scholarly journals Sirtuins Are Evolutionarily Conserved Viral Restriction Factors

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Emre Koyuncu ◽  
Hanna G. Budayeva ◽  
Yana V. Miteva ◽  
Dante P. Ricci ◽  
Thomas J. Silhavy ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
Rna Virus ◽  
Immune Defense ◽  
Human Pathogens ◽  
Activity Increase ◽  
Virus Growth ◽  
Cell Defense ◽  
Influenza A H1n1 ◽  
Evolutionarily Conserved

ABSTRACTThe seven human sirtuins are a family of ubiquitously expressed and evolutionarily conserved NAD+-dependent deacylases/mono-ADP ribosyltransferases that regulate numerous cellular and organismal functions, including metabolism, cell cycle, and longevity. Here, we report the discovery that all seven sirtuins have broad-range antiviral properties. We demonstrate that small interfering RNA (siRNA)-mediated knockdown of individual sirtuins and drug-mediated inhibition of sirtuin enzymatic activity increase the production of virus progeny in infected human cells. This impact on virus growth is observed for both DNA and RNA viruses. Importantly, sirtuin-activating drugs inhibit the replication of diverse viruses, as we demonstrate for human cytomegalovirus, a slowly replicating DNA virus, and influenza A (H1N1) virus, an RNA virus that multiplies rapidly. Furthermore, sirtuin defense functions are evolutionarily conserved, since CobB, the sirtuin homologue inEscherichia coli, protects against bacteriophages. Altogether, our findings establish sirtuins as broad-spectrum and evolutionarily conserved components of the immune defense system, providing a framework for elucidating a new set of host cell defense mechanisms and developing sirtuin modulators with antiviral activity.IMPORTANCEWe live in a sea of viruses, some of which are human pathogens. These pathogenic viruses exhibit numerous differences: DNA or RNA genomes, enveloped or naked virions, nuclear or cytoplasmic replication, diverse disease symptoms, etc. Most antiviral drugs target specific viral proteins. Consequently, they often work for only one virus, and their efficacy can be compromised by the rapid evolution of resistant variants. There is a need for the identification of host proteins with broad-spectrum antiviral functions, which provide effective targets for therapeutic treatments that limit the evolution of viral resistance. Here, we report that sirtuins present such an opportunity for the development of broad-spectrum antiviral treatments, since our findings highlight these enzymes as ancient defense factors that protect against a variety of viral pathogens.

scholarly journals Viruses harness YxxØ motif to interact with host AP2M1 for replication: A vulnerable broad-spectrum antiviral target

2020 ◽  
Vol 6 (35) ◽  
pp. eaba7910
Author(s):  
Shuofeng Yuan ◽  
Hin Chu ◽  
Jingjing Huang ◽  
Xiaoyu Zhao ◽  
Zi-Wei Ye ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
Host Protein ◽  
Influenza A Viruses ◽  
Protein Protein Interaction ◽  
Enterovirus A71 ◽  
Evolutionarily Conserved ◽  
Immunodeficiency Virus

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.

scholarly journals Evolution and Antiviral Specificities of Interferon-Induced Mx Proteins of Bats against Ebola, Influenza, and Other RNA Viruses

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Jonas Fuchs ◽  
Martin Hölzer ◽  
Mirjam Schilling ◽  
Corinna Patzina ◽  
Andreas Schoen ◽  
...  
Keyword(s):  
Viral Replication ◽  
Positive Selection ◽  
Influenza A ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Immune Defense ◽  
Influenza Viruses ◽  
Large Set ◽  
Human Pathogens ◽  
Zoonotic Infections

ABSTRACT Bats serve as a reservoir for various, often zoonotic viruses, including significant human pathogens such as Ebola and influenza viruses. However, for unknown reasons, viral infections rarely cause clinical symptoms in bats. A tight control of viral replication by the host innate immune defense might contribute to this phenomenon. Transcriptomic studies revealed the presence of the interferon-induced antiviral myxovirus resistance (Mx) proteins in bats, but detailed functional aspects have not been assessed. To provide evidence that bat Mx proteins might act as key factors to control viral replication we cloned Mx1 cDNAs from three bat families, Pteropodidae, Phyllostomidae, and Vespertilionidae. Phylogenetically these bat Mx1 genes cluster closely with their human ortholog MxA. Using transfected cell cultures, minireplicon systems, virus-like particles, and virus infections, we determined the antiviral potential of the bat Mx1 proteins. Bat Mx1 significantly reduced the polymerase activity of viruses circulating in bats, including Ebola and influenza A-like viruses. The related Thogoto virus, however, which is not known to infect bats, was not inhibited by bat Mx1. Further, we provide evidence for positive selection in bat Mx1 genes that might explain species-specific antiviral activities of these proteins. Together, our data suggest a role for Mx1 in controlling these viruses in their bat hosts. IMPORTANCE Bats are a natural reservoir for various viruses that rarely cause clinical symptoms in bats but are dangerous zoonotic pathogens, like Ebola or rabies virus. It has been hypothesized that the interferon system might play a key role in controlling viral replication in bats. We speculate that the interferon-induced Mx proteins might be key antiviral factors of bats and have coevolved with bat-borne viruses. This study evaluated for the first time a large set of bat Mx1 proteins spanning three major bat families for their antiviral potential, including activity against Ebola virus and bat influenza A-like virus, and we describe here their phylogenetic relationship, revealing patterns of positive selection that suggest a coevolution with viral pathogens. By understanding the molecular mechanisms of the innate resistance of bats against viral diseases, we might gain important insights into how to prevent and fight human zoonotic infections caused by bat-borne viruses.

