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1.
BMC Infect Dis ; 21(1): 365, 2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33865314

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) share similar symptoms with influenza A (IA), but it is more worthwhile to understand the disparities of the two infections regarding their clinical characteristics on admission. METHODS: A total of 71 age-matched pediatric IA and COVID-19 patient pairs were formed and their clinical data on admission were compared. RESULTS: Fever, cough, nasal congestion and nausea/vomiting were the most common symptoms on admission for both infections but occurred less often in COVID-19. The IA patients were more likely to have lower-than-normal levels of lymphocyte count and percentage and to have higher-than-normal levels of activated partial thromboplastin time, prothrombin time, serum C-reactive protein, and serum procalcitonin, while the COVID-19 patients had higher odds of having lower-than-normal levels of neutrophil count and percentage. CONCLUSIONS: This study suggests that influenza A is more symptomatic than COVID-19 for children and might be an overall more severe infection at the time of admission.


Assuntos
/diagnóstico , Diagnóstico Diferencial , Influenza Humana/diagnóstico , Avaliação de Sintomas , Adolescente , Proteína C-Reativa , Criança , Pré-Escolar , China , Tosse , Feminino , Febre , Hospitalização , Humanos , Lactente , Recém-Nascido , Influenza Humana/patologia , Contagem de Leucócitos , Masculino , Náusea , Neutrófilos , Tempo de Tromboplastina Parcial , Pró-Calcitonina , Estudos Retrospectivos , Vômito
2.
Sci Rep ; 11(1): 6638, 2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33758267

RESUMO

Pandemics, like the 1918 Spanish Influenza and COVID-19, spread through regions of the World in subsequent waves. Here we propose a consistent picture of the wave pattern based on the epidemic Renormalisation Group (eRG) framework, which is guided by the global symmetries of the system under time rescaling. We show that the rate of spreading of the disease can be interpreted as a time-dilation symmetry, while the final stage of an epidemic episode corresponds to reaching a time scale-invariant state. We find that the endemic period between two waves is a sign of instability in the system, associated to near-breaking of the time scale-invariance. This phenomenon can be described in terms of an eRG model featuring complex fixed points. Our results demonstrate that the key to control the arrival of the next wave of a pandemic is in the strolling period in between waves, i.e. when the number of infections grows linearly. Thus, limiting the virus diffusion in this period is the most effective way to prevent or delay the arrival of the next wave. In this work we establish a new guiding principle for the formulation of mid-term governmental strategies to curb pandemics and avoid recurrent waves of infections, deleterious in terms of human life loss and economic damage.


Assuntos
/epidemiologia , Influenza Humana/epidemiologia , Modelos Teóricos , /patologia , Política de Saúde , Humanos , Influenza Humana/patologia , Pandemias , /isolamento & purificação
3.
Methods Mol Biol ; 2212: 1-15, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733346

RESUMO

A mass-based protein phylogeny method, known as phylonumerics, is described to build phylogenetic-like trees using a purpose-built MassTree algorithm. These trees are constructed from sets of numerical mass map data for each protein without the need for gene or protein sequences. Such trees have been shown to be highly congruent with conventional sequence-based trees and provide a reliable means to study the evolutionary history of organisms. Mutations determined from the differences in the mass of peptide pairs across different mass sets are computed by the algorithm and displayed at branch nodes across the tree. By definition, since the trees display a phylogeny representing expressed proteins, all mutations are non-synonymous. The frequency of these mutations and a mutation score based on a sum of these frequencies weighted based upon their position to the root of the tree are output. The algorithm also outputs lists of pairs of mutations separated along interconnected branches of the tree. Those which co-occur or which occur consecutively, or near consecutively, and that are separated by a distance less than the average distance for all mutation pairs, are putatively assigned to be epistatic pairs. These pairs are examined further with a focus on non-conservative substitutions given their importance in driving structural and functional change and protein and organismal evolution. The application of the method is demonstrated for the H3 hemagglutinin protein of type A human H3N2 strains of the influenza virus. The most frequent ancestral mutations within epistatic pairs occur within antigenic site domains while the descendant mutations occur either at other antigenic sites or elsewhere in the protein. Both predominate at reported glycosylation sites. The results for this protein further support a "small steps" evolutionary model for the influenza virus where non-conservative mutations that involve the least structural change are favored over those involving substantive change, which may risk the virus's own extinction.


