Two formulations of the industrial surfactant, Toximul, differentially reduce mouse weight gain and hepatic glycogen in vivo during early development: effects of exposure to Influenza B Virus

ABSTRACT Type B influenza viruses can cause substantial morbidity and mortality in the population, and vaccination remains by far the best means of protection against infections with these viruses. Here, we report the construction of mutant influenza B viruses for potential use as improved live-virus vaccine candidates. Employing reverse genetics, we altered the NS1 gene, which encodes a type I interferon (IFN) antagonist. The resulting NS1 mutant viruses induced IFN and, as a consequence, were found to be attenuated in vitro and in vivo. The absence of pathogenicity of the NS1 mutants in both BALB/c and C57BL/6 PKR−/− mice was confirmed. We also provide evidence that influenza B virus NS1 mutants induce a self-adjuvanted immune response and confer effective protection against challenge with both homologous and heterologous B virus strains in mice.

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FluB-RAM and FluB-RANS: Genome Rearrangement as Safe and Efficacious Live Attenuated Influenza B Virus Vaccines

Vaccines ◽

10.3390/vaccines9080897 ◽

2021 ◽

Vol 9 (8) ◽

pp. 897

Author(s):

Stivalis Cardenas-Garcia ◽

C. Joaquín Cáceres ◽

Aarti Jain ◽

Ginger Geiger ◽

Jong-Suk Mo ◽

...

Keyword(s):

Genome Rearrangement ◽

Natural Infection ◽

The Elderly ◽

Respiratory Pathogen ◽

Influenza B Virus ◽

Influenza B ◽

B Virus ◽

Cellular Immune

Influenza B virus (IBV) is considered a major respiratory pathogen responsible for seasonal respiratory disease in humans, particularly severe in children and the elderly. Seasonal influenza vaccination is considered the most efficient strategy to prevent and control IBV infections. Live attenuated influenza virus vaccines (LAIVs) are thought to induce both humoral and cellular immune responses by mimicking a natural infection, but their effectiveness has recently come into question. Thus, the opportunity exists to find alternative approaches to improve overall influenza vaccine effectiveness. Two alternative IBV backbones were developed with rearranged genomes, rearranged M (FluB-RAM) and a rearranged NS (FluB-RANS). Both rearranged viruses showed temperature sensitivity in vitro compared with the WT type B/Bris strain, were genetically stable over multiple passages in embryonated chicken eggs and were attenuated in vivo in mice. In a prime-boost regime in naïve mice, both rearranged viruses induced antibodies against HA with hemagglutination inhibition titers considered of protective value. In addition, antibodies against NA and NP were readily detected with potential protective value. Upon lethal IBV challenge, mice previously vaccinated with either FluB-RAM or FluB-RANS were completely protected against clinical disease and mortality. In conclusion, genome re-arrangement renders efficacious LAIV candidates to protect mice against IBV.

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The NB Protein of Influenza B Virus Is Not Necessary for Virus Replication In Vitro

Journal of Virology ◽

10.1128/jvi.77.10.6050-6054.2003 ◽

2003 ◽

Vol 77 (10) ◽

pp. 6050-6054 ◽

Cited By ~ 46

Author(s):

Masato Hatta ◽

Yoshihiro Kawaoka

Keyword(s):

Cell Culture ◽

Virus Replication ◽

Wild Type Virus ◽

Influenza B Virus ◽

Influenza B ◽

Type Virus ◽

Wild Type ◽

B Virus

ABSTRACT The NB protein of influenza B virus is thought to function as an ion channel and therefore would be expected to have an essential function in viral replication. Because direct evidence for its absolute requirement in the viral life cycle is lacking, we generated NB knockout viruses by reverse genetics and tested their growth properties both in vitro and in vivo. Mutants not expressing NB replicated as efficiently as the wild-type virus in cell culture, whereas in mice they showed restricted growth compared with findings for the wild-type virus. Thus, the NB protein is not essential for influenza B virus replication in cell culture but promotes efficient growth in mice.

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Experimental Infection Using Mouse-Adapted Influenza B Virus in a Mouse Model

Viruses ◽

10.3390/v12040470 ◽

2020 ◽

Vol 12 (4) ◽

pp. 470 ◽

Cited By ~ 1

Author(s):

Elena Prokopyeva ◽

Olga Kurskaya ◽

Ivan Sobolev ◽

Mariia Solomatina ◽

Tatyana Murashkina ◽

...

Keyword(s):

Influenza Vaccine ◽

Drug Testing ◽

Protective Efficacy ◽

Influenza B Virus ◽

Infection Model ◽

Influenza B ◽

Post Inoculation ◽

B Virus

Every year, influenza B viruses (IBVs) contribute to annual illness, and infection can lead to serious respiratory disease among humans. More attention is needed in several areas, such as increasing virulence or pathogenicity of circulating B viruses and developing vaccines against current influenza. Since preclinical trials of anti-influenza drugs are mainly conducted in mice, we developed an appropriate infection model, using an antigenically-relevant IBV strain, for furtherance of anti-influenza drug testing and influenza vaccine protective efficacy analysis. A Victoria lineage (clade 1A) IBV was serially passaged 17 times in BALB/c mice, and adaptive amino acid substitutions were found in hemagglutinin (HA) (T214I) and neuraminidase (NA) (D432N). By electron microscopy, spherical and elliptical IBV forms were noted. Light microscopy showed that mouse-adapted IBVs caused influenza pneumonia on day 6 post inoculation. We evaluated the illness pathogenicity, viral load, and histopathological features of mouse-adapted IBVs and estimated anti-influenza drugs and vaccine efficiency in vitro and in vivo. Assessment of an investigational anti-influenza drug (oseltamivir ethoxysuccinate) and an influenza vaccine (Ultrix®, SPBNIIVS, Saint Petersburg, Russia) showed effectiveness against the mouse-adapted influenza B virus.

