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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.
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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 , FemeninoRESUMEN
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.
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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 PresiónRESUMEN
Influenza is an important zoonotic disease that persistently threatens global public health. While it is widely acknowledged that probiotics can modulate the host response to protect the host against infectious disease, the prophylactic efficacy on respiratory viral infection and the detailed mechanism remains elusive. Lactobacillus, the most commonly used probiotic widely applied in food production, has garnered significant attention. In our study utilizing both C57BL/6 and BALB/c mouse models, we explored the protective effect against two strains of influenza virus, A/Mink/China/01/2014(H9N2) and A/California/04/2009(H1N1), through the administration of Lactiplantibacillus plantarum strain 16 (L. plantarum 16) and Lacticaseibacillus rhamnosus strain P118 (L. rhamnosus P118), aiming to identify robust probiotic strains with antiviral properties. Our findings indicate that administering L. plantarum 16 or L. rhamnosus P118 alone does not provide sufficient protection against influenza. However, the co-administration of L. plantarum 16 and L. rhamnosus P118 dramatically reduces viral titers in the respiratory tract and lung, thereby markedly alleviating the clinical symptoms, improving prognosis, and reducing mortality. The mechanisms underlying this effect involve the modulation of host gut microbiota and metabolism through the co-administration of L. plantarum 16 and L. rhamnosus P118, resulting in enrichment of Firmicutes and enhancement of phenylalanine-related metabolism, ultimately leading to an augmentation of the antiviral immune response. Notably, we identified that the circulating metabolic molecule 2-Hydroxycinnamic acid plays a significant role in combating influenza. Our data suggest the potential utility of L. plantarum 16 and L. rhamnosus P118 two-bacterium or 2-Hydroxycinnamic acid in preventing influenza.IMPORTANCEVaccination represents the most optimal strategy to control influenza. Nevertheless, influenza viruses constantly evolve due to antigenic drift and shift, leading to the need for regular updates on influenza vaccines. Additionally, vaccination failure poses significant challenges to influenza prevention. Therefore, it is essential and beneficial to identify novel or universal antiviral measures to protect against influenza. While cumulative data suggest that probiotics offer protection against infectious diseases, the specific mechanisms, such as the effective metabolites or components, remain largely unknown. Our research discovered the capacity of combinational two-bacterium Lactiplantibacillus plantarum 16 and Lacticaseibacillus rhamnosus P118 to fight against influenza infection in a mouse model. The protection may occur through modulating the host's gut microbiota and metabolism, further influencing the host's antiviral immune response. Notably, we have identified a novel metabolic molecule, 2-Hydroxycinnamic acid, capable of enhancing antiviral response and restricting viral replication in vivo.
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In March 2023, our pediatric intensive care unit (PICU) retrospectively examined six cases of pediatric necrotizing tracheobronchitis (NTB), focusing on co-infections with influenza A virus (IAV) and Staphylococcus aureus (S. aureus). This study aimed to elucidate NTB's clinical characteristics, diagnostics, and therapeutic approaches. Diagnostics included symptom assessment, microbiological testing that confirmed all patients were positive for IAV H1N1 with a predominant S. aureus co-infection, and bronchoscopy. The patients predominantly exhibited fever, cough, and dyspnea. Laboratory analysis revealed decreased lymphocyte counts and elevated infection markers like C-reactive protein and procalcitonin. Chest computed tomography (CT) scans detected tracheobronchial obstructions in half of the cases, while bronchoscopy showed severe mucosal congestion, edema, necrosis, and purulent-hemorrhagic exudates. Treatments encompassed comprehensive strategies like oxygen therapy, intubation, bronchoscopic interventions, thoracentesis, oseltamivir, and a regimen of antibiotics. Our findings suggested potential correlations between clinical markers, notably lymphocyte count and procalcitonin, and clinical interventions such as the number of rescues and intensive care unit (ICU) duration. This research highlights the importance of early detection and the role of bronchoscopy and specific markers in assessing NTB, advocating for continued research in larger cohorts to better understand its clinical trajectory and refine treatment approaches for this challenging pediatric disease.
