Classical drug digitoxin inhibits influenza cytokine storm, with implications for COVID-19 therapy

AbstractInfluenza viruses, corona viruses and related pneumotropic viruses cause sickness and death partly by inducing a hyper-proinflammatory response by immune cells and cytokines in the host airway. Here we show that the cardiac glycoside digitoxin suppresses this response induced by influenza virus strain A/Wuhan/H3N2/359/95 in the cotton rat lung. The cytokines TNFα, GRO/KC, MIP2, MCP1, TGFβ, and IFNγ. are significantly and differentially reduced. Since the hyper-proinflammatory expression of cytokines is a host response, we suggest that digitoxin may have therapeutic potential for not only influenza and but also for coronavirus infections.

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The Mechanism behind Influenza Virus Cytokine Storm

Viruses ◽

10.3390/v13071362 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1362

Author(s):

Yinuo Gu ◽

Xu Zuo ◽

Siyu Zhang ◽

Zhuoer Ouyang ◽

Shengyu Jiang ◽

...

Keyword(s):

Influenza Virus ◽

Recent Literature ◽

Cell Communication ◽

Influenza Viruses ◽

Viral Clearance ◽

Cytokine Storm ◽

Biological Factors ◽

Severe Influenza ◽

Immune Pathology ◽

Biological Differences

Influenza viruses are still a serious threat to human health. Cytokines are essential for cell-to-cell communication and viral clearance in the immune system, but excessive cytokines can cause serious immune pathology. Deaths caused by severe influenza are usually related to cytokine storms. The recent literature has described the mechanism behind the cytokine–storm network and how it can exacerbate host pathological damage. Biological factors such as sex, age, and obesity may cause biological differences between different individuals, which affects cytokine storms induced by the influenza virus. In this review, we summarize the mechanism behind influenza virus cytokine storms and the differences in cytokine storms of different ages and sexes, and in obesity.

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Knockout of IRF7 Highlights its Modulator Function of Host Response Against Avian Influenza Virus and the Involvement of MAPK and TOR Signaling Pathways in Chicken

Genes ◽

10.3390/genes11040385 ◽

2020 ◽

Vol 11 (4) ◽

pp. 385

Author(s):

Tae Hyun Kim ◽

Colin Kern ◽

Huaijun Zhou

Keyword(s):

Influenza Virus ◽

Avian Influenza ◽

Avian Influenza Virus ◽

Signaling Pathways ◽

Cell Lines ◽

Host Response ◽

Antiviral Response ◽

Influenza Viruses ◽

Interferon Response ◽

Type I

Interferon regulatory factor 7 (IRF7) is known as the master transcription factor of the type I interferon response in mammalian species along with IRF3. Yet birds only have IRF7, while they are missing IRF3, with a smaller repertoire of immune-related genes, which leads to a distinctive immune response in chickens compared to in mammals. In order to understand the functional role of IRF7 in the regulation of the antiviral response against avian influenza virus in chickens, we generated IRF7-/- chicken embryonic fibroblast (DF-1) cell lines and respective controls (IRF7wt) by utilizing the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system. IRF7 knockout resulted in increased viral titers of low pathogenic avian influenza viruses. Further RNA-sequencing performed on H6N2-infected IRF7-/- and IRF7wt cell lines revealed that the deletion of IRF7 resulted in the significant down-regulation of antiviral effectors and the differential expression of genes in the MAPK (mitogen-activated protein kinase) and mTOR (mechanistic target of rapamycin) signaling pathways. Dynamic gene expression profiling of the host response between the wildtype and IRF7 knockout revealed potential signaling pathways involving AP1 (activator protein 1), NF-κB (nuclear factor kappa B) and inflammatory cytokines that may complement chicken IRF7. Our findings in this study provide novel insights that have not been reported previously, and lay a solid foundation for enhancing our understanding of the host antiviral response against the avian influenza virus in chickens.

