The relationship between in vivo antiviral activity and pharmacokinetic parameters of peramivir in influenza virus infection model in mice

ABSTRACT A cyclic polyisoprenoid compound, geranylgeranylacetone (GGA), has been used as antiulcer drug. GGA is also a potent inducer of heat shock proteins (HSPs). HSPs are considered to induce an antiviral effect; however, the detailed mechanism is unknown. To determine whether GGA might show antiviral activity and what the mechanism is, the effect of GGA against influenza virus (strain PR8) infection in vivo and in vitro was investigated. The results demonstrated that GGA treatment strongly suppressed the deleterious consequences of PR8 replication and was accompanied by an increase in HSP70 gene expression in mice. Results from in vitro analyses demonstrated that GGA significantly inhibited the synthesis of PR8-associated proteins and prominently enhanced expression of human myxovirus resistance 1 (MxA) followed by increased HSP70 transcription. Moreover, GGA augmented the expression of an interferon-inducible double-strand RNA-activated protein kinase (PKR) gene and promoted PKR autophosphorylation and concomitantly α subunit of eukaryotic initiation factor 2 phosphorylation during PR8 infection. It is proposed that GGA-induced HSP70 has potent antiviral activity by enhancement of antiviral factors and can clinically achieve protection from influenza virus infection.

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Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo

Biomaterials ◽

10.1016/j.biomaterials.2017.05.028 ◽

2017 ◽

Vol 138 ◽

pp. 22-34 ◽

Cited By ~ 43

Author(s):

Sumati Bhatia ◽

Daniel Lauster ◽

Markus Bardua ◽

Kai Ludwig ◽

Stefano Angioletti-Uberti ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza Virus Infection

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Directed Evolution of an Influenza Reporter Virus To Restore Replication and Virulence and Enhance Noninvasive Bioluminescence Imaging in Mice

Journal of Virology ◽

10.1128/jvi.00593-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 4

Author(s):

Hui Cai ◽

Meisui Liu ◽

Charles J. Russell

Keyword(s):

Gene Expression ◽

Influenza Virus ◽

Virus Infection ◽

Directed Evolution ◽

Influenza Virus Infection ◽

Foreign Gene ◽

Reporter Virus ◽

Wild Type ◽

Bioluminescence Signal

ABSTRACTReporter viruses provide a powerful tool to study infection, yet incorporating a nonessential gene often results in virus attenuation and genetic instability. Here, we used directed evolution of a luciferase-expressing pandemic H1N1 (pH1N1) 2009 influenza A virus in mice to restore replication kinetics and virulence, increase the bioluminescence signal, and maintain reporter gene expression. An unadapted pH1N1 virus withNanoLuc luciferaseinserted into the 5′ end of the PA gene segment grew to titers 10-fold less than those of the wild type in MDCK cells and in DBA/2 mice and was less virulent. For 12 rounds, we propagated DBA/2 lung samples with the highest bioluminescence-to-titer ratios. Every three rounds, we comparedin vivoreplication, weight loss, mortality, and bioluminescence. Mouse-adapted virus after 9 rounds (MA-9) had the highest relative bioluminescence signal and had wild-type-like fitness and virulence in DBA/2 mice. Using reverse genetics, we discovered fitness was restored in virus rPB2-MA9/PA-D479N by a combination of PA-D479N and PB2-E158G amino acid mutations andPB2noncoding mutations C1161T and C1977T. rPB2-MA9/PA-D479N has increased mRNA transcription, which helps restore wild-type-like phenotypes in DBA/2 and BALB/c mice. Overall, the results demonstrate that directed evolution that maximizes foreign-gene expression while maintaining genetic stability is an effective method to restore wild-type-likein vivofitness of a reporter virus. Virus rPB2-MA9/PA-D479N is expected to be a useful tool for noninvasive imaging of pH1N1 influenza virus infection and clearance while analyzing virus-host interactions and developing new therapeutics and vaccines.IMPORTANCEInfluenza viruses contribute to 290,000 to 650,000 deaths globally each year. Infection is studied in mice to learn how the virus causes sickness and to develop new drugs and vaccines. During experiments, scientists have needed to euthanize groups of mice at different times to measure the amount of infectious virus in mouse tissues. By inserting a foreign gene that causes infected cells to light up, scientists could see infection spread in living mice. Unfortunately, adding an extra gene not needed by the virus slowed it down and made it weaker. Here, we used a new strategy to restore the fitness and lethality of an influenza reporter virus; we adapted it to mouse lungs and selected for variants that had the greatest light signal. The adapted virus can be used to study influenza virus infection, immunology, and disease in living mice. The strategy can also be used to adapt other viruses.

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Multicolor two-photon imaging of in vivo cellular pathophysiology upon influenza virus infection using the two-photon IMPRESS

Nature Protocols ◽

10.1038/s41596-019-0275-y ◽

2020 ◽

Vol 15 (3) ◽

pp. 1041-1065 ◽

Cited By ~ 6

Author(s):

Hiroshi Ueki ◽

I-Hsuan Wang ◽

Dongming Zhao ◽

Matthias Gunzer ◽

Yoshihiro Kawaoka

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza Virus Infection ◽

Two Photon ◽

Photon Imaging ◽

Two Photon Imaging

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Murine interferon lambdas (type III interferons) exhibit potent antiviral activity in vivo in a poxvirus infection model

Journal of General Virology ◽

10.1099/vir.0.80904-0 ◽

2005 ◽

Vol 86 (6) ◽

pp. 1589-1596 ◽

Cited By ~ 79

Author(s):

