Mechanism of Host Defense Suppression Induced by Viral Infection: Mode of Action of Inosiplex as an Antiviral Agent

AbstractMarine viruses are major evolutionary and biogeochemical drivers of microbial life in the ocean. Host response to viral infection typically includes virus-induced rewiring of metabolic network to supply essential building blocks for viral assembly, as opposed to activation of anti-viral host defense. Nevertheless, there is a major bottleneck to accurately discern between viral hijacking strategies and host defense responses when averaging bulk population response. Here we use Emiliania huxleyi, a bloom-forming alga and its specific virus (EhV), as one of the most ecologically important host-virus model system in the ocean. Using automatic microfluidic setup to capture individual algal cells, we quantified host and virus gene expression on a single-cell resolution during the course of infection. We revealed high heterogeneity in viral gene expression among individual cells. Simultaneous measurements of expression profiles of host and virus genes at a single-cell level allowed mapping of infected cells into newly defined infection states and uncover a yet unrecognized early phase in host response that occurs prior to viral expression. Intriguingly, resistant cells emerged during viral infection, showed unique expression profiles of metabolic genes which can provide the basis for discerning between viral resistant and sensitive cells within heterogeneous populations in the marine environment. We propose that resolving host-virus arms race at a single-cell level will provide important mechanistic insights into viral life cycles and will uncover host defense strategies.

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To kill or to cure: options in host defense against viral infection

Current Opinion in Immunology ◽

10.1016/s0952-7915(96)80034-3 ◽

1996 ◽

Vol 8 (4) ◽

pp. 478-483 ◽

Cited By ~ 179

Author(s):

Luca G Guidotti ◽

Francis V Chisari

Keyword(s):

Viral Infection ◽

Host Defense

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Potyviral Gene-Silencing Suppressor HCPro Interacts with Salicylic Acid (SA)-Binding Protein 3 to Weaken SA-Mediated Defense Responses

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi-06-17-0128-fi ◽

2018 ◽

Vol 31 (1) ◽

pp. 86-100 ◽

Cited By ~ 18

Author(s):

Sylvain Poque ◽

Hui-Wen Wu ◽

Chung-Hao Huang ◽

Hao-Wen Cheng ◽

Wen-Chi Hu ◽

...

Keyword(s):

Salicylic Acid ◽

Viral Infection ◽

Host Defense ◽

Binding Protein ◽

Constitutive Expression ◽

Defense Responses ◽

Negative Regulator ◽

Bimolecular Fluorescence Complementation ◽

Silencing Suppressor ◽

Ability To Act

The viral infection process is a battle between host defense response and pathogen antagonizing action. Several studies have established a tight link between the viral RNA silencing suppressor (RSS) and the repression of salicylic acid (SA)-mediated defense responses, nonetheless host factors directly linking an RSS and the SA pathway remains unidentified. From yeast two-hybrid analysis, we identified an interaction between the potyviral RSS helper-component proteinase (HCPro) and SA–binding protein SABP3. Co-localization and bimolecular fluorescence complementation analyses validated the direct in vivo interaction between Turnip mosaic virus (TuMV) HCPro and the Arabidopsis homologue of SABP3, AtCA1. Additionally, transient expression of TuMV HCPro demonstrated its ability to act as a negative regulator of AtCA1. When the plants of the AtCA1 knockout mutant line were inoculated with TuMV, our results indicated that AtCA1 is essential to restrict viral spreading and accumulation, induce SA accumulation, and trigger the SA pathway. Unexpectedly, the AtCA1 overexpression line also displayed a similar phenotype, suggesting that the constitutive expression of AtCA1 antagonizes the SA pathway. Taken together, our results depict AtCA1 as an essential regulator of SA defense responses. Moreover, the interaction of potyviral HCPro with this regulator compromises the SA pathway to weaken host defense responses and facilitate viral infection.

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Studies on the mode of action of the new antiviral agent hydroxyphosphonylmethoxypropyl adenine (HPMPA) using bovine herpesvirus-1

Antiviral Research ◽

10.1016/0166-3542(88)90120-9 ◽

1988 ◽

Vol 9 (1-2) ◽

pp. 107

Keyword(s):

Mode Of Action ◽

Antiviral Agent ◽

Bovine Herpesvirus ◽

Bovine Herpesvirus 1 ◽

Herpesvirus 1

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Measuring thousands of single vesicle leakage events reveals the mode of action of antimicrobial peptides

10.1101/2021.08.13.455434 ◽

2021 ◽

Author(s):

Kareem Al Nahas ◽

Marcus Fletcher ◽

Katharine Hammond ◽

Christian Nehls ◽

Jehangir Cama ◽

...