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Bronquitis , Coinfección , Gripe Humana , Infecciones Estafilocócicas , Staphylococcus aureus , Traqueítis , Humanos , Coinfección/diagnóstico , Masculino , Femenino , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/complicaciones , Gripe Humana/complicaciones , Gripe Humana/diagnóstico , Preescolar , Traqueítis/diagnóstico , Traqueítis/microbiología , Traqueítis/complicaciones , Bronquitis/diagnóstico , Bronquitis/microbiología , Bronquitis/complicaciones , Estudios Retrospectivos , Staphylococcus aureus/aislamiento & purificación , Lactante , Niño , Broncoscopía/métodos , Unidades de Cuidado Intensivo Pediátrico , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Necrosis , Virus de la Influenza A/aislamiento & purificaciónRESUMEN
The prevalence of highly pathogenic avian influenza (HPAI) A(H5N1) viruses has increased in wild birds and poultry worldwide, and concomitant outbreaks in mammals have occurred. During 2023, outbreaks of HPAI H5N1 virus infections were reported in cats in South Korea. The H5N1 clade 2.3.4.4b viruses isolated from 2 cats harbored mutations in the polymerase basic protein 2 gene encoding single amino acid substitutions E627K or D701N, which are associated with virus adaptation in mammals. Hence, we analyzed the pathogenicity and transmission of the cat-derived H5N1 viruses in other mammals. Both isolates caused fatal infections in mice and ferrets. We observed contact infections between ferrets, confirming the viruses had high pathogenicity and transmission in mammals. Most HPAI H5N1 virus infections in humans have occurred through direct contact with poultry or a contaminated environment. Therefore, One Health surveillance of mammals, wild birds, and poultry is needed to prevent potential zoonotic threats.
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Introduction: Influenza A virus (IAV) infection is a global respiratory disease, which annually leads to 3-5 million cases of severe illness, resulting in 290,000-650,000 deaths. Additionally, during the past century, four global IAV pandemics have claimed millions of human lives. The epithelial lining of the trachea plays a vital role during IAV infection, both as point of viral entry and replication as well as in the antiviral immune response. Tracheal tissue is generally inaccessible from human patients, which makes animal models crucial for the study of the tracheal host immune response. Method: In this study, pigs were inoculated with swine- or human-adapted H1N1 IAV to gain insight into how host adaptation of IAV shapes the innate immune response during infection. In-depth multi-omics analysis (global proteomics and RNA sequencing) of the host response in upper and lower tracheal tissue was conducted, and results were validated by microfluidic qPCR. Additionally, a subset of samples was selected for histopathological examination. Results: A classical innate antiviral immune response was induced in both upper and lower trachea after infection with either swine- or human-adapted IAV with upregulation of genes and higher abundance of proteins associated with viral infection and recognition, accompanied by a significant induction of interferon stimulated genes with corresponding higher proteins concentrations. Infection with the swine-adapted virus induced a much stronger immune response compared to infection with a human-adapted IAV strain in the lower trachea, which could be a consequence of a higher viral load and a higher degree of inflammation. Discussion: Central components of the JAK-STAT pathway, apoptosis, pyrimidine metabolism, and the cytoskeleton were significantly altered depending on infection with swine- or human-adapted virus and might be relevant mechanisms in relation to antiviral immunity against putative zoonotic IAV. Based on our findings, we hypothesize that during host adaptation, IAV evolve to modulate important host cell elements to favor viral infectivity and replication.
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Infecciones por Orthomyxoviridae , Proteómica , Tráquea , Animales , Tráquea/inmunología , Tráquea/virología , Porcinos , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Proteómica/métodos , Humanos , Adaptación al Huésped/inmunología , Inmunidad Innata , Subtipo H1N1 del Virus de la Influenza A/inmunología , Interacciones Huésped-Patógeno/inmunología , MultiómicaRESUMEN
Emerging viruses, such as novel influenza A viruses (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose a constant threat to animal and human health. Identification of host cell factors necessary for viral replication but dispensable for cellular survival might reveal novel, attractive targets for therapeutic intervention. Proteolytic activation of IAV hemagglutinin (HA) and SARS-CoV-2 spike protein (S) by the type II transmembrane serine protease (TTSPs), e.g. TMPRSS2 is sought to be critical for viral spread and pathogenesis. Here, we investigated the secondary structure of TMPRSS2 mRNA coding sequence and designed TMPRSS2-specific antisense oligonucleotides (ASOs). Several of these ASOs markedly reduced the TMPRSS2 expression and decreased IAV infection and SARS-CoV-2 entry into cells.