Assuntos
Epistasia Genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/virologia , Algoritmos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Vírus da Influenza A Subtipo H3N2/metabolismo , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/patologia , Mutação , Filogenia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
4.
BMC Infect Dis ; 21(1): 164, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568082

RESUMO

BACKGROUND: Although vaccination is one of the main countermeasures against influenza epidemic, it is highly essential to make informed prevention decisions to guarantee that limited vaccination resources are allocated to the places where they are most needed. Hence, one of the fundamental steps for decision making in influenza prevention is to characterize its spatio-temporal trend, especially on the key problem about how influenza transmits among adjacent places and how much impact the influenza of one place could have on its neighbors. To solve this problem while avoiding too much additional time-consuming work on data collection, this study proposed a new concept of spatio-temporal route as well as its estimation methods to construct the influenza transmission network. METHODS: The influenza-like illness (ILI) data of Sichuan province in 21 cities was collected from 2010 to 2016. A joint pattern based on the dynamic Bayesian network (DBN) model and the vector autoregressive moving average (VARMA) model was utilized to estimate the spatio-temporal routes, which were applied to the two stages of learning process respectively, namely structure learning and parameter learning. In structure learning, the first-order conditional dependencies approximation algorithm was used to generate the DBN, which could visualize the spatio-temporal routes of influenza among adjacent cities and infer which cities have impacts on others in influenza transmission. In parameter learning, the VARMA model was adopted to estimate the strength of these impacts. Finally, all the estimated spatio-temporal routes were put together to form the final influenza transmission network. RESULTS: The results showed that the period of influenza transmission cycle was longer in Western Sichuan and Chengdu Plain than that in Northeastern Sichuan, and there would be potential spatio-temporal routes of influenza from bordering provinces or municipalities into Sichuan province. Furthermore, this study also pointed out several estimated spatio-temporal routes with relatively high strength of associations, which could serve as clues of hot spot areas detection for influenza surveillance. CONCLUSIONS: This study proposed a new framework for exploring the potentially stable spatio-temporal routes between different places and measuring specific the sizes of transmission effects. It could help making timely and reliable prediction of the spatio-temporal trend of infectious diseases, and further determining the possible key areas of the next epidemic by considering their neighbors' incidence and the transmission relationships.


Assuntos
Influenza Humana/transmissão , Análise Espaço-Temporal , Algoritmos , Teorema de Bayes , Humanos , Influenza Humana/patologia , Modelos Teóricos
5.
JCI Insight ; 6(6)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33600379

RESUMO

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury after viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and SARS coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell prorepair function after lung injury remains unknown. Here, we showed that aging results in a cell-autonomous impairment of reparative Treg cell function after experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provided insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Strategies to restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.


Assuntos
Envelhecimento/fisiologia , Vírus da Influenza A , Influenza Humana/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Linfócitos T Reguladores/patologia , Fatores Etários , Envelhecimento/metabolismo , Animais , /metabolismo , /virologia , Humanos , Influenza Humana/complicações , Influenza Humana/metabolismo , Influenza Humana/virologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Pneumonia Viral/etiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Linfócitos T Reguladores/metabolismo
6.
JAMA Netw Open ; 4(2): e2037053, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33566109