Nathan W. Bartlett ◽

Karen Buttigieg ◽

Sergei V. Kotenko ◽

Geoffrey L. Smith

Keyword(s):

Virus Infection ◽

Antiviral Activity ◽

Janus Kinase ◽

Human Interferon ◽

Infection Model ◽

Type I ◽

Type Iii ◽

Potent Antiviral Activity ◽

Cell Extracts

Human interferon lambdas (IFN-λs) (type III IFNs) exhibit antiviral activity in vitro by binding to a receptor complex distinct from that used by type I and type II IFNs, and subsequent signalling through the Janus kinase signal transducers and activators of transcription (STAT) pathway. However, evidence for a function of type III IFNs during virus infection in vivo is lacking. Here, the expression of murine IFN-λs by recombinant vaccinia virus (VACV) is described and these proteins are shown to have potent antiviral activity in vivo. VACV expressing murine IFN-λ2 (vIFN-λ2) and IFN-λ3 (vIFN-λ3) showed normal growth in tissue culture and expressed N-glycosylated IFN-λ in infected cell extracts and culture supernatants. The role that murine IFN-λs play during virus infection was assessed in two different mouse models. vIFN-λ2 and vIFN-λ3 were avirulent for mice infected intranasally and induced no signs of illness or weight loss, in contrast to control viruses. Attenuation of vIFN-λ2 was associated with increases in lymphocytes in bronchial alveolar lavages and CD4+ T cells in total-lung lymphocyte preparations. In addition, vIFN-λ2 was cleared more rapidly from infected lungs and, in contrast to control viruses, did not disseminate to the brain. Expression of IFN-λ2 also attenuated VACV in an intradermal-infection model, characterized by a delay in lesion onset and reduced lesion size. Thus, by characterizing murine IFN-λs within a mouse infection model, the potent antiviral and immunostimulatory activity of IFN-λs in response to poxvirus infection has been demonstrated.

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Prevention of Murine Influenza a Virus Pneumonitis by Surfactant Nano-Emulsions

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632020001100104 ◽

2000 ◽

Vol 11 (1) ◽

pp. 41-49 ◽

Cited By ~ 28

Author(s):

Brian W Donovan ◽

Jon D Reuter ◽

Zhengyi Cao ◽

Andrzej Myc ◽

Kent J Johnson ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Influenza A ◽

Therapeutic Potential ◽

Clinical Signs ◽

Influenza Virus Infection ◽

Initial Study ◽

Ionic Surfactant ◽

Nano Emulsion

Non-ionic surfactant nano-emulsions have extensive anti-microbial activity and are biocompatible with skin and mucous membranes at effective concentrations. Two nano-emulsion formulations (8N8 and 20N10) made from soybean oil, tributyl phosphate and Triton X-100, were tested for their ability to prevent murine influenza virus pneumonia in vivo. In the initial study, CD-1 mice were administered various dilutions of the nano-emulsions intranasally, and safe dosages and concentrations were determined. Non-toxic concentrations of the nano-emulsions were then mixed with influenza virus and applied to the nares of mice. Animals receiving mixtures of two different emulsions (8N8 or 20N10) and a LD50 of virus survived the challenge without evidence of viral infection. To determine if the nano-emulsions could prevent influenza virus infection in vivo when used as a prophylactic treatment, the nano-emulsions (8N8 at 1.0% and 20N10 at 1.0% or 0.2%) were applied to mouse nares 90 min before exposure to 5×105 p.f.u./ml virus by nebulized aerosol. Animals pretreated with the nano-emulsions had significantly decreased clinical signs of infection. Only 26.0% (8N8 at 1.0%), 31.25% (20N10 at 1.0%) and 37.0% (20N10 at 0.2%) of animals pretreated with nano-emulsion died from pneumonitis, whereas >80.0% of mock pretreated animals succumbed to infection ( P<0.005). These findings suggest that non-ionic surfactant nano-emulsions have therapeutic potential for the prevention of influenza virus infection in vivo.

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Plasmacytoid dendritic cells and Toll-like receptor 7-dependent signalling promote efficient protection of mice against highly virulent influenza A virus

Journal of General Virology ◽

10.1099/vir.0.039065-0 ◽

2012 ◽

Vol 93 (3) ◽

pp. 555-559 ◽

Cited By ~ 25

Author(s):

Michael M. Kaminski ◽

Annette Ohnemus ◽

Marius Cornitescu ◽

Peter Staeheli

Keyword(s):

Dendritic Cells ◽

Influenza Virus ◽

Virus Infection ◽

Influenza A Virus ◽

Virus Resistance ◽

Influenza A ◽

Influenza Virus Infection ◽

Plasmacytoid Dendritic Cells ◽

Toll Like Receptor

Types I and III interferons (IFNs) elicit protective antiviral immune responses during influenza virus infection. Although many cell types can synthesize IFN in response to virus infection, it remains unclear which IFN sources contribute to antiviral protection in vivo. We found that mice carrying functional alleles of the Mx1 influenza virus resistance gene partially lost resistance to infection with a highly pathogenic H7N7 influenza A virus strain if Toll-like receptor 7 (TLR7) signalling was compromised. This effect was achieved by deleting either the TLR7 gene or the gene encoding the TLR7 adaptor molecule MyD88. A similar decrease of influenza virus resistance was observed when animals were deprived of plasmacytoid dendritic cells (pDCs) at day 1 post-infection. Our results provide in vivo proof that pDCs contribute to the protection of the lung against influenza A virus infections, presumably via signals from TLR7.

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