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A total of 1019 samples collected on 726 Spanish swine farms suffering from outbreaks of respiratory disease were screened for influenza A viruses (IAVs) using a RT-qPCR method. A subset of positive samples was further analyzed using a subtype-specific RT-qPCR method (n: 142) and Sanger sequencing (n: 64). A total of 19.4% samples from 23% farms tested positive, with infection being most common in suckling (53.6%) and weaning pigs (30.2%). Viruses belonging to four HA subtypes (H1av, H1hu, H1pdm, H3) were detected, with subtypes H1avN2, H1huN2 and H1avN1 accounting for over half of the specimens. An optimized protocol with newly designed primers allowed the detection of H3 viruses in a significant number of samples (21%). A comparison of antigenic positions revealed that circulating strains exhibited mutations with vaccine strains in a significant percentage of amino acid residues, both in the NA protein (27.8-43.3%) and particularly in the HA protein (51-75.3%).
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We tested the ability of six peridomestic wildlife species to replicate a highly pathogenic (HP) clade 2.3.4.4b AIV (H5N1) isolated in the U.S. during 2022. All tested species replicated and shed virus, at least to some degree. Of the six species evaluated (house sparrows (Passer domesticus), European starlings (Sturnus vulgaris), feral pigeons (Columba livia), striped skunks (Mephitis mephitis), Virginia opossums (Didelphis virginiana), and cottontails (Sylvilagus sp.)), striped skunks and Virginia opossums shed the highest viral titers of 106.3 PFU/mL and 105.0 PFU/mL, respectively. Overall, the results of this study indicate that certain peridomestic species could pose a biosecurity threat to poultry operations in some situations. In addition, this study and field reports indicate that the HP AIVs circulating in the U.S. during 2022-2024 may have an extremely broad range of species that can be impacted by and/or replicate and shed these viruses.
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The chemical constituents of Saxifraga stolonifera, S. fortunei, S. nipponica, S. cortusifolia, and S. rebunshirensis were investigated for structure and virucidal activity. In addition to the Saxifraga species-derived tannins, 30 compounds (1-30) were isolated from the five species. 5-Hydroxy-4-methoxy-3-O-(6-O-caffeoyl)-ß-D-glucopyranosyl benzoic acid (1) and kaempferol 3-O-ß-d-xylopyranosyl-(1â¯ââ¯2)-ß-D-xylopyranoside (2) were identified as undescribed compounds. Although 1 was isolated as the (E)-isomer of its caffeoyl moiety, under light it became over time a mixture of the (Z)-isomer (1a) and (E)-isomer (1). Kaempferol 3-O-ß-d-xylopyranosyl-(1â¯ââ¯2)-ß-D-glucopyranoside (3) was an analog of 2 and a known compound, whose NMR assignment was reconsidered and described. 6-Isopropyl-5,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione (30) was expected to be a racemic mixture based on its optical rotation and X-ray crystallography data. The virucidal activities of the isolated compounds (1-30) against influenza A virus, severe acute respiratory syndrome coronavirus 2, feline calicivirus, and murine norovirus were evaluated to identify the presence of compounds other than the Saxifraga species-derived tannins, which exhibited virucidal activities. Although the isolated compound activities were relatively weak compared to those of Saxifraga species-derived tannins, the potential virucidal activity of the compounds with galloyl groups was confirmed.