RESUMO

Importance: Alpha 1-adrenergic receptor blocking agents (α1-blockers) have been reported to have protective benefits against hyperinflammation and cytokine storm syndrome, conditions that are associated with mortality in patients with coronavirus disease 2019 and other severe respiratory tract infections. However, studies of the association of α1-blockers with outcomes among human participants with respiratory tract infections are scarce. Objective: To examine the association between the receipt of α1-blockers and outcomes among adult patients hospitalized with influenza or pneumonia. Design, Setting, and Participants: This population-based cohort study used data from Danish national registries to identify individuals 40 years and older who were hospitalized with influenza or pneumonia between January 1, 2005, and November 30, 2018, with follow-up through December 31, 2018. In the main analyses, patients currently receiving α1-blockers were compared with those not receiving α1-blockers (defined as patients with no prescription for an α1-blocker filled within 365 days before the index date) and those currently receiving 5α-reductase inhibitors. Propensity scores were used to address confounding factors and to compute weighted risks, absolute risk differences, and risk ratios. Data were analyzed from April 21 to December 21, 2020. Exposures: Current receipt of α1-blockers compared with nonreceipt of α1-blockers and with current receipt of 5α-reductase inhibitors. Main Outcomes and Measures: Death within 30 days of hospital admission and risk of intensive care unit (ICU) admission. Results: A total of 528 467 adult patients (median age, 75.0 years; interquartile range, 64.4-83.6 years; 273 005 men [51.7%]) were hospitalized with influenza or pneumonia in Denmark between 2005 and 2018. Of those, 21 772 patients (4.1%) were currently receiving α1-blockers compared with a population of 22 117 patients not receiving α1-blockers who were weighted to the propensity score distribution of those receiving α1-blockers. In the propensity score-weighted analyses, patients receiving α1-blockers had lower 30-day mortality (15.9%) compared with patients not receiving α1-blockers (18.5%), with a corresponding risk difference of -2.7% (95% CI, -3.2% to -2.2%) and a risk ratio (RR) of 0.85 (95% CI, 0.83-0.88). The risk of ICU admission was 7.3% among patients receiving α1-blockers and 7.7% among those not receiving α1-blockers (risk difference, -0.4% [95% CI, -0.8% to 0%]; RR, 0.95 [95% CI, 0.90-1.00]). A comparison between 18 280 male patients currently receiving α1-blockers and 18 228 propensity score-weighted male patients currently receiving 5α-reductase inhibitors indicated that those receiving α1-blockers had lower 30-day mortality (risk difference, -2.0% [95% CI, -3.4% to -0.6%]; RR, 0.89 [95% CI, 0.82-0.96]) and a similar risk of ICU admission (risk difference, -0.3% [95% CI, -1.4% to 0.7%]; RR, 0.96 [95% CI, 0.83-1.10]). Conclusions and Relevance: This cohort study's findings suggest that the receipt of α1-blockers is associated with protective benefits among adult patients hospitalized with influenza or pneumonia.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Mortalidade Hospitalar , Hospitalização , Inflamação/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Unidades de Terapia Intensiva , Pneumonia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , /patologia , Estudos de Coortes , Dinamarca , Feminino , Humanos , Inflamação/etiologia , Influenza Humana/mortalidade , Influenza Humana/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pandemias , Pneumonia/mortalidade , Pneumonia/patologia , Pontuação de Propensão , Índice de Gravidade de Doença
7.
J Clin Invest ; 131(6)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33492309

RESUMO

The immunopathology of coronavirus disease 2019 (COVID-19) remains enigmatic, causing immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSCs) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied the blood and airways of patients with COVID-19 across disease severities at multiple time points. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of patients with COVID-19 compared with healthy controls. M-MDSCs isolated from patients with COVID-19 suppressed T cell proliferation and IFN-γ production partly via an arginase 1-dependent (Arg-1-dependent) mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. Patients with COVID-19 had fewer T cells and downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expanded in the blood of patients with COVID-19, suppressed T cells, and were strongly associated with disease severity, indicating a role for M-MDSCs in the dysregulated COVID-19 immune response.


Assuntos
/imunologia , Células Supressoras Mieloides/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Arginase/sangue , /patologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Influenza Humana/sangue , Influenza Humana/imunologia , Influenza Humana/patologia , Interferon gama/sangue , Interleucina-6/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/patologia , Pandemias , Sistema Respiratório/imunologia , Sistema Respiratório/patologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/patologia , Adulto Jovem
8.
Am J Pathol ; 191(4): 669-685, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33453177

