RESUMEN
The influenza virus (IFV) imposes a considerable health and economic burden globally, requiring a comprehensive understanding of its pathogenic mechanisms. Ferroptosis, an iron-dependent lipid peroxidation cell death pathway, holds unique implications for the antioxidant defense system, with possible contributions to inflammation. This exploration focuses on the dynamic interplay between ferroptosis and the host defense against viruses, emphasizing the influence of IFV infections on the activation of the ferroptosis pathway. IFV causes different types of cell death, including apoptosis, necrosis, and ferroptosis. IFV-induced ferroptotic cell death is mediated by alterations in iron homeostasis, intensifying the accumulation of reactive oxygen species and promoting lipid peroxidation. A comprehensive investigation into the mechanism of ferroptosis in viral infections, specifically IFV, has great potential to identify therapeutic strategies. This understanding may pave the way for the development of drugs using ferroptosis inhibitors, presenting an effective approach to suppress viral infections.
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Ferroptosis , Gripe Humana , Hierro , Peroxidación de Lípido , Orthomyxoviridae , Especies Reactivas de Oxígeno , Humanos , Gripe Humana/virología , Gripe Humana/metabolismo , Animales , Orthomyxoviridae/fisiología , Orthomyxoviridae/patogenicidad , Especies Reactivas de Oxígeno/metabolismo , Hierro/metabolismo , ApoptosisRESUMEN
In this issue of Cell Host & Microbe, Karakus et al. find that an influenza virus enters cells by exclusively binding to a protein instead of sugars.
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Gripe Humana , Internalización del Virus , Humanos , Gripe Humana/virología , Virus de la Influenza A/fisiología , Animales , Orthomyxoviridae/fisiologíaRESUMEN
The devastating effects of COVID-19 have highlighted the importance of prophylactic and therapeutic strategies to combat respiratory diseases. Stimulator of interferon gene (STING) is an essential component of the host defense mechanisms against respiratory viral infections. Although the role of the cGAS/STING signaling axis in the innate immune response to DNA viruses has been thoroughly characterized, mounting evidence shows that it also plays a key role in the prevention of RNA virus infections. In this study, we investigated the role of STING activation during Influenza virus (IFV) infection. In both mouse bone marrow-derived macrophages and monocytic cell line THP-1 differentiated with PMA, we found that dimeric amidobenzimidazole (diABZI), a STING agonist, had substantial anti-IFV activity against multiple strains of IFV, including A/H1N1, A/H3N2, B/Yamagata, and B/Victoria. On the other hand, a pharmacological antagonist of STING (H-151) or the loss of STING in human macrophages leads to enhanced viral replication but suppressed IFN expression. Furthermore, diABZI was antiviral against IFV in primary air-liquid interface cultures of nasal epithelial cells. Our data suggest that STING agonists may serve as promising therapeutic antiviral agents to combat IFV.
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Antivirales , Inmunidad Innata , Macrófagos , Proteínas de la Membrana , Animales , Humanos , Inmunidad Innata/efectos de los fármacos , Ratones , Antivirales/farmacología , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/virología , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Células THP-1 , Replicación Viral/efectos de los fármacos , Gripe Humana/inmunología , Gripe Humana/virología , Gripe Humana/tratamiento farmacológico , Perros , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , Orthomyxoviridae/efectos de los fármacos , Orthomyxoviridae/inmunología , Orthomyxoviridae/fisiología , Bencimidazoles/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Influenza virus infection is initiated by the attachment of the viral haemagglutinin (HA) protein to sialic acid receptors on the host cell surface. Most virus particles enter cells through clathrin-mediated endocytosis (CME). However, it is unclear how viral binding signals are transmitted through the plasma membrane triggering CME. Here we found that metabotropic glutamate receptor subtype 2 (mGluR2) and potassium calcium-activated channel subfamily M alpha 1 (KCa1.1) are involved in the initiation and completion of CME of influenza virus using an siRNA screen approach. Influenza virus HA directly interacted with mGluR2 and used it as an endocytic receptor to initiate CME. mGluR2 interacted and activated KCa1.1, leading to polymerization of F-actin, maturation of clathrin-coated pits and completion of the CME of influenza virus. Importantly, mGluR2-knockout mice were significantly more resistant to different influenza subtypes than the wild type. Therefore, blocking HA and mGluR2 interaction could be a promising host-directed antiviral strategy.
