients exposed to VPA in our health department (defined as case). We ascertained VPA regimen (all the time (AT) (292 days) or at least 20% of the study period (notAT) (≥58 days) and if VPA levels were in therapeutic range (ATR) (50-100mcg/mL) in the last 24 months. We calculated the cumulative incidence of SARS-CoV-2 infection and hospital admission in the cases, comparing it with the general unexposed VPA population (controls). RESULTS: During the study period, 6183 PCR+ were detected among 281,035 inhabitants, of these, 746 were hospitalized. 691 patients were on VPA notAT and 628 (90.1%) AT. The indication for VPA use was epilepsy in 54.9%. The incidence of PCR+ was 1.736% (OR 0.785 (95%CI 0.443-1.390) and 1.910% (OR 0.865 (95%CI 0.488-1.533), on VPA notAT and VPA AT patients, respectively vs. 2.201% in people without VPA regimen. Those patients with VPA ATR had a lower risk of PCR + (OR 0.233 (95%CI 0.057-0.951) notAT; OR 0.218 (95%CI 0.053-0.890) AT). Hospital admission incidence was lower in patient on VPA (OR was 0.543 (95% CI 0.076-3.871). CONCLUSION: Patients with VPA within the therapeutic range had a reduction of SARS-Cov-2 infection incidence greater than 75%. There is a downward trend in the risk of COVID-19 admission by SARS-CoV-2 in patients on VPA therapy. These findings warrant further investigation.

Asunto(s)

COVID-19 , Epilepsia , Ácido Valproico , Humanos , Ácido Valproico/uso terapéutico , Estudios de Casos y Controles , Masculino , Femenino , Persona de Mediana Edad , COVID-19/epidemiología , Estudios Retrospectivos , Adulto , Anciano , Epilepsia/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19 , Incidencia , Antivirales/uso terapéutico , Anticonvulsivantes/uso terapéutico , Hospitalización/estadística & datos numéricos , SARS-CoV-2

RESUMEN

PURPOSE: The aim of the study was to determine outcomes after heart transplantation for cytomegalovirus (CMV) mismatched patients (D+/R-) who underwent a surveillance and preemptive therapy protocol, compared to nonmismatch patients. METHODS: A review of patient records from January 2010 to December 2020 with follow-up to October 2023 was done. The protocol consisted weekly surveillance with CMV PCR starting 4 weeks after transplant continuing up until the patient seroconverts or up to 3 months posttransplant if the patient does not seroconvert. Valganciclovir was given for 2 weeks to those who seroconverted. RESULTS: Two hundred and twenty-one patients were included, and 23% were mismatched patients. Overall survival was not different between CMV groups (p = NS). Causes of death and morbidities were also not significantly different (p = NS). Sixty-six percent of mismatch patients seroconverted, and there was also a significantly older donor age in the seroconverted patients compared to nonseroconverted patients (41 ± 11 vs. 29 ± 12 years, p < 0.005), indicating a higher risk donor profile. A multivariate Cox regression including donor age showed that there was no increase in mortality in the seroconverted mismatches compared to nonmismatch patients (p = NS). CONCLUSIONS: There is no significant increased mortality or morbidity using a CMV surveillance and preemptive therapy protocol. The effect of donor age on seroconversion of mismatches requires further validation.

Asunto(s)

Antivirales , Infecciones por Citomegalovirus , Citomegalovirus , Supervivencia de Injerto , Trasplante de Corazón , Humanos , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/mortalidad , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/epidemiología , Femenino , Masculino , Citomegalovirus/aislamiento & purificación , Estudios de Seguimiento , Adulto , Pronóstico , Estudios Retrospectivos , Antivirales/uso terapéutico , Factores de Riesgo , Rechazo de Injerto/prevención & control , Rechazo de Injerto/etiología , Rechazo de Injerto/mortalidad , Tasa de Supervivencia , Persona de Mediana Edad , Complicaciones Posoperatorias/prevención & control , Donantes de Tejidos/provisión & distribución