scholarly journals Comprehensive Transcriptomic Analysis Identifies Novel Antiviral Factors Against Influenza A Virus Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Ao Zhou ◽  
Xia Dong ◽  
Mengyun Liu ◽  
Bin Tang
Keyword(s):  
Epithelial Cells ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Broad Spectrum ◽  
Influenza A ◽  
Cell Types ◽  
Immune Defense ◽  
Host Responses ◽  
Different Cell Types ◽  
Host Genes

Influenza A virus (IAV) has a higher genetic variation, leading to the poor efficiency of traditional vaccine and antiviral strategies targeting viral proteins. Therefore, developing broad-spectrum antiviral treatments is particularly important. Host responses to IAV infection provide a promising approach to identify antiviral factors involved in virus infection as potential molecular drug targets. In this study, in order to better illustrate the molecular mechanism of host responses to IAV and develop broad-spectrum antiviral drugs, we systematically analyzed mRNA expression profiles of host genes in a variety of human cells, including transformed and primary epithelial cells infected with different subtypes of IAV by mining 35 microarray datasets from the GEO database. The transcriptomic results showed that IAV infection resulted in the difference in expression of amounts of host genes in all cell types, especially those genes participating in immune defense and antiviral response. In addition, following the criteria of P<0.05 and |logFC|≥1.5, we found that some difference expression genes were overlapped in different cell types under IAV infection via integrative gene network analysis. IFI6, IFIT2, ISG15, HERC5, RSAD2, GBP1, IFIT3, IFITM1, LAMP3, USP18, and CXCL10 might act as key antiviral factors in alveolar basal epithelial cells against IAV infection, while BATF2, CXCL10, IFI44L, IL6, and OAS2 played important roles in airway epithelial cells in response to different subtypes of IAV infection. Additionally, we also revealed that some overlaps (BATF2, IFI44L, IFI44, HERC5, CXCL10, OAS2, IFIT3, USP18, OAS1, IFIT2) were commonly upregulated in human primary epithelial cells infected with high or low pathogenicity IAV. Moreover, there were similar defense responses activated by IAV infection, including the interferon-regulated signaling pathway in different phagocyte types, although the differentially expressed genes in different phagocyte types showed a great difference. Taken together, our findings will help better understand the fundamental patterns of molecular responses induced by highly or lowly pathogenic IAV, and the overlapped genes upregulated by IAV in different cell types may act as early detection markers or broad-spectrum antiviral targets.

scholarly journals Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

2020 ◽  
Author(s):  
Einat. B. Vitner ◽  
Roy Avraham ◽  
Hagit Achdout ◽  
Hadas Tamir ◽  
Avi Agami ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
Cell Membranes ◽  
Rna Viruses ◽  
Rna Virus ◽  
Antiviral Drugs ◽  
Membrane Dynamics ◽  
Biologically Active ◽  
Phase Iii ◽  
Glucosylceramide Synthase

AbstractThe need for antiviral drugs is real and relevant. Broad spectrum antiviral drugs have a particular advantage when dealing with rapid disease outbreaks, such as the current COVID-19 pandemic. Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target. We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection.One Sentence SummaryAn analogue of Cerdelga®, an FDA-approved drug, is effective against a broad range of RNA-viruses including the newly emerging SARS-CoV-2.