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Endocitosis , Ratones Noqueados , Receptores de Glutamato Metabotrópico , Animales , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/genética , Ratones , Humanos , Internalización del Virus , Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Clatrina/metabolismo , Infecciones por Orthomyxoviridae/virología , Infecciones por Orthomyxoviridae/metabolismo , Células HEK293 , Actinas/metabolismo , Perros , Células de Riñón Canino Madin Darby , Receptores Virales/metabolismo , Receptores Virales/genética , Gripe Humana/virología , Gripe Humana/metabolismo , Orthomyxoviridae/fisiología , Orthomyxoviridae/genética , Orthomyxoviridae/metabolismoRESUMEN
Following infection, influenza viruses strive to establish a new host cellular environment optimized for efficient viral replication and propagation. Influenza viruses use or hijack numerous host factors and machinery not only to fulfill their own replication process but also to constantly evade the host's antiviral and immune response. For this purpose, influenza viruses appear to have formulated diverse strategies to manipulate the host proteins or signaling pathways. One of the most effective tactics is to specifically induce the degradation of the cellular proteins that are detrimental to the virus life cycle. Here, we summarize the cellular factors that are deemed to have been purposefully degraded by influenza virus infection. The focus is laid on the mechanisms for the protein ubiquitination and degradation in association with facilitated viral amplification. The fate of influenza viral infection of hosts is heavily reliant on the outcomes of the interplay between the virus and the host antiviral immunity. Understanding the processes of how influenza viruses instigate the protein destruction pathways could provide a foundation for the development of advanced therapeutics to target host proteins and conquer influenza.
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Interacciones Huésped-Patógeno , Orthomyxoviridae , Ubiquitinación , Replicación Viral , Humanos , Orthomyxoviridae/metabolismo , Orthomyxoviridae/fisiología , Gripe Humana/metabolismo , Gripe Humana/virología , Proteolisis , AnimalesRESUMEN
During secondary infection with influenza virus, plasma cells (PCs) develop within the lung, providing a local source of antibodies. However, the site and mechanisms that regulate this process are poorly defined. Here, we show that while circulating memory B cells entered the lung during rechallenge and were activated within inducible bronchus-associated lymphoid tissues (iBALTs), resident memory B (BRM) cells responded earlier, and their activation occurred in a different niche: directly near infected alveoli. This process required NK cells but was largely independent of CD4 and CD8 T cells. Innate stimuli induced by virus-like particles containing ssRNA triggered BRM cell differentiation in the absence of cognate antigen, suggesting a low threshold of activation. In contrast, expansion of PCs in iBALTs took longer to develop and was critically dependent on CD4 T cells. Our work demonstrates that spatially distinct mechanisms evolved to support pulmonary secondary PC responses, and it reveals a specialized function for BRM cells as guardians of the alveoli.
