scholarly journals Antiviral Activity of Chrysin against Influenza Virus Replication via Inhibition of Autophagy

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1350
Author(s):  
Seong-Ryeol Kim ◽  
Myeong-Seon Jeong ◽  
Seo-Hyeon Mun ◽  
Jaewon Cho ◽  
Min-Duk Seo ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
Time Course ◽  
Respiratory Infections ◽  
A549 Cells ◽  
Enterovirus 71 ◽  
Influenza Viruses ◽  
High Morbidity ◽  
Early Stages ◽  
Infected Cells

Influenza viruses cause respiratory infections in humans and animals, which have high morbidity and mortality rates. Although several drugs that inhibit viral neuraminidase are used to treat influenza infections, the emergence of resistant viruses necessitates the urgent development of new antiviral drugs. Chrysin (5,7-dihydroxyflavone) is a natural flavonoid that exhibits antiviral activity against enterovirus 71 (EV71) by inhibiting viral 3C protease activity. In this study, we evaluated the antiviral activity of chrysin against influenza A/Puerto Rico/8/34 (A/PR/8). Chrysin significantly inhibited A/PR/8-mediated cell death and the replication of A/PR/8 at concentrations up to 2 mM. Viral hemagglutinin expression was also markedly decreased by the chrysin treatment in A/PR/8-infected cells. Through the time course experiment and time-of-addition assay, we found that chrysin inhibited viral infection at the early stages of the replication cycle. Additionally, the nucleoprotein expression of A/PR/8 in A549 cells was reduced upon treatment with chrysin. Regarding the mechanism of action, we found that chrysin inhibited autophagy activation by increasing the phosphorylation of mammalian target of rapamycin (mTOR). We also confirmed a decrease in LC3B expression and LC3-positive puncta levels in A/PR/8-infected cells. These results suggest that chrysin exhibits antiviral activity by activating mTOR and inhibiting autophagy to inhibit the replication of A/PR/8 in the early stages of infection.

IFITM proteins that restrict the early stages of respiratory virus infection do not influence late-stage replication

2021 ◽  
Author(s):  
Tina Meischel ◽  
Svenja Fritzlar ◽  
Fernando Villalon-Letelier ◽  
Melkamu B. Tessema ◽  
Andrew G. Brooks ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Antiviral Activity ◽  
Influenza A ◽  
Respiratory Viruses ◽  
Parainfluenza Virus ◽  
Early Stages ◽  
Infected Cells ◽  
Cellular Entry ◽  
Overexpression System ◽  
Late Stages

Interferon-induced transmembrane (IFITM) proteins inhibit a broad range of enveloped viruses by blocking entry into host cells. We used an inducible overexpression system to investigate if IFITM1, IFITM2 and IFITM3 could modulate early and/or late stages of influenza A virus (IAV) or parainfluenza virus (PIV)-3 infection in human A549 airway epithelial cells. IAV and PIV-3 represent respiratory viruses which utilise distinct cellular entry pathways. We verify entry by endocytosis for IAV, whereas PIV-3 infection was consistent with fusion at the plasma membrane. Following induction prior to infection, all three IFITM proteins restricted the percentage of IAV-infected cells at 8 hours post-infection. In contrast, prior induction of IFITM1 and IFITM2 did not inhibit PIV-3 infection, although a modest reduction was observed with IFITM3. siRNA-mediated knockdown of endogenous IFITM1, IFITM2 and IFITM3 expression, in the presence or absence of pre-treatment with type I interferon, resulted in increased IAV, but not PIV-3, infection. This suggests that while all three IFITMs display antiviral activity against IAV, they do not restrict the early stages of PIV-3 infection. IAV and PIV-3 infection culminates in viral egress through budding at the plasma membrane. Inducible expression of IFITM1, IFITM2 or IFITM3 immediately after infection did not impact titres of infectious virus released from IAV or PIV-3 infected cells. Our findings show that IFITM proteins differentially restrict the early stages of infection of two respiratory viruses with distinct cellular entry pathways, but do not influence the late stages of replication for either virus. IMPORTANCE Interferon-induced transmembrane (IFITM) proteins restrict the initial stages of infection for several respiratory viruses, however their potential to modulate the later stages of virus replication has not been explored. In this study we highlight the utility of an inducible overexpression system to assess the impact of IFITM proteins on either early or late stage replication of two respiratory viruses. We demonstrate antiviral activity by IFITM1, IFITM2 and IFITM3 against influenza A virus (IAV) but not parainfluenza virus (PIV)-3 during the early stages of cellular infection. Furthermore, IFITM induction following IAV or PIV-3 infection does not restrict the late stages of replication of either virus. Our findings show that IFITM proteins can differentially restrict the early stages of infection of two viruses with distinct cellular entry pathways, yet do not influence the late stages of replication for either virus.