RESUMEN

BACKGROUND: Respiratory syncytial virus (RSV) is associated with substantial morbidity among infants. This study modelled the potential public health and economic impact of nirsevimab, a long-acting monoclonal antibody, as an immunoprophylactic strategy for all infants in Spain in their first RSV season. METHODS: A static decision-analytic model of the Spanish birth cohort during its first RSV season was developed to estimate the impact of nirsevimab on RSV-related health events and costs versus the standard of practice (SoP). Spain-specific costs and epidemiological data were used as model inputs. Modelled outcomes included RSV-related outpatient visits, emerging room (ER) visits, hospitalisations - including pediatric intensive care unit (PICU) admission, mechanical ventilation, and inpatient mortality. RESULTS: Under the current SoP, RSV caused 151,741 primary care visits, 38,798 ER visits, 12,889 hospitalisations, 1,412 PICU admissions, and 16 deaths over a single season, representing a cost of €71.8 million from a healthcare payer perspective. Universal immunisation of all infants with nirsevimab was expected to prevent 97,157 primary care visits (64.0% reduction), 24,789 ER visits (63.9%), 8,185 hospitalisations (63.5%), 869 PICU admissions (61.5%), and 9 inpatient deaths (52.6%), saving €47.8 million (62.4%) in healthcare costs. CONCLUSIONS: These results suggest that immunisation with nirsevimab of all infants experiencing their first RSV season in Spain is likely to prevent thousands of RSV-related health events and save considerable costs versus the current SoP.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Infecciones por Virus Sincitial Respiratorio , Humanos , Infecciones por Virus Sincitial Respiratorio/prevención & control , Infecciones por Virus Sincitial Respiratorio/economía , España/epidemiología , Lactante , Recién Nacido , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/economía , Hospitalización/estadística & datos numéricos , Hospitalización/economía , Femenino , Masculino , Antivirales/uso terapéutico , Antivirales/economía , Costos de la Atención en Salud/estadística & datos numéricos

RESUMEN

Remdesivir therapy has been declared as efficient in the early stages of Covid-19. Of the 339 patients (males 55.8%, age 71(59;77) years) with a detectable viral load, 140 were treated with remdesivir (of those 103 in the ICU and 57 immunosuppressed) and retrospectively compared with 199 patients (of those 82 in the ICU and 28 immunosuppressed) who were denied therapy due to advanced Covid-19. The viral load was estimated by detecting nucleocapsid antigen in serum (n = 155, median 217(28;1524)pg/ml), antigen in sputum (n = 18, COI 18(4.6;32)), nasopharyngeal antigen (n = 44, COI 17(8;35)) and the real-time PCR (n = 122, Ct 21(18;27)). After adjustment for confounders, patients on remdesivir had better 12-month survival (HR 0.66 (0.44;0.98), p = 0.039), particularly when admitted to the ICU (HR 0.49 (0.29;0.81), p = 0.006). For the immunocompromised patients, the difference did not reach statistical significance (HR 0.55 (0.18;1.69), p = 0.3). The other most significant confounders were age, ICU admission, mechanical ventilation, leukocyte/lymphocyte ratio, admission creatinine and immunosuppression. The impact of monoclonal antibodies or previous vaccinations was not significant. Despite frequent immune suppression including haemato-oncology diseases, lymphopenia, and higher inflammatory markers in the remdesivir group, the results support remdesivir administration with respect to widely available estimates of viral load in patients with high illness severity.

Asunto(s)

Adenosina Monofosfato , Alanina , Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , SARS-CoV-2 , Carga Viral , Humanos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/uso terapéutico , Masculino , Femenino , Carga Viral/efectos de los fármacos , Anciano , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/fisiología , Persona de Mediana Edad , COVID-19/virología , COVID-19/mortalidad , Antivirales/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Cuidados Críticos , Unidades de Cuidados Intensivos , Índice de Severidad de la Enfermedad

RESUMEN

BACKGROUND: Direct acting antivirals (DAAs) for the Hepatitis C virus (HCV) have shifted the World Health Organisation global strategic focus to the elimination of HCV by 2030. In England, the UK Health Security Agency (UKHSA) led a national 'patient re-engagement exercise', using routine surveillance data, which was delivered through the HCV Operational Delivery Networks (ODNs) with support from National Health Service England (NHSE), to help find and support people with a positive HCV PCR test result to access treatment. We report a quantitative evaluation of outcomes of this exercise. METHODS: Individuals with a recorded positive HCV antibody or PCR result between 1996 and 2017 were identified using UKHSA's records of HCV laboratory diagnosis. Linkage with established health-care datasets helped to enhance patient identification and minimise attempts to contact deceased or previously treated individuals. From September to November 2018 each ODN was provided with a local list of diagnosed individuals. ODNs were asked to perform further data quality checks through local systems and then write to each individual's GP to inform them that the individual would be contacted by the ODN to offer confirmatory HCV PCR testing, assessment and treatment unless the GP advised otherwise. Outcomes of interest were receipt of treatment, a negative PCR result, and death. Data were collected in 2022. RESULTS: Of 176,555 individuals with a positive HCV laboratory report, 55,329 individuals were included in the exercise following linkage to healthcare datasets and data reconciliation. Participants in the study had a median age of 51 years (IQR: 43, 59), 36,779 (66.5%) were males, 47,668 (86.2%) were diagnosed before 2016 and 11,148 (20.2%) lived in London. Of the study population, 7,442 (13.4%) had evidence of treatment after the re-engagement exercise commenced, 6,435 (11.6%) were reported as PCR negative (96% had no previous treatment records), 4,195 (7.6%) had prescription data indicating treatment before the exercise commenced or were reported to have been treated previously by their ODN, and 2,990 (5.4%) had died. The status of 32,802 (59.3%) people remains unknown. CONCLUSIONS: A substantial number of those included had treatment recorded after the exercise commenced, however, many more remain unengaged. Evaluation of the exercise highlighted areas that could be streamlined to improve future exercises.