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Linfocitos T CD4-Positivos , Pulmón , Infecciones por Orthomyxoviridae , Células Plasmáticas , Animales , Células Plasmáticas/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Pulmón/inmunología , Pulmón/virología , Pulmón/patología , Ratones , Linfocitos T CD4-Positivos/inmunología , Ratones Endogámicos C57BL , Células Asesinas Naturales/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Células B de Memoria/inmunología , Activación de Linfocitos/inmunología , Orthomyxoviridae/inmunología , Orthomyxoviridae/fisiologíaRESUMEN
Macrophages are important target cells for diverse viruses and thus represent a valuable system for studying virus biology. Isolation of primary human macrophages is done by culture of dissociated tissues or from differentiated blood monocytes, but these methods are both time consuming and result in low numbers of recovered macrophages. Here, we explore whether macrophages derived from human induced pluripotent stem cells (iPSCs)-which proliferate indefinitely and potentially provide unlimited starting material-could serve as a faithful model system for studying virus biology. Human iPSC-derived monocytes were differentiated into macrophages and then infected with HIV-1, dengue virus, or influenza virus as model human viruses. We show that iPSC-derived macrophages support the replication of these viruses with kinetics and phenotypes similar to human blood monocyte-derived macrophages. These iPSC-derived macrophages were virtually indistinguishable from human blood monocyte-derived macrophages based on surface marker expression (flow cytometry), transcriptomics (RNA sequencing), and chromatin accessibility profiling. iPSC lines were additionally generated from non-human primate (chimpanzee) fibroblasts. When challenged with dengue virus, human and chimpanzee iPSC-derived macrophages show differential susceptibility to infection, thus providing a valuable resource for studying the species-tropism of viruses. We also show that blood- and iPSC-derived macrophages both restrict influenza virus at a late stage of the virus lifecycle. Collectively, our results substantiate iPSC-derived macrophages as an alternative to blood monocyte-derived macrophages for the study of virus biology. IMPORTANCE: Macrophages have complex relationships with viruses: while macrophages aid in the removal of pathogenic viruses from the body, macrophages are also manipulated by some viruses to serve as vessels for viral replication, dissemination, and long-term persistence. Here, we show that iPSC-derived macrophages are an excellent model that can be exploited in virology.
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Virus del Dengue , VIH-1 , Células Madre Pluripotentes Inducidas , Macrófagos , Modelos Biológicos , Orthomyxoviridae , Virología , Animales , Humanos , Diferenciación Celular/genética , VIH-1/crecimiento & desarrollo , VIH-1/fisiología , Células Madre Pluripotentes Inducidas/citología , Macrófagos/citología , Macrófagos/metabolismo , Macrófagos/virología , Orthomyxoviridae/crecimiento & desarrollo , Orthomyxoviridae/fisiología , Pan troglodytes , Virus del Dengue/crecimiento & desarrollo , Virus del Dengue/fisiología , Fibroblastos/citología , Monocitos/citología , Replicación Viral , Citometría de Flujo , Perfilación de la Expresión Génica , Ensamble y Desensamble de Cromatina , Tropismo Viral , Virología/métodos , Biomarcadores/análisis , Biomarcadores/metabolismoRESUMEN
Despite lacking a DNA intermediate, orthomyxoviruses complete their replication cycle in the nucleus and generate multiple transcripts by usurping the host splicing machinery. This biology results in dynamic changes of relative viral transcripts over time and dictates the replicative phase of the infection. Here, we demonstrate that the family of archaeal L7Ae proteins uniquely inhibit the splicing biology of influenza A virus, influenza B virus, and Salmon isavirus, revealing a common strategy utilized by Orthomyxoviridae members to achieve this dynamic. L7Ae-mediated inhibition of virus biology was lost with the generation of a splicing-independent strain of influenza A virus and attempts to select for an escape mutant resulted in variants that conformed to host splicing biology at significant cost to their overall fitness. As L7Ae recognizes conventional kink turns in various RNAs, these data implicate the formation of a similar structure as a shared strategy adopted by this virus family to coordinate their replication cycle. IMPORTANCE Here, we demonstrate that a family of proteins from archaea specifically inhibit this splicing biology of all tested members of the Orthomyxoviridae family. We show that this inhibition extends to influenza A virus, influenza B virus, and isavirus genera, while having no significant impact on the mammalian transcriptome or proteome. Attempts to generate an escape mutant against L7Ae-mediated inhibition resulted in mutations surrounding the viral splice sites and a significant loss of viral fitness. Together, these findings reveal a unique biology shared among diverse members of the Orthomyxoviridae family that may serve as a means to generate future universal therapeutics.