RESUMO

Excessive neutrophil influx, their released neutrophil extracellular traps (NETs), and extracellular histones are associated with disease severity in influenza-infected patients. Neutrophil chemokine receptor CXC chemokine receptor 2 (CXCR2) is a critical target for suppressing neutrophilic inflammation. Herein, temporal dynamics of neutrophil activity and NETosis were investigated to determine the optimal timing of treatment with the CXCR2 antagonist, SCH527123 (2-hydroxy-N,N-dimethyl-3-[2-([(R)-1-(5-methyl-furan-2-yl)-propyl]amino)-3,4-dioxo-cyclobut-1-enylamino]-benzamide), and its efficacy together with antiviral agent, oseltamivir, was tested in murine and piglet influenza-pneumonia models. SCH527123 plus oseltamivir markedly improved survival of mice infected with lethal influenza, and diminished lung pathology in swine-influenza-infected piglets. Mechanistically, addition of SCH527123 in the combination treatment attenuated neutrophil influx, NETosis, in both mice and piglets. Furthermore, neutrophils isolated from influenza-infected mice showed greater susceptibility to NETotic death when stimulated with a CXCR2 ligand, IL-8. In addition, CXCR2 stimulation induced nuclear translocation of neutrophil elastase, and enhanced citrullination of histones that triggers chromatin decondensation during NET formation. Studies on temporal dynamics of neutrophils and NETs during influenza thus provide important insights into the optimal timing of CXCR2 antagonist treatment for attenuating neutrophil-mediated lung pathology. These findings reveal that pharmacologic treatment with CXCR2 antagonist together with an antiviral agent could significantly ameliorate morbidity and mortality in virulent and sublethal influenza infections.


Assuntos
Benzamidas/farmacologia , Ciclobutanos/farmacologia , Influenza Humana/mortalidade , Infecções por Orthomyxoviridae/patologia , Oseltamivir/farmacologia , Receptores de Interleucina-8B/efeitos dos fármacos , Animais , Armadilhas Extracelulares/microbiologia , Humanos , Influenza Humana/patologia , Elastase de Leucócito/efeitos dos fármacos , Pulmão/patologia , Camundongos , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Infecções por Orthomyxoviridae/mortalidade , Suínos
9.
Eur J Radiol ; 134: 109442, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33321459

RESUMO

PURPOSE: The vascular enlargement (VE) pattern differs from previously described imaging patterns for pneumonia. This study aimed to investigate the incidence, computed tomography (CT) characteristics, and diagnostic value of the VE pattern in coronavirus disease 2019 (COVID-19). METHOD: The CT data of 106 patients with COVID-19 from January 19 to February 29, 2020, and 52 patients with influenza virus pneumonia (IVP) from January 2018 to February 2020 were retrospectively collected. The incidences of the VE pattern between the two groups were compared. The CT manifestations of COVID-19 were analyzed with a particular focus on the VE pattern's specific CT signs, dynamic changes, and relationships with lesion size and disease severity. RESULTS: Peripheral and multilobar ground-glass opacities (GGOs) or mixed GGOs with various sizes and morphologies were typical features of COVID-19 on initial CT. The VE pattern was more common in COVID-19 (88/106, 83.02 %) than in IVP (10/52, 19.23 %) on initial CT (P < 0.001). Three special VE-pattern-specific CT signs, including central vascular sign, ginkgo leaf sign, and comb sign, were identified. Four types of dynamic changes in the VE pattern were observed on initial and follow-up CT, which were closely associated with the evolution of lesions and the time interval from the onset of symptoms to initial CT scan. The VE pattern in COVID-19 was more commonly seen in larger lesions and patients with severe-critical type (all P < 0.001). CONCLUSIONS: The VE pattern is a valuable CT sign for differentiating COVID-19 from IVP, which correlates with more extensive or serious disease. A good understanding of the CT characteristics of the VE pattern may contribute to the early and accurate diagnosis of COVID-19 and prediction of the evolution of lesions.