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Between 2013 and 2018, the novel A/Anhui/1/2013 (AH/13)-lineage H7N9 virus caused at least five waves of outbreaks in humans, totaling 1,567 confirmed human cases in China. Surveillance data indicated a disproportionate distribution of poultry infected with this AH/13-lineage virus, and laboratory experiments demonstrated that this virus can efficiently spread among chickens but not among Pekin ducks. The underlying mechanism of this selective transmission remains unclear. In this study, we demonstrated the absence of Neu5Gc expression in chickens across all respiratory and gastrointestinal tissues. However, Neu5Gc expression varied among different duck species and even within the tissues of the same species. The AH/13-lineage viruses exclusively bind to acetylneuraminic acid (Neu5Ac), in contrast to wild waterbird H7 viruses that bind both Neu5Ac and N-glycolylneuraminic acid (Neu5Gc). The level of Neu5Gc expression influences H7 virus replication and facilitates adaptive mutations in these viruses. In summary, our findings highlight the critical role of Neu5Gc in affecting the host range and interspecies transmission dynamics of H7 viruses among avian species.IMPORTANCEMigratory waterfowl, gulls, and shorebirds are natural reservoirs for influenza A viruses (IAVs) that can occasionally spill over to domestic poultry, and ultimately humans. This study showed wild-type H7 IAVs from waterbirds initially bind to glycan receptors terminated with N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc). However, after enzootic transmission in chickens, the viruses exclusively bind to Neu5Ac. The absence of Neu5Gc expression in gallinaceous poultry, particularly chickens, exerts selective pressure, shaping IAV populations, and promoting the acquisition of adaptive amino acid substitutions in the hemagglutinin protein. This results in the loss of Neu5Gc binding and an increase in virus transmissibility in gallinaceous poultry, particularly chickens. Consequently, the transmission capability of these poultry-adapted H7 IAVs in wild water birds decreases. Timely intervention, such as stamping out, may help reduce virus adaptation to domestic chicken populations and lower the risk of enzootic outbreaks, including those caused by IAVs exhibiting high pathogenicity.
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Increased circulating tissue inhibitor of metalloproteinases-1 (TIMP-1) levels have been observed in patients with acute lung injury (ALI). However, the sex-specific regulation of TIMP-1 and the underlying molecular mechanisms have not been well elucidated. In this study, we found that plasma TIMP-1 levels were significantly higher in COVID-19 and H1N1 patients compared with those in healthy subjects (n = 25). TIMP-1 concentrations were significantly different between males and females in each disease group. Among female but not male patients, TIMP-1 levels significantly correlated with the PaO2/FiO2 ratio and hospital length of stay. Using the mouse model of ALI induced by the H1N1 virus, we found that TIMP-1 is strikingly induced in PDGFRα-positive cells in the murine lungs. Moreover, female mice showed a higher Timp-1 expression in the lungs on day 3 postinfection. Mechanistically, we observed that estrogen can upregulate TIMP-1 expression in lung fibroblasts, not epithelial cells. In addition, overexpression of estrogen receptor α (ERα) increased the TIMP-1 promoter activity. In summary, TIMP-1 is an estrogen-responsive gene, and its promoter activity is regulated by ERα. Circulating TIMP-1 may serve as a sex-specific marker, reflecting the severity and worst outcomes in female patients with SARS-CoV2- and IAV-related ALI.
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Lesión Pulmonar Aguda , Biomarcadores , COVID-19 , Receptor alfa de Estrógeno , Inhibidor Tisular de Metaloproteinasa-1 , Lesión Pulmonar Aguda/genética , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/sangre , Animales , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/sangre , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Femenino , Masculino , Humanos , Ratones , COVID-19/metabolismo , COVID-19/genética , COVID-19/sangre , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genética , Biomarcadores/sangre , Biomarcadores/metabolismo , Estrógenos/sangre , Persona de Mediana Edad , Subtipo H1N1 del Virus de la Influenza A , Pulmón/metabolismo , SARS-CoV-2 , Adulto , Regulación de la Expresión Génica , Ratones Endogámicos C57BL , Factores Sexuales , Caracteres Sexuales , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Orthomyxoviridae/sangre , Infecciones por Orthomyxoviridae/genéticaRESUMEN