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Proteínas Arqueales , Orthomyxoviridae , Empalme del ARN , Proteínas Arqueales/genética , Proteínas Arqueales/metabolismo , Orthomyxoviridae/fisiología , Empalme del ARN/fisiología , Humanos , Animales , Perros , Células Vero , Chlorocebus aethiops , Células A549 , Células HEK293 , Interacciones Microbiota-Huesped , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/virologíaRESUMEN
The subunits of the influenza hemagglutinin (HA) trimer are synthesized as single-chain precursors (HA0s) that are proteolytically cleaved into the disulfide-linked polypeptides HA1 and HA2. Cleavage is required for activation of membrane fusion at low pH, which occurs at the beginning of infection following transfer of cell-surface-bound viruses into endosomes. Activation results in extensive changes in the conformation of cleaved HA. To establish the overall contribution of cleavage to the mechanism of HA-mediated membrane fusion, we used cryogenic electron microscopy (cryo-EM) to directly image HA0 at neutral and low pH. We found extensive pH-induced structural changes, some of which were similar to those described for intermediates in the refolding of cleaved HA at low pH. They involve a partial extension of the long central coiled coil formed by melting of the preexisting secondary structure, threading it between the membrane-distal domains, and subsequent refolding as extended helices. The fusion peptide, covalently linked at its N terminus, adopts an amphipathic helical conformation over part of its length and is repositioned and packed against a complementary surface groove of conserved residues. Furthermore, and in contrast to cleaved HA, the changes in HA0 structure at low pH are reversible on reincubation at neutral pH. We discuss the implications of covalently restricted HA0 refolding for the cleaved HA conformational changes that mediate membrane fusion and for the action of antiviral drug candidates and cross-reactive anti-HA antibodies that can block influenza infectivity.
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Glicoproteínas Hemaglutininas del Virus de la Influenza , Fusión de Membrana , Orthomyxoviridae , Internalización del Virus , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Humanos , Concentración de Iones de Hidrógeno , Orthomyxoviridae/fisiología , Conformación ProteicaRESUMEN
Influenza viruses remain a constant global threat with significant health and socioeconomic impact every year and have the potential to cause devastating pandemics [...].
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Gripe Aviar/virología , Gripe Humana/virología , Orthomyxoviridae/fisiología , Animales , Anticuerpos Antivirales/inmunología , Aves , Humanos , Inmunidad , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Gripe Aviar/genética , Gripe Aviar/inmunología , Gripe Aviar/prevención & control , Gripe Humana/genética , Gripe Humana/inmunología , Gripe Humana/prevención & control , Orthomyxoviridae/genética , VacunaciónRESUMEN
Influenza is prevalent in temperate countries during winter when the environment is dry and cold; however, in tropical and subtropical countries, it is prevalent during the hot, humid rainy season. Thus, temperature and humidity conditions affect influenza outbreaks in different climates. Although the reason for this may be related to host conditions and the conditions under which the virus can survive, it is difficult to analyze changes in host viral responses owing to environmental changes at the cellular level. In the current study, to find candidate genes related with temperature, we analyzed the effects of low-temperature stimulation on influenza virus infection using immortalized respiratory cell lines with the same genetic background established in our laboratory. Although two cell lines with different immune response strengths exhibited enhancement of influenza virus replication following low-temperature stimulation, the mechanisms and degrees were different. In cell lines that showed greater changes, promotion of viral replication was found to involve genes related to temperature, including TRPM2 and CARHSP1. In particular, CARHSP1 expression was decreased by low-temperature stimulation in several respiratory cell lines. In knockdown experiments, because reduction of interferon-ß production and sensitivity were observed, the decline may create an environment in which the initial infection cannot be controlled. This procedure may be effective for identifying candidate genes related to the host/viral responses to changes in temperature, and these results can help elucidate the relationships of temperature, humidity, and host responses with viral infection.
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Proteínas de Unión al ADN/metabolismo , Gripe Humana , Orthomyxoviridae , Fosfoproteínas/metabolismo , Factores de Transcripción/metabolismo , Calcio , Regulación hacia Abajo , Calor , Humanos , Interferón beta/genética , Orthomyxoviridae/fisiología , Temperatura , Replicación ViralRESUMEN
The development of safe and effective vaccines in a record time after the emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a remarkable achievement, partly based on the experience gained from multiple viral outbreaks in the past decades. However, the Coronavirus Disease 2019 (COVID-19) crisis also revealed weaknesses in the global pandemic response and large gaps that remain in our knowledge of the biology of coronaviruses (CoVs) and influenza viruses, the 2 major respiratory viruses with pandemic potential. Here, we review current knowns and unknowns of influenza viruses and CoVs, and we highlight common research challenges they pose in 3 areas: the mechanisms of viral emergence and adaptation to humans, the physiological and molecular determinants of disease severity, and the development of control strategies. We outline multidisciplinary approaches and technological innovations that need to be harnessed in order to improve preparedeness to the next pandemic.