Asunto(s)

Antivirales , Humanos , Masculino , Antivirales/uso terapéutico , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Inglaterra/epidemiología , Hepatitis C/tratamiento farmacológico , Hepatitis C/diagnóstico , Anciano , Aceptación de la Atención de Salud/estadística & datos numéricos , Hepacivirus/aislamiento & purificación

RESUMEN

Background: The high infectivity of coronaviruses has led to increased interest in developing new strategies to prevent virus spread. Silver nanoparticles (AgNPs) and graphene oxide (GO) have attracted much attention in the antiviral field. We investigated the potential antiviral activity of GO and AgNPs combined in the nanocomposite GO-Ag against murine betacoronavirus MHV using an in vitro model. Methods: GO, AgNPs, and GO-Ag characterization (size distribution, zeta potential, TEM visualization, FT-IR, and EDX analysis) and XTT assay were performed. The antiviral activity of GO-Ag nanocomposites was evaluated by RT-qPCR and TCID50 assays. The results were compared with free AgNPs and pure GO. Cell growth and morphology of MHV-infected hepatocytes treated with GO-Ag composites were analyzed by JuLI™Br. Immunofluorescence was used to visualize the cell receptor used by MHV. Ultrastructural SEM analysis was performed to examine cell morphology after MHV infection and GO-Ag composite treatment. Results: A significant reduction in virus titer was observed for all nanocomposites tested, ranging from 3.2 to 7.3 log10 TCID50. The highest titer reduction was obtained for GO 5 µg/mL - Ag 25 µg/mL in the post-treatment method. These results were confirmed by RT-qPCR analysis. The results indicate that GO-Ag nanocomposites exhibited better antiviral activity compared to AgNPs and GO. Moreover, the attachment of AgNPs to the GO flake platform reduced their cytotoxicity. In addition, the GO-Ag composite modulates the distribution of the Ceacam1 cell receptor and can modulate cell morphology. Conclusion: Graphene oxide sheets act as a stabilizing agent, inhibiting the accumulation of AgNPs and reducing their cellular toxicity. The GO-Ag composite can physically bind and inhibit murine betacoronavirus from entering cells. Furthermore, the constant presence of GO-Ag can inhibit MHV replication and significantly limit its extracellular release. In conclusion, GO-Ag shows promise as an antiviral coating on solid surfaces to minimize virus transmission and spread.

Asunto(s)

Antivirales , Grafito , Nanopartículas del Metal , Nanocompuestos , Plata , Grafito/farmacología , Grafito/química , Plata/química , Plata/farmacología , Animales , Nanocompuestos/química , Antivirales/farmacología , Antivirales/química , Ratones , Nanopartículas del Metal/química , Virus de la Hepatitis Murina/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/virología , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Línea Celular

RESUMEN

Human parainfluenza virus type 3 (HPIV-3) can cause severe respiratory tract infections. There are no convenient small-animal infection models. Here, we show viral replication in the upper and lower airways of AG129 mice (double IFNα/ß and IFNγ receptor knockout mice) upon intranasal inoculation. By multiplex fluorescence RNAscope and immunohistochemistry followed by confocal microscopy, we demonstrate viral tropism to ciliated cells and club cells of the bronchiolar epithelium. HPIV-3 causes a marked lung pathology. No virus transmission of the virus was observed by cohousing HPIV-3-infected AG129 mice with other mice. Oral treatment with GS-441524, the parent nucleoside of remdesivir, reduced infectious virus titers in the lung, with a relatively normal histology. Intranasal treatment also affords an antiviral effect. Thus, AG129 mice serve as a robust preclinical model for developing therapeutic and prophylactic strategies against HPIV-3. We suggest further investigation of GS-441524 and its prodrug forms to treat HPIV-3 infection in humans.

Asunto(s)

Antivirales , Modelos Animales de Enfermedad , Pulmón , Ratones Noqueados , Virus de la Parainfluenza 3 Humana , Infecciones por Respirovirus , Animales , Pulmón/virología , Pulmón/patología , Pulmón/efectos de los fármacos , Ratones , Virus de la Parainfluenza 3 Humana/efectos de los fármacos , Virus de la Parainfluenza 3 Humana/fisiología , Antivirales/farmacología , Infecciones por Respirovirus/tratamiento farmacológico , Infecciones por Respirovirus/virología , Humanos , Replicación Viral/efectos de los fármacos , Femenino , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/metabolismo , Receptor de Interferón alfa y beta/deficiencia , Adenosina/análogos & derivados , Adenosina/farmacología , Tropismo Viral , Benzamidas , Ftalimidas