The ever-increasing antigenic diversity of the hemagglutinin (HA) of influenza A virus (IAV) poses a significant challenge for effective vaccine development. Notably, the matrix protein 2 (M2) is a highly conserved 97 amino acid long transmembrane tetrameric protein present in the envelope of IAV. More than 99â¯% of IAV strains circulating in American swine herds share the identical pandemic (pdm) isoform of M2, making it an ideal target antigen for a vaccine that could elicit broadly protective immunity. Here, using soluble nanoscale membrane assemblies termed nanodiscs (NDs), we designed this membrane mimetic nanostructures displaying full-length M2 in its natural transmembrane configuration (M2ND). Intramuscular (IM) immunization of swine with M2ND mixed with conventional emulsion adjuvant elicited M2-specific IgG antibodies in the serum that recognized influenza virions and M2-specific interferon-γ secreting cells present in the blood. Intranasal (IN) immunization with M2ND adjuvanted with a mycobacterial extract elicited M2-specific IgA in mucosal secretions that also recognized IAV. Immunization with an influenza whole inactivated virus (WIV) vaccine supplemented with a concurrent IM injection of M2ND mixed with an emulsion adjuvant increased the level of protective immunity afforded by the former against a challenge with an antigenically distinct H3N2 IAV, as exhibited by an enhanced elimination of virus from the lung. The lone IM administration of the M2ND vaccine mixed with an emulsion adjuvant provided measurable protection as evidenced by a >10-fold reduction or complete elimination of the challenge virus from the lung, but it did not diminish the viral load in nasal secretions nor the extent of pneumonia that ensued after the virus challenge. In contrast, an improved formulation of the M2ND vaccine that incorporated synthetic CpG oligodeoxynucleotides (CpG-ODN) in the nanostructures administered alone, via the IN and IM routes combined, provided a significant level of protective immunity against IAV as evidenced by a decreased viral load in both the upper and lower respiratory tracts and fully eliminated the occurrence of pneumonia in 89â¯% of the pigs immunized with this biologic. Notably, to be effective, the M2 protein must be displayed in the ND assemblies, as shown by the observation that simply mixing M2 with empty NDs incorporating CpG-ODN (eND-CpG-ODN) did not provide protective immunity. This novel M2-based vaccine offers great promise to help increase the breadth of protection afforded by conventional WIV vaccines against the diversity of IAV in circulation and, plausibly, as a broadly protective stand-alone biologic.
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This study compared the safety and pharmacokinetics of a single oral dose of onradivir, an inhibitor of polymerase basic protein 2 in influenza A virus, in patients with hepatic impairment and healthy participants with normal hepatic function. Eight participants with mild hepatic impairment (Child-Pugh A), eight participants with moderate hepatic impairment (Child-Pugh B), and eight healthy matched controls were enrolled in this open-label, parallel-group clinical trial. After the administration of 600 mg of onradivir, pharmacokinetic parameters were calculated for each cohort and compared. Onradivir was generally well tolerated by all participants. No serious adverse events (AEs) and no deaths were reported during the study. Six patients with moderate hepatic impairment and three patients with mild hepatic impairment reported AEs, all of which were mild and quickly resolved. Compared with the normal liver function group, the maximum concentration, area under the curve from time zero to the last measurable concentration, and area under the curve from time zero to infinity were 103%, 68.5%, and 69.2% higher, respectively, in the mild hepatic impairment group. In the moderate hepatic impairment group, these increases were 101%, 197%, and 204%, respectively. Overall, there were clinically relevant differences in onradivir exposure between patients with mild or moderate hepatic impairment and normal controls. These data imply that onradivir dose adjustment is warranted in patients with mild or moderate hepatic impairment. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05856513).
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Objective: This study aims to enhance understanding of necrotizing pneumonia and toxic shock syndrome by analyzing an adult case of community-acquired necrotizing pneumonia caused by co-infection of Influenza A (H1N1) and Staphylococcus aureus with LukS-PV and LukF-PV virulence factor genes. Method: The clinical data of one patient admitted to the intensive care unit (ICU) with co-infection of Influenza A (H1N1) and Staphylococcus aureus was retrospectively analyzed. Results: The patient exhibited typical clinical manifestations of viral and Staphylococcus aureus co-infection, including necrotizing pneumonia and toxic shock syndrome. The presence of LukS-PV and LukF-PV virulence factor genes of Staphylococcus aureus was detected in the patient's bronchoalveolar lavage fluid. Unfortunatelyï¼although antiviral agents (oseltamivir) and antibiotics (linezolid, imipenem-cilastatin) were timely administrated, as well as corticosteroids for anti-inflammatory purposes, the patient's condition was progressively deteriorated and eventually led to death. Conclusion: Clinical practitioners should be vigilant about the co-infection of Influenza virus and Staphylococcus aureus, particularly when the latter carries virulence factors. The presence of virulence factor genes of Staphylococcus aureus can lead to necrotizing pneumonia with a poor prognosis. This is a particular concern because both infections can be life threatening in young adults.