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COVID-19/virología , Gripe Humana/virología , Orthomyxoviridae/fisiología , SARS-CoV-2/fisiología , Animales , Antivirales , COVID-19/terapia , COVID-19/transmisión , Desarrollo de Medicamentos , Evolución Molecular , Humanos , Gripe Humana/terapia , Gripe Humana/transmisión , Orthomyxoviridae/inmunología , SARS-CoV-2/inmunología , Selección Genética , Carga Viral , Vacunas ViralesRESUMEN
Canine influenza virus (CIV) is an emerging virus that is associated with major hidden hazards to the canine population and public health. Until now, how canine uses its innate immunity to restrict CIV replication is seldomly investigated. Recently, studies on interferon-inducible transmembrane (IFITM) of several major hosts of influenza virus (human, chicken, duck, pig) indicated it can potently restrict the viral replication. Here, the gene locus of five previously annotated canine IFITM (caIFITM) genes was determined on chromosome 18 using multiple bioinformatics strategies, provisionally designated as caIFITM1, caIFITM2a, caIFITM2b, caIFITM3, and caIFITM5. An analysis on protein sequences between caIFITM and its homologs indicated they shared the same conserved amino acids important for the antiviral activity. Expression profile analysis showed that caIFITM was constitutively expressed in tissues and MDCK cell line. After treatment with interferon or infection with influenza virus, the expression level of caIFITM increased with different degrees in vitro. An animal challenge study demonstrated CIV infection resulted in upregulation of caIFITM in beagles. caIFITMs had a similar subcellular localization to their human homologs. caIFITM1 was present at the cell surface and caIFITM3 was present perinuclearly and colocalized with LAMP1-containing compartments. Finally, we generated A549 cell lines stably expressing caIFITM and challenged them with influenza virus. The result demonstrated caIFITM1, caIFITM2a, caIFITM2b, and caIFITM3 had a potent antiviral activity against influenza virus. Our study will help better understand the evolutional pattern of IFITM and its role in the host's defense against virus infection.
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Antígenos de Diferenciación/fisiología , Enfermedades de los Perros/inmunología , Infecciones por Orthomyxoviridae/inmunología , Orthomyxoviridae/fisiología , Replicación Viral/fisiología , Células A549 , Animales , Antígenos de Diferenciación/genética , Perros , Humanos , Inmunidad Innata , Células de Riñón Canino Madin Darby , Infecciones por Orthomyxoviridae/veterinaria , Infecciones por Orthomyxoviridae/virologíaRESUMEN
The Madin-Darby Canine Kidney (MDCK) cell line is among the most commonly used cell lines for the production of influenza virus vaccines. As cell culture-based manufacturing is poised to replace egg-based processes, increasing virus production is of paramount importance. To shed light on factors affecting virus productivity, we isolated a subline, H1, which had twice the influenza virus A (IAV) productivity of the parent (P) through cell cloning, and characterized H1 and P in detail on both physical and molecular levels. Transcriptome analysis revealed that within a few hours after IAV infection, viral mRNAs constituted over one fifth of total mRNA, with several viral genes more highly expressed in H1 than P. Functional analysis of the transcriptome dynamics showed that H1 and P responded similarly to IAV infection, and were both subjected to host shutoff and inflammatory responses. Importantly, H1 was more active in translation and RNA processing intrinsically and after infection. Furthermore, H1 had more subdued inflammatory and antiviral responses. Taken together, we postulate that the high productivity of IAV hinges on the balance between suppression of host functions to divert cellular resources and the sustaining of sufficient activities for virus replication. Mechanistic insights into virus productivity can facilitate the process optimization and cell line engineering for advancing influenza vaccine manufacturing.