Keyword(s):

Antimicrobial Peptides ◽

Host Defense ◽

Mode Of Action ◽

Antimicrobial Agents ◽

Spatiotemporal Resolution ◽

Detailed Understanding ◽

Modes Of Action ◽

Structure Activity ◽

Single Vesicle

Host defense or antimicrobial peptides hold promise for providing new pipelines of effective antimicrobial agents. Their activity quantified against model phospholipid membranes is fundamental to a detailed understanding of their structure-activity relationships. However, existing characterization assays lack the resolution necessary to achieve this insight. Leveraging a highly parallelized microfluidic platform for trapping and studying thousands of giant unilamellar vesicles, we conducted quantitative long-term microscopy studies to monitor the membrane-disruptive activity of archetypal antimicrobial peptides with a high spatiotemporal resolution. We described the modes of action of these peptides via measurements of the disruption of the vesicle population under the conditions of continuous peptide dosing using a range of concentrations, and related the observed modes with the molecular activity mechanisms of these peptides. The study offers an effective approach for characterizing membrane-targeting antimicrobial agents in a standardized manner, and for assigning specific modes of action to the corresponding antimicrobial mechanisms.

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Identification and Semisynthesis of (–)-Anisomelic Acid as an Oral Antiviral Agent against SARS-CoV-2 in Mice

10.26434/chemrxiv-2021-fcb6z-v2 ◽

2021 ◽

Author(s):

Hai-Xin Yu ◽

Nan Zheng ◽

Chi-Tai Yeh ◽

Chien-Ming Lee ◽

Qi Zhang ◽

...

Keyword(s):

Drug Discovery ◽

Oral Administration ◽

Viral Infection ◽

Lung Tissue ◽

Cytopathic Effect ◽

Antiviral Agent ◽

Starting Material ◽

Viral Titers

(–)-Anisomelic acid (AA), isolated from Anisomeles indica (L.) Kuntze (Labiatae) leaves, is a macrocyclic cembranolide with a trans-fused α-methylene-β-lactone motif. Cytopathic effect assays showed that the anti-SARS-CoV-2 effect of AA (IC50 = 4.3 μM) is comparable to that of remdesivir (IC50 = 2.1 μM), and more potent than that of molnupiravir (IC50 = 27.8 μM). Challenge studies in SARS-CoV-2-infected K18-hACE2 mice showed that oral administration of AA and remdesivir can both reduce the viral titers in the lung tissue at the same level. To facilitate drug discovery, we used a semisynthetic approach to shorten the project timelines. The enantioselective semisynthesis of AA from the naturally enriched and commercially available starting material (+)-costunolide was achieved in five steps with a 27% overall yield. The developed chemistry provides opportunities for developing AA-based novel ligands for selectively targeting proteins involved in viral infection.

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Cell-to-cell infection by HIV contributes over half of virus infection

eLife ◽

10.7554/elife.08150 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 69

Author(s):

Shingo Iwami ◽

Junko S Takeuchi ◽

Shinji Nakaoka ◽

Fabrizio Mammano ◽

François Clavel ◽

...

Keyword(s):

Virus Infection ◽

Viral Infection ◽

Quantitative Information ◽

Viral Fitness ◽

Cell Infection ◽

Immunodeficiency Virus ◽

Mathematical Investigation ◽

Infection Mode ◽

Hiv 1

Cell-to-cell viral infection, in which viruses spread through contact of infected cell with surrounding uninfected cells, has been considered as a critical mode of virus infection. However, since it is technically difficult to experimentally discriminate the two modes of viral infection, namely cell-free infection and cell-to-cell infection, the quantitative information that underlies cell-to-cell infection has yet to be elucidated, and its impact on virus spread remains unclear. To address this fundamental question in virology, we quantitatively analyzed the dynamics of cell-to-cell and cell-free human immunodeficiency virus type 1 (HIV-1) infections through experimental-mathematical investigation. Our analyses demonstrated that the cell-to-cell infection mode accounts for approximately 60% of viral infection, and this infection mode shortens the generation time of viruses by 0.9 times and increases the viral fitness by 3.9 times. Our results suggest that even a complete block of the cell-free infection would provide only a limited impact on HIV-1 spread.

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Baloxavir: A Novel Antiviral Agent in the Treatment of Influenza

Clinical Infectious Diseases ◽

10.1093/cid/ciaa107 ◽

2020 ◽

Vol 71 (7) ◽

pp. 1790-1794 ◽

Cited By ~ 6

Author(s):

George M Abraham ◽

Jacob B Morton ◽

Louis D Saravolatz

Keyword(s):

Adverse Event ◽

Single Dose ◽

Antiviral Activity ◽

Mode Of Action ◽

Antiviral Agent ◽

Viral Transcription ◽

Neuraminidase Inhibitors ◽

Adverse Event Profile ◽

Essential Protein ◽

Dependent Endonuclease

Abstract Baloxavir marboxil (formerly S-033188) is a prodrug of baloxavir acid (S-033447) and inhibits cap-dependent endonuclease, an essential protein involved in the initiation of viral transcription by cleaving capped mRNA bound to PB2. Its adverse event profile is comparable to oseltamivir but is still vulnerable to resistance. The single-dose baloxavir marboxil is an appealing antiviral regimen for the treatment of influenza among outpatients when compared with longer, twice-daily regimens of oral and inhaled neuraminidase inhibitors. This review focuses on the mode of action, antiviral activity, pharmacokinetics, clinical indications, and safety profiles of this drug. Considerations for formulary addition and its place in therapy are also discussed.

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