scholarly journals Antiviral Activity of Isoquinolone Derivatives against Influenza Viruses and Their Cytotoxicity

2021 ◽  
Vol 14 (7) ◽  
pp. 650
Author(s):  
Yejin Jang ◽  
Jinhe Han ◽  
Xiaoli Li ◽  
Hyunjin Shin ◽  
Won-Jea Cho ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Influenza A ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Polymerase Activity ◽  
Influenza Viruses ◽  
Viral Polymerase ◽  
Chemical Library ◽  
Design And Synthesis ◽  
Chemical Derivatives

Influenza viruses are one of the major causative agents for human respiratory infections. Currently, vaccines and antivirals approved for preventing and treating viral infections are available. However, limited protection efficacy and frequent emergence of drug-resistant viruses stand for a need for the development of antivirals with different chemical skeletons from existing drugs. Screening of a chemical library identified an isoquinolone compound (1) as a hit with 50% effective concentrations (EC50s) between 0.2 and 0.6 µM against the influenza A and B viruses. However, it exhibited severe cytotoxic effects with a 50% cytotoxic concentration (CC50) of 39.0 µM in canine kidney epithelial cells. To address this cytotoxic issue, we synthesized an additional 22 chemical derivatives. Through structure-activity, as well as structure-cytotoxicity relationship studies, we discovered compound 21 that has higher EC50 values ranging from 9.9 to 18.5 µM, but greatly alleviated cytotoxicity with a CC50 value over 300 µM. Mode-of-action and cell type-dependent antiviral experiments indicated that it targets viral polymerase activity and functions also in human cells. Here, we present a new class of viral polymerase inhibitors with a core skeleton of isoquinolone, of which antiviral activity could be better improved through following design and synthesis of its derivatives for drug development.

scholarly journals Surveillance of influenza A H1N1 2009 among school children during 2009 and 2010 in São Paulo, Brazil

2012 ◽  
Vol 45 (5) ◽  
pp. 563-566 ◽  
Author(s):  
Sandra Baltazar Guatura ◽  
Aripuana Sakurada Aranha Watanabe ◽  
Clarice Neves Camargo ◽  
Ana Maria Passos ◽  
Sheila Negrini Parmezan ◽  
...  
Keyword(s):  
School Children ◽  
Influenza A ◽  
Respiratory Infections ◽  
Vaccination Campaign ◽  
Sao Paulo ◽  
Morbidity Rate ◽  
High Morbidity ◽  
São Paulo ◽  
High Morbidity Rate ◽  
Influenza A H1n1

INTRODUCTION: Influenza A H1N1 2009 is associated with a high morbidity rate among children around the world, including Brazil. This survey was conducted on samples of symptomatic children (< 12 years) to investigate the influenza virus as the etiological agent of respiratory infections in a day care school in a health facility during the first and second pandemic wave of H1N1 (2009-2010) in São Paulo, Brazil. METHODS: Influenza infections were determined by real-time PCR in 34% (47/137) of children with a median age of 5 years (8 months - 12 years), from June to October 2009 and in 16% (14/85) of those with median age of 6 years (1-12 years), from March to November 2010. RESULTS: In general, most positive cases (64%) occurred in children aged 5-12 years, this age group was significantly the most affected (39.8%, p = 0.001, OR = 8.3, CI 95% 1.9-36.9). Wheezing was reported by 31% (19/61) and dyspnea by 23% (14/61) of the studied patients. An outbreak of influenza H1N1 with an attack rate of 35.7% among children (median age 6 years) was documented in April 2010, before the vaccination campaign against the pandemic virus was extended for children up to 5 years in Brazil. CONCLUSIONS: Therefore, the study reinforces the recommendation to immunize school children to reduce the incidence of the disease.

scholarly journals Influenza A and B viruses in the population of Vojvodina, Serbia

2014 ◽  
Vol 66 (1) ◽  
pp. 43-50 ◽  
Author(s):  
J. Radovanov ◽  
V. Milosevic ◽  
I. Hrnjakovic ◽  
V. Petrovic ◽  
M. Ristic ◽  
...  
Keyword(s):  
Influenza A ◽  
Respiratory Infections ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Nasopharyngeal Swab ◽  
Influenza B ◽  
Influenza A Viruses ◽  
B Virus ◽  
Life Threatening ◽  
Seasonal Epidemic