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Células de Riñón Canino Madin Darby , Orthomyxoviridae/genética , Orthomyxoviridae/fisiología , Transcriptoma , Replicación Viral/fisiología , Animales , Apoptosis , Línea Celular , Perros , Hemaglutinación , Humanos , Virus de la Influenza A/fisiología , Vacunas contra la Influenza/inmunología , Gripe HumanaRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has forced the implementation of unprecedented public health measures strategies which might also have a significant impact on the spreading of other viral pathogens such as influenza and Respiratory Syncytial Virus (RSV) . The present study compares the incidences of the most relevant respiratory viruses before and during the SARS-CoV-2 pandemic in emergency room patients. We analyzed the results of in total 14,946 polymerase chain reaction point-of-care tests (POCT-PCR) for Influenza A, Influenza B, RSV and SARS-CoV-2 in an adult and a pediatric emergency room between December 1, 2018 and March 31, 2021. Despite a fivefold increase in the number of tests performed, the positivity rate for Influenza A dropped from 19.32% (165 positives of 854 tests in 2018/19), 14.57% (149 positives of 1023 in 2019-20) to 0% (0 positives of 4915 tests) in 2020/21. In analogy, the positivity rate for Influenza B and RSV dropped from 0.35 to 1.47%, respectively, 10.65-21.08% to 0% for both in 2020/21. The positivity rate for SARS-CoV2 reached 9.74% (110 of 1129 tests performed) during the so-called second wave in December 2020. Compared to the two previous years, seasonal influenza and RSV incidence was eliminated during the COVID-19 pandemic. Corona-related measures and human behavior patterns could lead to a significant decline or even complete suppression of other respiratory viruses such as influenza and RSV.
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COVID-19/epidemiología , Gripe Humana/diagnóstico , Pruebas en el Punto de Atención/estadística & datos numéricos , Infecciones por Virus Sincitial Respiratorio/diagnóstico , COVID-19/virología , Hospitales/estadística & datos numéricos , Humanos , Incidencia , Gripe Humana/epidemiología , Gripe Humana/virología , Orthomyxoviridae/genética , Orthomyxoviridae/aislamiento & purificación , Orthomyxoviridae/fisiología , Pandemias , Reacción en Cadena de la Polimerasa , Infecciones por Virus Sincitial Respiratorio/epidemiología , Infecciones por Virus Sincitial Respiratorio/virología , Virus Sincitial Respiratorio Humano/genética , Virus Sincitial Respiratorio Humano/aislamiento & purificación , Virus Sincitial Respiratorio Humano/fisiología , Estudios RetrospectivosRESUMEN
This paper addresses the development of predictive models for distinguishing pre-symptomatic infections from uninfected individuals. Our machine learning experiments are conducted on publicly available challenge studies that collected whole-blood transcriptomics data from individuals infected with HRV, RSV, H1N1, and H3N2. We address the problem of identifying discriminatory biomarkers between controls and eventual shedders in the first 32 h post-infection. Our exploratory analysis shows that the most discriminatory biomarkers exhibit a strong dependence on time over the course of the human response to infection. We visualize the feature sets to provide evidence of the rapid evolution of the gene expression profiles. To quantify this observation, we partition the data in the first 32 h into four equal time windows of 8 h each and identify all discriminatory biomarkers using sparsity-promoting classifiers and Iterated Feature Removal. We then perform a comparative machine learning classification analysis using linear support vector machines, artificial neural networks and Centroid-Encoder. We present a range of experiments on different groupings of the diseases to demonstrate the robustness of the resulting models.