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Stringent Response in Mycobacteria: From Biology to Therapeutic Potential

Pathogens ◽

10.3390/pathogens10111417 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1417

Author(s):

Kuldeepkumar Ramnaresh Gupta ◽

Gunjan Arora ◽

Abid Mattoo ◽

Andaleeb Sajid

Keyword(s):

Immune Cells ◽

Biofilm Formation ◽

Host Response ◽

Latent Infection ◽

Therapeutic Potential ◽

Stringent Response ◽

Host Immunity ◽

Stress Conditions ◽

Human Pathogen ◽

Synthesis And Degradation

Mycobacterium tuberculosis is a human pathogen that can thrive inside the host immune cells for several years and cause tuberculosis. This is due to the propensity of M. tuberculosis to synthesize a sturdy cell wall, shift metabolism and growth, secrete virulence factors to manipulate host immunity, and exhibit stringent response. These attributes help M. tuberculosis to manage the host response, and successfully establish and maintain an infection even under nutrient-deprived stress conditions for years. In this review, we will discuss the importance of mycobacterial stringent response under different stress conditions. The stringent response is mediated through small signaling molecules called alarmones “(pp)pGpp”. The synthesis and degradation of these alarmones in mycobacteria are mediated by Rel protein, which is both (p)ppGpp synthetase and hydrolase. Rel is important for all central dogma processes—DNA replication, transcription, and translation—in addition to regulating virulence, drug resistance, and biofilm formation. Rel also plays an important role in the latent infection of M. tuberculosis. Here, we have discussed the literature on alarmones and Rel proteins in mycobacteria and highlight that (p)ppGpp-analogs and Rel inhibitors could be designed and used as antimycobacterial compounds against M. tuberculosis and non-tuberculous mycobacterial infections.

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A Study on Host Tropism Determinants of Influenza Virus Using Machine Learning

Current Bioinformatics ◽

10.2174/1574893614666191104160927 ◽

2020 ◽

Vol 15 (2) ◽

pp. 121-134 ◽

Cited By ~ 2

Author(s):

Eunmi Kwon ◽

Myeongji Cho ◽

Hayeon Kim ◽

Hyeon S. Son

Keyword(s):

Machine Learning ◽

Amino Acids ◽

Influenza Virus ◽

Random Forest ◽

Physicochemical Properties ◽

Protein Sequences ◽

Influenza Viruses ◽

Host Tropism ◽

Post Hoc ◽

Ha Protein

Background: The host tropism determinants of influenza virus, which cause changes in the host range and increase the likelihood of interaction with specific hosts, are critical for understanding the infection and propagation of the virus in diverse host species. Methods: Six types of protein sequences of influenza viral strains isolated from three classes of hosts (avian, human, and swine) were obtained. Random forest, naïve Bayes classification, and knearest neighbor algorithms were used for host classification. The Java language was used for sequence analysis programming and identifying host-specific position markers. Results: A machine learning technique was explored to derive the physicochemical properties of amino acids used in host classification and prediction. HA protein was found to play the most important role in determining host tropism of the influenza virus, and the random forest method yielded the highest accuracy in host prediction. Conserved amino acids that exhibited host-specific differences were also selected and verified, and they were found to be useful position markers for host classification. Finally, ANOVA analysis and post-hoc testing revealed that the physicochemical properties of amino acids, comprising protein sequences combined with position markers, differed significantly among hosts. Conclusion: The host tropism determinants and position markers described in this study can be used in related research to classify, identify, and predict the hosts of influenza viruses that are currently susceptible or likely to be infected in the future.

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Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

Scientific Reports ◽

10.1038/s41598-020-79590-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

James D. Allen ◽

Ted M. Ross

Keyword(s):

Influenza Virus ◽

Immune Responses ◽

Influenza A ◽

Seasonal Influenza ◽

Influenza Viruses ◽

Next Generation ◽

Virus Infections ◽

Wild Type ◽

Influenza Hemagglutinin ◽

H3n2 Influenza

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

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Tannic acid-functionalized HEPA filter materials for influenza virus capture

Scientific Reports ◽

10.1038/s41598-020-78929-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Subin Kim ◽

Jinhyo Chung ◽

Sang Hyun Lee ◽

Jeong Hyeon Yoon ◽

Dae-Hyuk Kweon ◽

...