At present, two influenza A viruses, H1N1pdm09 and H3N2, along with influenza B virus co-circulate in the human population, causing endemic and seasonal epidemic acute febrile respiratory infections, sometimes with life-threatening complications. Detection of influenza viruses in nasopharyngeal swab samples was done by real-time RT-PCR. There were 60.2% (53/88) positive samples in 2010/11, 63.4% (52/82) in 2011/12, and 49.9% (184/369) in 2012/13. Among the positive patients, influenza A viruses were predominant during the first two seasons, while influenza B type was more active during 2012/13. Subtyping of influenza A positive samples revealed the presence of A (H1N1)pdm09 in 2010/11, A (H3N2) in 2011/12, while in 2012/13, both subtypes were detected. The highest seroprevalence against influenza A was in the age-group 30-64, and against influenza B in adults aged 30-64 and >65.

scholarly journals Specific therapy and emergency prevention of flu

2021 ◽  
pp. 116-123
Author(s):  
Wassili M. Delyagin
Keyword(s):  
Influenza A ◽  
Respiratory Infections ◽  
Age Groups ◽  
Antiviral Drug ◽  
Risk Groups ◽  
Diagnostic Methods ◽  
High Morbidity ◽  
Low Birth Weight Infants ◽  
Food Treatment ◽  
Number Of Patients

Influenza A and B epidemics, occasionally pandemics, are characterized by high morbidity and mortality rates. In most cases, an uncomplicated disease ends with recovery, but unfavorable outcomes, up to lethal, are possible, especially in premature, low birth weight, infants and young children, old people, pregnant and postpartum women, with chronic diseases, immunocompromised, receiving salicylates and anticoagulants. The use of modern diagnostic methods allows early detection of patients with influenza, distinguishing them from the total number of patients with respiratory infections. This allows you to optimize the timing of the examination, avoid unnecessary prescription of antibiotics, and timely prescribe specific chemotherapy and chemoprophylaxis. During epidemics, in the presence of an epidemiological history, the conclusion of the clinician is decisive for the diagnosis. Vaccination is an excellent method of preventing or relieving the flu. However, in case of an unfavorable course of the disease, in risk groups, in closed groups, it is recommended to use chemotherapy, pre-exposure or post-exposure chemoprophylaxis. Numerous studies have proven the effectiveness of the use of the drug oseltamivir, a specific blocker of the virus neuraminidase. As a result, its replication stops. The drug does not complicate the vaccination, it can be used in vaccinated people, in all age groups, is available in different dosages, and can be used with food. Treatment for uncomplicated influenza lasts 5 days. In certain situations, chemoprophylaxis and chemotherapy with the specific antiviral drug oseltamivir can help control influenza outbreaks in certain populations.

scholarly journals Epidemiology of Respiratory Pathogens among Elderly Nursing Home Residents with Acute Respiratory Infections in Corsica, France, 2013–2017

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Shirley Masse ◽  
Lisandru Capai ◽  
Alessandra Falchi
Keyword(s):  
Nursing Home ◽  
Influenza A ◽  
Respiratory Infections ◽  
Nursing Home Residents ◽  
Respiratory Viruses ◽  
Sudden Onset ◽  
Influenza Viruses ◽  
Influenza B ◽  
Acute Respiratory Infections ◽  
Respiratory Pathogens

Background. The current study aims to describe the demographical and clinical characteristics of elderly nursing home (NH) residents with acute respiratory infections (ARIs) during four winter seasons (2013/2014–2016/2017), as well as the microbiological etiology of these infections. Methods. Seventeen NHs with at least one ARI resident in Corsica, France, were included. An ARI resident was defined as a resident developing a sudden onset of any constitutional symptoms in addition to any respiratory signs. Nasopharyngeal swabs from ARI residents were screened for the presence of 21 respiratory agents, including seasonal influenza viruses. Results. Of the 107 ARI residents enrolled from NHs, 61 (57%) were positive for at least one of the 21 respiratory pathogens. Forty-one (38.3%) of the 107 ARI residents had influenza: 38 (92%) were positive for influenza A (100% A(H3N2)) and three (8%) for influenza B/Victoria. Axillary fever (≥38°C) was significantly more common among patients infected with influenza A(H3N2). Conclusion. The circulation of seasonal respiratory viruses other than influenza A(H3N2) seems to be sporadic among elderly NH residents. Investigating the circulation of respiratory viruses in nonwinter seasons seems to be important in order to understand better the dynamic of their year-round circulation in NHs.

scholarly journals Expression of 9-O- and 7,9-O-Acetyl Modified Sialic Acid in Cells and Their Effects on Influenza Viruses