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Simulación por Computador , Gripe Humana/virología , Infecciones por Picornaviridae/virología , Infecciones por Virus Sincitial Respiratorio/virología , Transcriptoma , Esparcimiento de Virus , Biomarcadores/metabolismo , Redes Reguladoras de Genes , Humanos , Gripe Humana/genética , Gripe Humana/metabolismo , Aprendizaje Automático , Orthomyxoviridae/patogenicidad , Orthomyxoviridae/fisiología , Infecciones por Picornaviridae/genética , Infecciones por Picornaviridae/metabolismo , Infecciones por Virus Sincitial Respiratorio/genética , Infecciones por Virus Sincitial Respiratorio/metabolismo , Virus Sincitiales Respiratorios/patogenicidad , Virus Sincitiales Respiratorios/fisiología , Rhinovirus/patogenicidad , Rhinovirus/fisiologíaRESUMEN
The global damage that a widespread viral infection can cause is evident from the ongoing COVID-19 pandemic. The importance of virus detection to prevent the spread of viruses has been reaffirmed by the pandemic and the associated social and economic damage. Surface plasmon resonance (SPR) in microscale and localized SPR (LSPR) in nanoscale virus sensing systems are thought to be useful as next-generation detection methods. Many studies have been conducted on ultra-sensitive technologies, especially those based on signal amplification. In some cases, it has been reported that even a low viral load can be measured, indicating that the virus can be detected in patients even in the early stages of the viral infection. These findings corroborate that SPR and LSPR are effective in minimizing false-positives and false-negatives that are prevalent in the existing virus detection techniques. In this review, the methods and signal responses of SPR and LSPR-based virus detection technologies are summarized. Furthermore, this review surveys some of the recent developments reported and discusses the limitations of SPR and LSPR-based virus detection as the next-generation detection technologies.
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Nanopartículas del Metal/química , SARS-CoV-2/fisiología , Resonancia por Plasmón de Superficie/métodos , Virión/aislamiento & purificación , COVID-19/diagnóstico , COVID-19/virología , Virus del Dengue/aislamiento & purificación , Virus del Dengue/fisiología , Humanos , Límite de Detección , Orthomyxoviridae/aislamiento & purificación , Orthomyxoviridae/fisiología , Sistemas de Atención de Punto , SARS-CoV-2/aislamiento & purificación , Virión/químicaRESUMEN
Kallikrein-related peptidases (KLKs) or kallikreins have been linked to diverse (patho) physiological processes, such as the epidermal desquamation and inflammation, seminal clot liquefaction, neurodegeneration, and cancer. Recent mounting evidence suggests that KLKs also represent important regulators of viral infections. It is well-established that certain enveloped viruses, including influenza and coronaviruses, require proteolytic processing of their hemagglutinin or spike proteins, respectively, to infect host cells. Similarly, the capsid protein of the non-enveloped papillomavirus L1 should be proteolytically cleaved for viral uncoating. Consequently, extracellular or membrane-bound proteases of the host cells are instrumental for viral infections and represent potential targets for drug development. Here, we summarize how extracellular proteolysis mediated by the kallikreins is implicated in the process of influenza (and potentially coronavirus and papillomavirus) entry into host cells. Besides direct proteolytic activation of viruses, KLK5 and 12 promote viral entry indirectly through proteolytic cascade events, like the activation of thrombolytic enzymes that also can process hemagglutinin, while additional functions of KLKs in infection cannot be excluded. In the light of recent evidence, KLKs represent potential host targets for the development of new antivirals. Humanized animal models to validate their key functions in viral infections will be valuable.
Asunto(s)
COVID-19/enzimología , COVID-19/virología , Interacciones Microbiota-Huesped/fisiología , Calicreínas/metabolismo , SARS-CoV-2 , Virosis/enzimología , Animales , Asma/etiología , Coronavirus/genética , Coronavirus/patogenicidad , Coronavirus/fisiología , Interacciones Microbiota-Huesped/genética , Humanos , Orthomyxoviridae/genética , Orthomyxoviridae/patogenicidad , Orthomyxoviridae/fisiología , Infecciones por Papillomavirus/enzimología , Infecciones por Papillomavirus/virología , Infecciones por Picornaviridae/complicaciones , Infecciones por Picornaviridae/enzimología , Infecciones por Picornaviridae/virología , Procesamiento Proteico-Postraduccional , Proteolisis , Rhinovirus/patogenicidad , SARS-CoV-2/genética , SARS-CoV-2/patogenicidad , SARS-CoV-2/fisiología , Infección por el Virus de la Varicela-Zóster/enzimología , Infección por el Virus de la Varicela-Zóster/virología , Proteínas Virales/genética , Proteínas Virales/metabolismo , Virosis/virología , Internalización del VirusRESUMEN