Assuntos
/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pneumonia/diagnóstico por imagem , Artéria Pulmonar/patologia , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/patologia , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Diagnóstico Diferencial , Feminino , Humanos , Influenza Humana/diagnóstico por imagem , Influenza Humana/patologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Pneumonia/patologia , Artéria Pulmonar/diagnóstico por imagem , Estudos Retrospectivos , Adulto Jovem
10.
PLoS One ; 15(11): e0241262, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33137167

RESUMO

The coronavirus disease 2019 (COVID-19) has become a pandemic. Rapidly distinguishing COVID-19 from other respiratory infections is a challenge for first-line health care providers. This retrospective study was conducted at the Taipei Medical University Hospital, Taiwan. Patients who visited the outdoor epidemic prevention screening station for respiratory infection from February 19 to April 30, 2020, were evaluated for blood biomarkers to distinguish COVID-19 from other respiratory infections. Monocyte distribution width (MDW) ≥ 20 (odds ratio [OR]: 8.39, p = 0.0110, area under curve [AUC]: 0.703) and neutrophil-to-lymphocyte ratio (NLR) < 3.2 (OR: 4.23, p = 0.0494, AUC: 0.673) could independently distinguish COVID-19 from common upper respiratory tract infections (URIs). Combining MDW ≥ 20 and NLR < 3.2 was more efficient in identifying COVID-19 (AUC: 0.840). Moreover, MDW ≥ 20 and NLR > 5 effectively identified influenza infection (AUC: 0.7055). Thus, MDW and NLR can distinguish COVID-19 from influenza and URIs.


Assuntos
Infecções por Coronavirus/patologia , Influenza Humana/patologia , Linfócitos/citologia , Monócitos/citologia , Neutrófilos/citologia , Pneumonia Viral/patologia , Área Sob a Curva , Biomarcadores/metabolismo , Infecções por Coronavirus/imunologia , Feminino , Humanos , Influenza Humana/imunologia , Linfócitos/metabolismo , Masculino , Monócitos/metabolismo , Neutrófilos/metabolismo , Razão de Chances , Pandemias , Projetos Piloto , Pneumonia Viral/imunologia , Curva ROC , Infecções Respiratórias/imunologia , Infecções Respiratórias/patologia
11.
Front Immunol ; 11: 572567, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33101294

RESUMO

Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposed to heightened morbidity and maternal death. A rapid, effective response to invasive pathogens is therefore essential in order to avoid overwhelming maternal infection and consequent fetal compromise. This sentinel response is mediated by the innate immune system: a heritable, highly evolutionarily conserved system comprising physical barriers, antimicrobial peptides (AMP) and a variety of immune cells-principally neutrophils, macrophages, dendritic cells, and natural killer cells-which express pattern-receptors that detect invariant molecular signatures unique to pathogenic micro-organisms. Recognition of these signatures during acute infection triggers signaling cascades that enhance antimicrobial properties such as phagocytosis, secretion of pro-inflammatory cytokines and activation of the complement system. As well as coordinating the initial immune response, macrophages and dendritic cells present microbial antigens to lymphocytes, initiating and influencing the development of specific, long-lasting adaptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections: Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.


Assuntos
Decídua/imunologia , Placenta/imunologia , Viroses/imunologia , Imunidade Adaptativa/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Dengue/imunologia , Dengue/patologia , Feminino , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/patologia , Hepatite E/imunologia , Hepatite E/patologia , Humanos , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Influenza Humana/imunologia , Influenza Humana/patologia , Febre Lassa/imunologia , Febre Lassa/patologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Gravidez
12.
Front Immunol ; 11: 574862, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042157

RESUMO

It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117+ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Mastócitos/imunologia , Pneumonia Viral/imunologia , Alvéolos Pulmonares/imunologia , Edema Pulmonar/imunologia , Trombose/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Influenza Humana/patologia , Influenza Humana/virologia , Interleucina-4/imunologia , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteínas Proto-Oncogênicas c-kit/imunologia , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/virologia , Edema Pulmonar/patologia , Edema Pulmonar/virologia , Trombose/patologia , Trombose/virologia
13.
Molecules ; 25(21)2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33105694