Keyword(s):

Influenza Virus ◽

Tannic Acid ◽

High Efficiency ◽

Influenza Viruses ◽

Capture Efficiency ◽

Protective Equipment ◽

Filter Materials ◽

Washing Process ◽

Pathogenic Viruses ◽

Cost Efficient

AbstractInfluenza, one of the most contagious and infectious diseases, is predominantly transmitted through aerosols, leading to the development of filter-based protective equipment. Though the currently available filters are effective at removing submicron-sized particulates, filter materials with enhanced virus-capture efficiency are still in demand. Coating or chemically modifying filters with molecules capable of binding influenza viruses has received attention as a promising approach for the production of virus-capturing filters. For this purpose, tannic acid (TA), a plant-derived polyphenol, is a promising molecule for filter functionalization because of its antiviral activities and ability to serve as a cost-efficient adhesive for various materials. This study demonstrates the facile preparation of TA-functionalized high-efficiency particulate air (HEPA) filter materials and their efficiency in influenza virus capture. Polypropylene HEPA filter fabrics were coated with TA via a dipping/washing process. The TA-functionalized HEPA filter (TA-HF) exhibits a high in-solution virus capture efficiency of up to 2,723 pfu/mm2 within 10 min, which is almost two orders of magnitude higher than that of non-functionalized filters. This result suggests that the TA-HF is a potent anti-influenza filter that can be used in protective equipment to prevent the spread of pathogenic viruses.

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Sequential Seasonal H1N1 Influenza Virus Infections Protect Ferrets against Novel 2009 H1N1 Influenza Virus

Journal of Virology ◽

10.1128/jvi.02257-12 ◽

2012 ◽

Vol 87 (3) ◽

pp. 1400-1410 ◽

Cited By ~ 45

Author(s):

Donald M. Carter ◽

Chalise E. Bloom ◽

Eduardo J. M. Nascimento ◽

Ernesto T. A. Marques ◽

Jodi K. Craigo ◽

...

Keyword(s):

Influenza Virus ◽

H1n1 Influenza ◽

Cross Reactivity ◽

Influenza Viruses ◽

The Novel ◽

Virus Infections ◽

H1n1 Influenza Virus ◽

Virus Shedding ◽

2009 H1n1 ◽

Novel H1n1 Influenza

ABSTRACTIndividuals <60 years of age had the lowest incidence of infection, with ∼25% of these people having preexisting, cross-reactive antibodies to novel 2009 H1N1 influenza. Many people >60 years old also had preexisting antibodies to novel H1N1. These observations are puzzling because the seasonal H1N1 viruses circulating during the last 60 years were not antigenically similar to novel H1N1. We therefore hypothesized that a sequence of exposures to antigenically different seasonal H1N1 viruses can elicit an antibody response that protects against novel 2009 H1N1. Ferrets were preinfected with seasonal H1N1 viruses and assessed for cross-reactive antibodies to novel H1N1. Serum from infected ferrets was assayed for cross-reactivity to both seasonal and novel 2009 H1N1 strains. These results were compared to those of ferrets that were sequentially infected with H1N1 viruses isolated prior to 1957 or more-recently isolated viruses. Following seroconversion, ferrets were challenged with novel H1N1 influenza virus and assessed for viral titers in the nasal wash, morbidity, and mortality. There was no hemagglutination inhibition (HAI) cross-reactivity in ferrets infected with any single seasonal H1N1 influenza viruses, with limited protection to challenge. However, sequential H1N1 influenza infections reduced the incidence of disease and elicited cross-reactive antibodies to novel H1N1 isolates. The amount and duration of virus shedding and the frequency of transmission following novel H1N1 challenge were reduced. Exposure to multiple seasonal H1N1 influenza viruses, and not to any single H1N1 influenza virus, elicits a breadth of antibodies that neutralize novel H1N1 even though the host was never exposed to the novel H1N1 influenza viruses.