Seasonal influenza is a common cause of hospital admission, especially in older people and those with comorbidities. The objective of this study was to determine influenza vaccine effectiveness (VE) in preventing intensive care admissions and shortening the length of stay (LOS) in hospitalized laboratory-confirmed influenza cases (HLCI) in Catalonia (Spain). A retrospective cohort study was carried out during the 2017-2018 season in HLCI aged ≥18 years from 14 public hospitals. Differences in means and proportions were assessed using a t-test or a chi-square test as necessary and the differences were quantified using standardized effect measures: Cohen's d for quantitative and Cohen's w for categorical variables. Adjusted influenza vaccine effectiveness in preventing severity was estimated by multivariate logistic regression where the adjusted VE = (1 - adjusted odds ratio) · 100%; adjustment was also made using the propensity score. We analyzed 1414 HLCI aged ≥18 years; 465 (33%) were vaccinated, of whom 437 (94%) were aged ≥60 years, 269 (57.8%) were male and 295 (63.4%) were positive for influenza type B. ICU admission was required in 214 (15.1%) cases. There were 141/1118 (12.6%) ICU admissions in patients aged ≥60 years and 73/296 (24.7%) in those aged <60 years (p < 0.001). The mean LOS and ICU LOS did not differ significantly between vaccinated and unvaccinated patients. There were 52/465 (11.2%) ICU admissions in vaccinated cases vs. 162/949 (17.1%) in unvaccinated cases. Patients admitted to the ICU had a longer hospital LOS (mean: 22.4 [SD 20.3] days) than those who were not (mean: 11.1 [SD 14.4] days); p < 0.001. Overall, vaccination was associated with a lower risk of ICU admission. Taking virus types A and B together, the estimated adjusted VE in preventing ICU admission was 31% (95% CI 1-52; p = 0.04). When stratified by viral type, the aVE was 40% for type A (95% CI -11-68; p = 0.09) and 25% for type B (95% CI -18-52; p = 0.21). Annual influenza vaccination may prevent ICU admission in cases of HLCI. A non-significantly shorter mean hospital stay was observed in vaccinated cases. Our results support the need to increase vaccination uptake and public perception of the benefits of influenza vaccination in groups at a higher risk of hospitalization and severe outcomes.
Asunto(s)
Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Orthomyxoviridae/inmunología , Adolescente , Adulto , Anciano , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Vacunas contra la Influenza/inmunología , Gripe Humana/diagnóstico , Gripe Humana/epidemiología , Gripe Humana/virología , Laboratorios/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Orthomyxoviridae/genética , Orthomyxoviridae/fisiología , Estudios Retrospectivos , Estaciones del Año , España/epidemiología , Vacunación , Eficacia de las Vacunas , Adulto JovenRESUMEN
The respiratory tract is constantly exposed to various airborne pathogens. Most vaccines against respiratory infections are designed for the parenteral routes of administration; consequently, they provide relatively minimal protection in the respiratory tract. A vaccination strategy that aims to induce the protective mucosal immune responses in the airway is urgently needed. The FcRn mediates IgG Ab transport across the epithelial cells lining the respiratory tract. By mimicking this natural IgG transfer, we tested whether FcRn delivers vaccine Ags to induce a protective immunity to respiratory infections. In this study, we designed a monomeric IgG Fc fused to influenza virus hemagglutinin (HA) Ag with a trimerization domain. The soluble trimeric HA-Fc were characterized by their binding with conformation-dependent HA Abs or FcRn. In wild-type, but not FcRn knockout, mice, intranasal immunization with HA-Fc plus CpG adjuvant conferred significant protection against lethal intranasal challenge with influenza A/PR/8/34 virus. Further, mice immunized with a mutant HA-Fc lacking FcRn binding sites or HA alone succumbed to lethal infection. Protection was attributed to high levels of neutralizing Abs, robust and long-lasting B and T cell responses, the presence of lung-resident memory T cells and bone marrow plasma cells, and a remarkable reduction of virus-induced lung inflammation. Our results demonstrate for the first time, to our knowledge, that FcRn can effectively deliver a trimeric viral vaccine Ag in the respiratory tract and elicit potent protection against respiratory infection. This study further supports a view that FcRn-mediated mucosal immunization is a platform for vaccine delivery against common respiratory pathogens.