RESUMO

Viral infections and associated diseases are responsible for a substantial number of mortality and public health problems around the world. Each year, infectious diseases kill 3.5 million people worldwide. The current pandemic caused by COVID-19 has become the greatest health hazard to people in their lifetime. There are many antiviral drugs and vaccines available against viruses, but they have many disadvantages, too. There are numerous side effects for conventional drugs, and active mutation also creates drug resistance against various viruses. This has led scientists to search herbs as a source for the discovery of more efficient new antivirals. According to the World Health Organization (WHO), 65% of the world population is in the practice of using plants and herbs as part of treatment modality. Additionally, plants have an advantage in drug discovery based on their long-term use by humans, and a reduced toxicity and abundance of bioactive compounds can be expected as a result. In this review, we have highlighted the important viruses, their drug targets, and their replication cycle. We provide in-depth and insightful information about the most favorable plant extracts and their derived phytochemicals against viral targets. Our major conclusion is that plant extracts and their isolated pure compounds are essential sources for the current viral infections and useful for future challenges.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antivirais/química , Antivirais/classificação , Antivirais/isolamento & purificação , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Descoberta de Drogas , HIV/efeitos dos fármacos , HIV/patogenicidade , HIV/fisiologia , Infecções por HIV/patologia , Infecções por HIV/virologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepacivirus/fisiologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Herpes Simples/patologia , Herpes Simples/virologia , Humanos , Influenza Humana/patologia , Influenza Humana/virologia , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/patogenicidade , Orthomyxoviridae/fisiologia , Pandemias , Compostos Fitoquímicos/química , Compostos Fitoquímicos/classificação , Compostos Fitoquímicos/isolamento & purificação , Plantas Medicinais , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Simplexvirus/efeitos dos fármacos , Simplexvirus/patogenicidade , Simplexvirus/fisiologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
14.
Sci Adv ; 6(35): eaba7910, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32923629

RESUMO

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Antivirais/farmacologia , Cinamatos/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , ortoaminobenzoatos/farmacologia , Células A549 , Animais , Betacoronavirus/efeitos dos fármacos , Sítios de Ligação/genética , Linhagem Celular Tumoral , Chlorocebus aethiops , Infecções por Coronavirus/patologia , Cães , Células HEK293 , Infecções por HIV/patologia , HIV-1/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/patologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pandemias , Pneumonia Viral/patologia , Ligação Proteica/genética , Transporte Proteico/efeitos dos fármacos , RNA Viral/genética , Receptor de Interferon alfa e beta/genética , Fator de Crescimento Transformador beta1/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Infecção por Zika virus/patologia
16.
PLoS Pathog ; 16(8): e1008760, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32790753

RESUMO

Influenza A viruses (IAVs) remain a significant global health burden. Activation of the innate immune response is important for controlling early virus replication and spread. It is unclear how early IAV replication events contribute to immune detection. Additionally, while many cell types in the lung can be infected, it is not known if all cell types contribute equally to establish the antiviral state in the host. Here, we use single-cycle influenza A viruses (scIAVs) to characterize the early immune response to IAV in vitro and in vivo. We found that the magnitude of virus replication contributes to antiviral gene expression within infected cells prior to the induction of a global response. We also developed a scIAV that is only capable of undergoing primary transcription, the earliest stage of virus replication. Using this tool, we uncovered replication stage-specific responses in vitro and in vivo. Using several innate immune receptor knockout cell lines, we identify RIG-I as the predominant antiviral detector of primary virus transcription and amplified replication in vitro. Through a Cre-inducible reporter mouse, we used scIAVs expressing Cre-recombinase to characterize cell type-specific responses in vivo. Individual cell types upregulate unique sets of antiviral genes in response to both primary virus transcription and amplified replication. We also identified antiviral genes that are only upregulated in response to direct infection. Altogether, these data offer insight into the early mechanisms of antiviral gene activation during influenza A infection.


Assuntos
Células Epiteliais/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/imunologia , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Infecções por Orthomyxoviridae/imunologia , Replicação Viral , Células A549 , Animais , Antivirais/farmacologia , Proteína DEAD-box 58/metabolismo , Cães , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Células HEK293 , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/genética , Vírus da Influenza A/isolamento & purificação , Influenza Humana/tratamento farmacológico , Influenza Humana/patologia , Influenza Humana/virologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia
17.
PLoS Pathog ; 16(8): e1008761, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32790758