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Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus

Viruses ◽

10.3390/v13020234 ◽

2021 ◽

Vol 13 (2) ◽

pp. 234

Author(s):

Sarah Al-Beltagi ◽

Cristian Alexandru Preda ◽

Leah V. Goulding ◽

Joe James ◽

Juan Pu ◽

...

Keyword(s):

Influenza Virus ◽

Respiratory Syncytial Virus ◽

Influenza A Virus ◽

Broad Spectrum ◽

Influenza A ◽

Respiratory Viruses ◽

Influenza Viruses ◽

Virus Challenge ◽

2009 H1n1 ◽

Syncytial Virus

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

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The efficacy of live and inactivated vaccines of Hong Kong influenza virus in an industrial community: A report to the Medical Research Council Committee on Influenza and other respiratory virus vaccines

Epidemiology and Infection ◽

10.1017/s0022172400022907 ◽

1973 ◽

Vol 71 (4) ◽

pp. 641-647 ◽

Cited By ~ 14

Author(s):

D. Hobson ◽

F. A. Baker ◽

R. L. Curry ◽

A. S. Beare ◽

P. M. O. Massey

Keyword(s):

Influenza Virus ◽

Hong Kong ◽

Medical Research ◽

Research Council ◽

Respiratory Virus ◽

Medical Research Council ◽

Influenza Viruses ◽

Protective Efficiency ◽

Industrial Community ◽

Inactivated Vaccines

Intranasal vaccines of inactivated or living attentuated A2/Hong Kong influenza viruses were compared for clinical acceptability, serological effects and protective efficiency against natural epidemic influenza in a large industrial and clerical population.

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Next Generation of Computationally Optimized Broadly Reactive HA Vaccines Elicited Cross-Reactive Immune Responses and Provided Protection against H1N1 Virus Infection

Vaccines ◽

10.3390/vaccines9070793 ◽

2021 ◽

Vol 9 (7) ◽

pp. 793

Author(s):

Ying Huang ◽

Monique S. França ◽

James D. Allen ◽

Hua Shi ◽

Ted M. Ross

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Immune Responses ◽

H1n1 Virus ◽

Influenza Virus Infection ◽

H1n1 Influenza ◽

Influenza Viruses ◽

Next Generation ◽

Wild Type ◽

Influenza A H1n1

Vaccination is the best way to prevent influenza virus infections, but the diversity of antigenically distinct isolates is a persistent challenge for vaccine development. In order to conquer the antigenic variability and improve influenza virus vaccine efficacy, our research group has developed computationally optimized broadly reactive antigens (COBRAs) in the form of recombinant hemagglutinins (rHAs) to elicit broader immune responses. However, previous COBRA H1N1 vaccines do not elicit immune responses that neutralize H1N1 virus strains in circulation during the recent years. In order to update our COBRA vaccine, two new candidate COBRA HA vaccines, Y2 and Y4, were generated using a new seasonal-based COBRA methodology derived from H1N1 isolates that circulated during 2013–2019. In this study, the effectiveness of COBRA Y2 and Y4 vaccines were evaluated in mice, and the elicited immune responses were compared to those generated by historical H1 COBRA HA and wild-type H1N1 HA vaccines. Mice vaccinated with the next generation COBRA HA vaccines effectively protected against morbidity and mortality after infection with H1N1 influenza viruses. The antibodies elicited by the COBRA HA vaccines were highly cross-reactive with influenza A (H1N1) pdm09-like viruses isolated from 2009 to 2021, especially with the most recent circulating viruses from 2019 to 2021. Furthermore, viral loads in lungs of mice vaccinated with Y2 and Y4 were dramatically reduced to low or undetectable levels, resulting in minimal lung injury compared to wild-type HA vaccines following H1N1 influenza virus infection.

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