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Karen N. Barnard ◽  
Brian R. Wasik ◽  
Justin R. LaClair ◽  
David W. Buchholz ◽  
Wendy S. Weichert ◽  
...  
Keyword(s):  
Cell Lines ◽  
Influenza A ◽  
A549 Cells ◽  
Sialic Acids ◽  
Influenza Viruses ◽  
Obvious Effect ◽  
Hek 293 ◽  
Chemically Modified ◽  
Modified Forms ◽  
In Cells

ABSTRACT Sialic acids (Sia) are widely displayed on the surfaces of cells and tissues. Sia come in a variety of chemically modified forms, including those with acetyl modifications at the C-7, C-8, and C-9 positions. Here, we analyzed the distribution and amounts of these acetyl modifications in different human and canine cells. Since Sia or their variant forms are receptors for influenza A, B, C, and D viruses, we examined the effects of these modifications on virus infections. We confirmed that 9-O-acetyl and 7,9-O-acetyl modified Sia are widely but variably expressed across cell lines from both humans and canines. Although they were expressed on the cell surfaces of canine MDCK cell lines, they were located primarily within the Golgi compartment of human HEK-293 and A549 cells. The O-acetyl modified Sia were expressed at low levels of 1 to 2% of total Sia in these cell lines. We knocked out and overexpressed the sialate O-acetyltransferase gene (CasD1) and knocked out the sialate O-acetylesterase gene (SIAE) using CRISPR/Cas9 editing. Knocking out CasD1 removed 7,9-O- and 9-O-acetyl Sia expression, confirming previous reports. However, overexpression of CasD1 and knockout of SIAE gave only modest increases in 9-O-acetyl levels in cells and no change in 7,9-O-acetyl levels, indicating that there are complex regulations of these modifications. These modifications were essential for influenza C and D infection but had no obvious effect on influenza A and B infection. IMPORTANCE Sialic acids are key glycans that are involved in many different normal cellular functions, as well as being receptors for many pathogens. However, Sia come in diverse chemically modified forms. Here, we examined and manipulated the expression of 7,9-O- and 9-O-acetyl modified Sia on cells commonly used in influenza virus and other research by engineering the enzymes that produce or remove the acetyl groups.

scholarly journals Antiviral Activity of Benzoic Acid Derivative NC-5 Against Influenza A Virus and Its Neuraminidase Inhibition

2019 ◽  
Vol 20 (24) ◽  
pp. 6261
Author(s):  
Min Guo ◽  
Jiawei Ni ◽  
Jie Yu ◽  
Jing Jin ◽  
Lingman Ma ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Benzoic Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Matrix Protein ◽  
Influenza Viruses ◽  
Drug Candidate ◽  
Dependent Manner ◽  
Drug Resistant

The currently available drugs against influenza A virus primarily target neuraminidase (NA) or the matrix protein 2 (M2) ion channel. The emergence of drug-resistant viruses requires the development of new antiviral chemicals. Our study applied a cell-based approach to evaluate the antiviral activity of a series of newly synthesized benzoic acid derivatives, and 4-(2,2-Bis(hydroxymethyl)-5-oxopyrrolidin-l-yl)-3-(5-cyclohexyl-4H-1,2,4-triazol-3-yl)amino). benzoic acid, termed NC-5, was found to possess antiviral activity. NC-5 inhibited influenza A viruses A/FM/1/47 (H1N1), A/Beijing/32/92 (H3N2) and oseltamivir-resistant mutant A/FM/1/47-H275Y (H1N1-H275Y) in a dose-dependent manner. The 50% effective concentrations (EC50) for H1N1 and H1N1-H275Y were 33.6 μM and 32.8 μM, respectively, which showed that NC-5 had a great advantage over oseltamivir in drug-resistant virus infections. The 50% cytotoxic concentration (CC50) of NC-5 was greater than 640 μM. Orally administered NC-5 protected mice infected with H1N1 and H1N1-H275Y, conferring 80% and 60% survival at 100 mg/kg/d, reducing body weight loss, and alleviating virus-induced lung injury. NC-5 could suppress NP and M1 protein expression levels during the late stages of viral biosynthesis and inhibit NA activity, which may influence virus release. Our study proved that NC-5 has potent anti-influenza activity in vivo and in vitro, meaning that it could be regarded as a promising drug candidate to treat infection with influenza viruses, including oseltamivir-resistant viruses.

scholarly journals Identification and Characterization of Novel Compounds with Broad-Spectrum Antiviral Activity against Influenza A and B Viruses