RESUMO

The virus-bacterial synergism implicated in secondary bacterial infections caused by Streptococcus pneumoniae following infection with epidemic or pandemic influenza A virus (IAV) is well documented. However, the molecular mechanisms behind such synergism remain largely ill-defined. In pneumocytes infected with influenza A virus, subsequent infection with S. pneumoniae leads to enhanced pneumococcal intracellular survival. The pneumococcal two-component system SirRH appears essential for such enhanced survival. Through comparative transcriptomic analysis between the ΔsirR and wt strains, a list of 179 differentially expressed genes was defined. Among those, the clpL protein chaperone gene and the psaB Mn+2 transporter gene, which are involved in the stress response, are important in enhancing S. pneumoniae survival in influenza-infected cells. The ΔsirR, ΔclpL and ΔpsaB deletion mutants display increased susceptibility to acidic and oxidative stress and no enhancement of intracellular survival in IAV-infected pneumocyte cells. These results suggest that the SirRH two-component system senses IAV-induced stress conditions and controls adaptive responses that allow survival of S. pneumoniae in IAV-infected pneumocytes.


Assuntos
Proteínas de Bactérias/metabolismo , Coinfecção/mortalidade , Vírus da Influenza A/patogenicidade , Influenza Humana/mortalidade , Pulmão/patologia , Infecções Pneumocócicas/mortalidade , Streptococcus pneumoniae/patogenicidade , Proteínas de Bactérias/genética , Sobrevivência Celular , Coinfecção/epidemiologia , Humanos , Influenza Humana/microbiologia , Influenza Humana/patologia , Influenza Humana/virologia , Pulmão/microbiologia , Pulmão/virologia , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/patologia , Infecções Pneumocócicas/virologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Streptococcus pneumoniae/metabolismo , Estresse Fisiológico , Virulência
18.
Blood Adv ; 4(13): 2967-2978, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32609845

RESUMO

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.


Assuntos
Plaquetas/virologia , Vírus da Influenza A/patogenicidade , Influenza Humana/complicações , Ácido N-Acetilneuramínico/metabolismo , Polissacarídeos/metabolismo , Trombocitopenia/etiologia , Animais , Plaquetas/metabolismo , Plaquetas/patologia , Modelos Animais de Doenças , Furões , Interações Hospedeiro-Patógeno , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/patogenicidade , Vírus da Influenza A Subtipo H3N2/fisiologia , Virus da Influenza A Subtipo H5N1/patogenicidade , Virus da Influenza A Subtipo H5N1/fisiologia , Vírus da Influenza A/fisiologia , Influenza Humana/metabolismo , Influenza Humana/patologia , Influenza Humana/virologia , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Trombocitopenia/metabolismo , Trombocitopenia/patologia , Trombocitopenia/virologia , Internalização do Vírus
19.
PLoS Pathog ; 16(6): e1008611, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32511263

RESUMO

Human infection with avian influenza A (H5N1) and (H7N9) viruses causes severe respiratory diseases. PB1-F2 protein is a critical virulence factor that suppresses early type I interferon response, but the mechanism of its action in relation to high pathogenicity is not well understood. Here we show that PB1-F2 protein of H7N9 virus is a particularly potent suppressor of antiviral signaling through formation of protein aggregates on mitochondria and inhibition of TRIM31-MAVS interaction, leading to prevention of K63-polyubiquitination and aggregation of MAVS. Unaggregated MAVS accumulated on fragmented mitochondria is prone to degradation by both proteasomal and lysosomal pathways. These properties are proprietary to PB1-F2 of H7N9 virus but not shared by its counterpart in WSN virus. A recombinant virus deficient of PB1-F2 of H7N9 induces more interferon ß in infected cells. Our findings reveal a subtype-specific mechanism for destabilization of MAVS and suppression of interferon response by PB1-F2 of H7N9 virus.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Subtipo H7N9 do Vírus da Influenza A/metabolismo , Influenza Humana/metabolismo , Agregação Patológica de Proteínas/metabolismo , Transdução de Sinais , Proteínas Virais/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Cães , Células HEK293 , Humanos , Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Humana/genética , Influenza Humana/patologia , Interferon beta/genética , Interferon beta/metabolismo , Células Madin Darby de Rim Canino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Agregação Patológica de Proteínas/genética , Células THP-1 , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais/genética
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