Influenza

2021 ◽  
Author(s):  
Leong Hoe Nam
Keyword(s):  
Influenza Virus ◽  
Pandemic Influenza ◽  
Influenza A ◽  
Respiratory Infections ◽  
Rna Virus ◽  
Treatment Options ◽  
Antigenic Drift ◽  
New Techniques ◽  
Influenza A H1n1 ◽  
Viral Respiratory Infections

The influenza virus is a segmented RNA virus with different mechanisms for mutations, and hence for minor (antigenic drift) and major (antigenic shift) changes. Influenza virus A was responsible for pandemics on average every 30 years in the past, with the most recent being the 2009 swine-origin influenza A H1N1 (SO-H1N1). The clinical picture is unspecific: seasonal or pandemic influenza cannot be differentiated from other viral respiratory infections on clinical grounds. PCR has become the standard for microbiological confirmation of the diagnosis. Treatment options remain limited with neuraminidase inhibitors (oseltamivir; zanamivir). Resistance may occur under treatment or under prophylaxis; however, it is still rare overall. Vaccination is still the preferred method for prevention. However, the long lead time for production (at least 6 months) poses a challenge. Innovative new techniques like cell culture or recombinant productions are urgently needed. Pandemic influenza vaccines for SO-H1N1 were shown to be effective and safe in children, pregnant women, adults, and also in elderly. Pre-pandemic vaccines (H5N1) are also available.

scholarly journals Segment 2 from influenza A(H1N1)pdm09 viruses confers temperature sensitive HA yield on candidate vaccine virus growth in eggs that is complemented by PB2 701D

2019 ◽  
Author(s):  
Saira Hussain ◽  
Matthew L. Turnbull ◽  
Rute M. Pinto ◽  
John W. McCauley ◽  
Othmar G. Engelhardt ◽  
...  
Keyword(s):  
Temperature Sensitivity ◽  
Influenza A ◽  
Reverse Genetics ◽  
High Growth ◽  
Candidate Vaccine ◽  
Virus Yield ◽  
Temperature Sensitive ◽  
Sequence Comparisons ◽  
Virus Growth ◽  
Influenza A H1n1

AbstractCandidate vaccine viruses (CVVs) for seasonal influenza A virus are made by reassortment of the antigenic virus with a high-yielding egg-adapted strain, typically A/Puerto Rico/8/34 (PR8). Many 2009 H1N1 pandemic (pdm09) high-growth reassortants (HGRs) selected by this process contain pdm09 segment 2 in addition to the antigenic genes. To investigate this, we made CVV mimics by reverse genetics (RG) that were either 6:2 or 5:3 reassortants between PR8 and two pdm09 strains, A/California/7/2009 (Cal7) and A/England/195/2009, differing in the source of segment 2. The 5:3 viruses replicated better in MDCK-SIAT1 cells than the 6:2 viruses, but the 6:2 CVVs gave higher HA antigen yields from eggs. This unexpected phenomenon reflected temperature sensitivity conferred by pdm09 segment 2, as HA yields from eggs for the 5:3 viruses improved substantially when viruses were grown at 35°C compared with 37.5°C, whereas 6:2 virus yield did not. Authentic 5:3 pdm09 HGRs, X-179A and X-181, were not markedly temperature-sensitive however, despite their PB1 sequences being identical to that of Cal7, suggestive of compensatory mutations elsewhere in the genome. Sequence comparisons of the PR8-derived backbone genes identified single changes in PB2 and NP, 5 in NS1, and 1 in NS2. PB2 N701D but not NP T130A affected the temperature dependency of viral transcription. Furthermore, introducing the PB2 701D change into a 5:3 CVV mimic improved and drastically reduced the temperature sensitivity of HA yield. We conclude that RG PR8 backbones used for vaccine manufacture in eggs should contain PB2 701D to maximise virus yield.

scholarly journals Abscess of the pontine dorsolateral tegmentum due to E. coli and influenza A(H1N1)pdm09 virus co-infection

2021 ◽  
Vol 106 (106(812)) ◽  
pp. 93-98
Author(s):  
A.J. Láinez Ramos-Bossini ◽  
L. Fernández-Navarro ◽  
M.C. Pérez-García ◽  
M. Rivera-Izquierdo
Keyword(s):  
Mechanical Ventilation ◽  
Broad Spectrum ◽  
Postoperative Period ◽  
Critically Ill Patients ◽  
Influenza A ◽  
E Coli ◽  
Pdm09 Virus ◽  
Influenza A H1n1 ◽  
Intracranial Lesions ◽  
Rule Out

Brain stem abscesses are rare entities that predominantly affect the pons. A wide variety of microorganisms may be implied, depending on the focus of dissemination. We present the case of a female patient with multiple comorbidities who developed multi-lobar pneumonia due to influenza A(H1N1)pdm09 virus during the postoperative period after an emergent cholecystectomy, requiring mechanical ventilation (MV). Following clinical improvement and withdrawal of MV, the patient did not recover consciousness. Forty-eight hours later, imaging exams showed an abscess in the left pontine dorsolateral tegmentum –a region recently associated with coma-. Despite the administration of broad-spectrum antibiotics, the patient died five days later. This case illustrates the importance of considering pontine abscesses as a cause of poor neurological course in critically ill patients, as well as the need for doing imaging exams to rule out intracranial lesions, particularly in coma-associated areas.