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Jun-Gyu Park ◽  
Ginés Ávila-Pérez ◽  
Aitor Nogales ◽  
Pilar Blanco-Lobo ◽  
Juan C. de la Torre ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Rna Polymerase Ii ◽  
Broad Spectrum ◽  
Influenza A ◽  
Viral Infections ◽  
Influenza Infection ◽  
Inhibitory Effect ◽  
Influenza Viruses ◽  
Influenza B ◽  
Genome Replication

ABSTRACT Influenza A (IAV) and influenza B (IBV) viruses are highly contagious pathogens that cause fatal respiratory disease every year, with high economic impact. In addition, IAV can cause pandemic infections with great consequences when new viruses are introduced into humans. In this study, we evaluated 10 previously described compounds with antiviral activity against mammarenaviruses for their ability to inhibit IAV infection using our recently described bireporter influenza A/Puerto Rico/8/34 (PR8) H1N1 (BIRFLU). Among the 10 tested compounds, eight (antimycin A [AmA], brequinar [BRQ], 6-azauridine, azaribine, pyrazofurin [PF], AVN-944, mycophenolate mofetil [MMF], and mycophenolic acid [MPA]), but not obatoclax or Osu-03012, showed potent anti-influenza virus activity under posttreatment conditions [median 50% effective concentration (EC50) = 3.80 nM to 1.73 μM; selective index SI for 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, >28.90 to 13,157.89]. AmA, 6-azauridine, azaribine, and PF also showed potent inhibitory effect in pretreatment (EC50 = 0.14 μM to 0.55 μM; SI-MTT = 70.12 to >357.14) or cotreatment (EC50 = 34.69 nM to 7.52 μM; SI-MTT = 5.24 to > 1,441.33) settings. All of the compounds tested inhibited viral genome replication and gene transcription, and none of them affected host cellular RNA polymerase II activities. The antiviral activity of the eight identified compounds against BIRFLU was further confirmed with seasonal IAVs (A/California/04/2009 H1N1 and A/Wyoming/3/2003 H3N2) and an IBV (B/Brisbane/60/2008, Victoria lineage), demonstrating their broad-spectrum prophylactic and therapeutic activity against currently circulating influenza viruses in humans. Together, our results identified a new set of antiviral compounds for the potential treatment of influenza viral infections. IMPORTANCE Influenza viruses are highly contagious pathogens and are a major threat to human health. Vaccination remains the most effective tool to protect humans against influenza infection. However, vaccination does not always guarantee complete protection against drifted or, more noticeably, shifted influenza viruses. Although U.S. Food and Drug Administration (FDA) drugs are approved for the treatment of influenza infections, influenza viruses resistant to current FDA antivirals have been reported and continue to emerge. Therefore, there is an urgent need to find novel antivirals for the treatment of influenza viral infections in humans, a search that could be expedited by repurposing currently approved drugs. In this study, we assessed the influenza antiviral activity of 10 compounds previously shown to inhibit mammarenavirus infection. Among them, eight drugs showed antiviral activities, providing a new battery of drugs that could be used for the treatment of influenza infections.

scholarly journals Defective RNA Replication and Late Gene Expression in Temperature-Sensitive Influenza Viruses Expressing Deleted Forms of the NS1 Protein

2004 ◽  
Vol 78 (8) ◽  
pp. 3880-3888 ◽  
Author(s):  
Ana M. Falcón ◽  
Rosa M. Marión ◽  
Thomas Zürcher ◽  
Paulino Gómez ◽  
Agustín Portela ◽  
...  
Keyword(s):  
Influenza A ◽  
Influenza Viruses ◽  
Temperature Sensitive ◽  
Restrictive Temperature ◽  
Permissive Temperature ◽  
Ns1 Protein ◽  
Late Gene Expression ◽  
Infected Cells ◽  
Defective Rna ◽  
Nucleocytoplasmic Export

ABSTRACT Influenza A virus mutants expressing C-terminally deleted forms of the NS1 protein (NS1-81 and NS1-110) were generated by plasmid rescue. These viruses were temperature sensitive and showed a small plaque size at the permissive temperature. The accumulation of virion RNA in mutant virus-infected cells was reduced at the restrictive temperature, while the accumulation of cRNA or mRNA was not affected, indicating that the NS1 protein is involved in the control of transcription versus replication processes in the infection. The synthesis and accumulation of late virus proteins were reduced in NS1-81 mutant-infected cells at the permissive temperature and were essentially abolished for both viruses at the restrictive temperature, while synthesis and accumulation of nucleoprotein (NP) were unaffected. Probably as a consequence, the nucleocytoplasmic export of virus NP was strongly inhibited at the restrictive temperature. These results indicate that the NS1 protein is essential for nuclear and cytoplasmic steps during the virus cycle.

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