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AbstractMultiple genetic variants of H1 and H3 influenza A viruses (IAVs) circulate concurrently in US swine farms. Understanding the spatial transmission patterns of IAVs among these farms is crucial for developing effective control strategies and mitigating the emergence of novel IAVs. In this study, we analyzed 1,909 IAV genomic sequences from 785 US swine farms, representing 33 farming systems across 12 states, primarily in the Midwest from 2004 to 2023. Bayesian phylogeographic analyses were performed to identify the dispersal patterns of both H1 and H3 virus genetic lineages and to elucidate their spatial migration patterns within and between different systems. Our results showed that both intra-system and inter-system migrations occurred between the swine farms, with intra-system migrations being more frequent. However, migration rates for H1 and H3 IAVs were similar between intra-system and inter-system migration events. Spatial migration patterns aligned with expected pig movement across different compartments of swine farming systems. Sow-Farms were identified as key sources of viruses, with bi-directional migration observed between these farms and other parts of the system, including Wean-to-Finish and Gilt-Development-Units. High intra-system migration was detected across farms in the same region, while spread to geographically distant intra- and inter- system farms was less frequently. These findings suggest that prioritizing resources towards systems frequently confronting influenza problems and targeting pivotal source farms, such as sow farms, could be an effective strategy for controlling influenza in US commercial swine operations.
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Caspase-8, an aspartate-specific cysteine protease that primarily functions as an initiator caspase to induce apoptosis, can downregulate innate immunity in part by cleaving RIPK1 and IRF3. However, patients with caspase-8 mutations or deficiency develop immunodeficiency and are prone to viral infections. The molecular mechanism underlying this controversy remains unknown. Whether caspase-8 enhances or suppresses antiviral responses against influenza A virus (IAV) infection remains to be determined. Here, we report that caspase-8 is readily activated in A549 and NL20 cells infected with the H5N1, H5N6, and H1N1 subtypes of IAV. Surprisingly, caspase-8 deficiency and two caspase-8 inhibitors, Z-VAD and Z-IETD, do not enhance but rather downregulate antiviral innate immunity, as evidenced by decreased TBK1, IRF3, IκBα, and p65 phosphorylation, decreased IL-6, IFN-ß, MX1, and ISG15 gene expression; and decreased IFN-ß production but increased virus replication. Mechanistically, caspase-8 cleaves and inactivates CYLD, a tumor suppressor that functions as a deubiquitinase. Caspase-8 inhibition suppresses CYLD cleavage, RIG-I and TAK1 ubiquitination, and innate immune signaling. In contrast, CYLD deficiency enhances IAV-induced RIG-I and TAK1 ubiquitination and innate antiviral immunity. Neither caspase-3 deficiency nor treatment with its inhibitor Z-DEVD affects CYLD cleavage or antiviral innate immunity. Our study provides evidence that caspase-8 activation in two human airway epithelial cell lines does not silence but rather enhances innate immunity by inactivating CYLD.
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Caspasa 8 , Proteína 58 DEAD Box , Enzima Desubiquitinante CYLD , Inmunidad Innata , Virus de la Influenza A , Gripe Humana , Quinasas Quinasa Quinasa PAM , Ubiquitinación , Humanos , Enzima Desubiquitinante CYLD/metabolismo , Enzima Desubiquitinante CYLD/genética , Caspasa 8/metabolismo , Caspasa 8/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Quinasas Quinasa Quinasa PAM/genética , Quinasas Quinasa Quinasa PAM/inmunología , Virus de la Influenza A/inmunología , Proteína 58 DEAD Box/metabolismo , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Células A549 , Animales , Transducción de Señal/inmunología , Receptores InmunológicosRESUMEN
Plastic bronchitis is a relatively uncommon illness that has been reported in all age groups. This case report describes a specific manifestation of plastic bronchitis in two pediatric brothers influenced by both smoke inhalation and influenza A virus infection. The therapeutic approach mainly involved symptomatic supportive care, antiviral therapy, repeated bronchoscopic alveolar lavage, and bronchial cast removal. Eventually, both patients went into remission. Bronchoscopy proved to be helpful in diagnosing and treating these cases.