scholarly journals Enisamium is a small molecule inhibitor of the influenza A virus and SARS-CoV-2 RNA polymerases

2020 ◽  
Author(s):  
Alexander P Walker ◽  
Haitian Fan ◽  
Jeremy R Keown ◽  
Victor Margitich ◽  
Jonathan M Grimes ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Influenza A Virus ◽  
Small Molecule ◽  
Broad Spectrum ◽  
Influenza A ◽  
Rna Synthesis ◽  
Rna Virus ◽  
Rna Polymerases ◽  
Influenza A Viruses ◽  
Molecule Inhibitor

AbstractInfluenza A virus and coronavirus strains cause a mild to severe respiratory disease that can result in death. Although vaccines exist against circulating influenza A viruses, such vaccines are ineffective against emerging pandemic influenza A viruses. Currently, no vaccine exists against coronavirus infections, including pandemic SARS-CoV-2, the causative agent of the Coronavirus Disease 2019 (COVID-19). To combat these RNA virus infections, alternative antiviral strategies are needed. A key drug target is the viral RNA polymerase, which is responsible for viral RNA synthesis. In January 2020, the World Health Organisation identified enisamium as a candidate therapeutic against SARS-CoV-2. Enisamium is an isonicotinic acid derivative that is an inhibitor of multiple influenza B and A virus strains in cell culture and clinically approved in 11 countries. Here we show using in vitro assays that enisamium and its putative metabolite, VR17-04, inhibit the activity of the influenza virus and the SARS-CoV-2 RNA polymerase. VR17-04 displays similar efficacy against the SARS-CoV-2 RNA polymerase as the nucleotide analogue remdesivir triphosphate. These results suggest that enisamium is a broad-spectrum small molecule inhibitor of RNA virus RNA synthesis, and implicate it as a possible therapeutic option for treating SARS-CoV-2 infection. Unlike remdesivir, enisamium does not require intravenous administration which may be advantageous for the development of COVID-19 treatments outside a hospital setting.ImportanceInfluenza A virus and SARS-CoV-2 are respiratory viruses capable of causing pandemics, and the latter is responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. Both viruses encode RNA polymerases which transcribe their RNA genomes and are important targets for antiviral drugs including remdesivir. Here, we show that the antiviral drug enisamium inhibits the RNA polymerases of both influenza A virus and SARS-CoV-2. Furthermore, we show that a putative metabolite of enisamium is a more potent inhibitor, inhibiting the SARS-CoV-2 RNA polymerase with similar efficiency to remdesivir. Our data offer insight into the mechanism of action for enisamium, and implicate it as a broad-spectrum antiviral which could be used in the treatment of SARS-CoV-2 infection.

scholarly journals A streamlined clinical metagenomic sequencing protocol for rapid pathogen identification

2020 ◽  
Author(s):  
Xiaofang Jia ◽  
Lvyin Hu ◽  
Min Wu ◽  
Yun Ling ◽  
Wei Wang ◽  
...  
Keyword(s):  
Illumina Sequencing ◽  
Influenza A ◽  
Rna Virus ◽  
Time Frame ◽  
Turnaround Time ◽  
Clinical Samples ◽  
Metagenomic Sequencing ◽  
Pathogen Identification ◽  
Influenza A H1n1 ◽  
Hiv 1

Abstract Metagenomic next generation sequencing (mNGS) holds promise as a diagnostic tool for unbiased pathogen identification and precision medicine. However, its medical utility depends largely on the assay simplicity and reproducibility. In the current study, we aimed to develop a streamlined Illumina and Oxford Nanopore-based DNA/RNA library preparation protocol and rapid data analysis pipeline. The Illumina sequencing based mNGS method was first developed and evaluated using a set of samples with known etiology. Its sensitivity for RNA virus (Influenza A, H1N1) was <6.4×102 EID50/mL, and a good correlation between viral loads and mapped reads was observed. Then the rapid turnaround time of Nanopore sequencing was testified by sequencing of an Influenza A virus and Adenoviruses. Further, 11 respiratory swabs or sputum samples pre-tested for a panel of pathogens were analyzed and the pathogens identified by illumina sequencing showed 81.8% concordance with qPCR-based results. Additional sequencing of cerebrospinal fluid (CSF) samples from HIV-1 positive patients with meningitis/encephalitis detected HIV-1 RNA and toxoplasma gondii sequences. In conclusion, we have developed a simplified protocol which realized facile metagenomic sequencing of a variety of clinical samples and pathogen identification in a clinically meaningful time frame.

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