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Bronquitis , Broncoscopía , Gripe Humana , Humanos , Gripe Humana/complicaciones , Gripe Humana/diagnóstico , Bronquitis/diagnóstico , Bronquitis/etiología , Masculino , Lesión por Inhalación de Humo/terapia , Lesión por Inhalación de Humo/complicaciones , Antivirales/uso terapéutico , Niño , Virus de la Influenza A/aislamiento & purificación , Lavado BroncoalveolarRESUMEN
Nuclear export of the viral ribonucleoprotein (vRNP) is a critical step in the influenza A virus (IAV) life cycle and may be an effective target for the development of anti-IAV drugs. The host factor ras-related nuclear protein (RAN) is known to participate in the life cycle of several viruses, but its role in influenza virus replication remains unknown. In the present study, we aimed to determine the function of RAN in influenza virus replication using different cell lines and subtype strains. We found that RAN is essential for the nuclear export of vRNP, as it enhances the binding affinity of XPO1 toward the viral nuclear export protein NS2. Depletion of RAN constrained the vRNP complex in the nucleus and attenuated the replication of various subtypes of influenza virus. Using in silico compound screening, we identified that bepotastine could dissociate the RAN-XPO1-vRNP trimeric complex and exhibit potent antiviral activity against influenza virus both in vitro and in vivo. This study demonstrates the important role of RAN in IAV replication and suggests its potential use as an antiviral target.
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Transporte Activo de Núcleo Celular , Antivirales , Proteína Exportina 1 , Virus de la Influenza A , Carioferinas , Replicación Viral , Proteína de Unión al GTP ran , Replicación Viral/efectos de los fármacos , Humanos , Proteína de Unión al GTP ran/metabolismo , Proteína de Unión al GTP ran/genética , Antivirales/farmacología , Animales , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/fisiología , Carioferinas/metabolismo , Carioferinas/antagonistas & inhibidores , Perros , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Células de Riñón Canino Madin Darby , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/genética , Ratones , Piperidinas/farmacología , Gripe Humana/virología , Células A549 , Nucleoproteínas/metabolismo , Nucleoproteínas/genética , Células HEK293 , Línea Celular , Núcleo Celular/metabolismo , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genéticaRESUMEN
Transmission is the first step for a microorganism to establish colonization in the respiratory tract and subsequent development of infectious disease. Streptococcus pneumoniae is a leading pathogen that colonizes the mucosal surfaces of the human upper respiratory tract and causes subsequent transmission and invasive infections especially in co-infection with influenza A virus. Host factors contributing to respiratory contagion are poorly understood. Transient receptor potential vanilloid (TRPV) channels have various roles in response to microoorganism. Inhibition of TRPV exacerbates invasive infection by Streptococcus pneumoniae, but it is unclear how TRPV channels influence pneumococcal transmission. Here, we describe the effect of inhibition of TRPV1 on pneumococcal transmission. We adopted a TRPV1-deficient infant mouse model of pneumococcal transmission during co-infection with influenza A virus. We also analyzed the expression of nasal mucin or pro-inflammatory cytokines. TRPV1 deficiency attenuated pneumococcal transmission and shedding during co-infection with influenza A virus. TRPV1 deficiency suppressed the expression of nasal mucin. In addition, there were increases in the expression of tumor necrosis factor-α and type I interferon, followed by the suppressed replication of influenza A virus in TRPV1-deficient mice. Inhibition of TRPV1 was shown to attenuate pneumococcal transmission by reducing shedding through the suppression of nasal mucin during co-infection with influenza A virus. Inhibition of TRPV1 suppressed nasal mucin by modulation of pro-inflammatory responses and regulation of replication of influenza A virus. TRPV1 could be a new target in preventive strategy against pneumococcal transmission.