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Defective interfering influenza A virus protects in vivo against disease caused by a heterologous influenza B virus

Journal of General Virology ◽

10.1099/vir.0.034132-0 ◽

2011 ◽

Vol 92 (9) ◽

pp. 2122-2132 ◽

Cited By ~ 27

Author(s):

Paul D. Scott ◽

Bo Meng ◽

Anthony C. Marriott ◽

Andrew J. Easton ◽

Nigel J. Dimmock

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

Type I ◽

Type I Ifn ◽

B Virus ◽

The Family

Influenza A and B viruses are major human respiratory pathogens that contribute to the burden of seasonal influenza. They are both members of the family Orthomyxoviridae but do not interact genetically and are classified in different genera. Defective interfering (DI) influenza viruses have a major deletion of one or more of their eight genome segments, which renders them both non-infectious and able to interfere in cell culture with the production of infectious progeny by a genetically compatible, homologous virus. It has been shown previously that intranasal administration of a cloned DI influenza A virus, 244/PR8, protects mice from various homologous influenza A virus subtypes and that it also protects mice from respiratory disease caused by a heterologous virus belonging to the family Paramyxoviridae. The mechanisms of action in vivo differ, with homologous and heterologous protection being mediated by probable genome competition and type I interferon (IFN), respectively. In the current study, it was shown that 244/PR8 also protects against disease caused by a heterologous influenza B virus (B/Lee/40). Protection from B/Lee/40 challenge was partially eliminated in mice that did not express a functional type I IFN receptor, suggesting that innate immunity, and type I IFN in particular, are important in mediating protection against this virus. It was concluded that 244/PR8 has the ability to protect in vivo against heterologous IFN-sensitive respiratory viruses, in addition to homologous influenza A viruses, and that it acts by fundamentally different mechanisms.

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Development of an Alternative Modified Live Influenza B Virus Vaccine

Journal of Virology ◽

10.1128/jvi.00056-17 ◽

2017 ◽

Vol 91 (12) ◽

Cited By ~ 3

Author(s):

Jefferson J. S. Santos ◽

Courtney Finch ◽

Troy Sutton ◽

Adebimpe Obadan ◽

Isabel Aguirre ◽

...

Keyword(s):

Influenza A ◽

The United States ◽

Influenza B Virus ◽

Influenza B ◽

Temperature Sensitive ◽

Complete Protection ◽

C Terminus ◽

B Virus

ABSTRACT Influenza B virus (IBV) is considered a major human pathogen, responsible for seasonal epidemics of acute respiratory illness. Two antigenically distinct IBV hemagglutinin (HA) lineages cocirculate worldwide with little cross-reactivity. Live attenuated influenza virus (LAIV) vaccines have been shown to provide better cross-protective immune responses than inactivated vaccines by eliciting local mucosal immunity and systemic B cell- and T cell-mediated memory responses. We have shown previously that incorporation of temperature-sensitive (ts) mutations into the PB1 and PB2 subunits along with a modified HA epitope tag in the C terminus of PB1 resulted in influenza A viruses (IAV) that are safe and effective as modified live attenuated (att) virus vaccines (IAV att). We explored whether analogous mutations in the IBV polymerase subunits would result in a stable virus with an att phenotype. The PB1 subunit of the influenza B/Brisbane/60/2008 strain was used to incorporate ts mutations and a C-terminal HA tag. Such modifications resulted in a B/Bris att strain with ts characteristics in vitro and an att phenotype in vivo. Vaccination studies in mice showed that a single dose of the B/Bris att candidate stimulated sterilizing immunity against lethal homologous challenge and complete protection against heterologous challenge. These studies show the potential of an alternative LAIV platform for the development of IBV vaccines. IMPORTANCE A number of issues with regard to the effectiveness of the LAIV vaccine licensed in the United States (FluMist) have arisen over the past three seasons (2013–2014, 2014–2015, and 2015–2016). While the reasons for the limited robustness of the vaccine-elicited immune response remain controversial, this problem highlights the critical importance of continued investment in LAIV development and creates an opportunity to improve current strategies so as to develop more efficacious vaccines. Our laboratory has developed an alternative strategy, the incorporation of 2 amino acid mutations and a modified HA tag at the C terminus of PB1, which is sufficient to attenuate the IBV. As a LAIV, this novel vaccine provides complete protection against IBV strains. The availability of attenuated IAV and IBV backbones based on contemporary strains offers alternative platforms for the development of LAIVs that may overcome current limitations.

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Lianhua-Qingwen Displays Antiviral and Anti-Inflammatory Activity and Synergistic Effects with Oseltamivir against Influenza B Virus Infection in the Mouse Model

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/3196375 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Chunguang Yang ◽

Yutao Wang ◽

Jiayang He ◽

Wen Yan ◽

Haiming Jiang ◽

...

Keyword(s):

Virus Infection ◽

Time Course ◽

Synergistic Effects ◽

Mrna Level ◽

Inflammatory Cells ◽

Influenza B Virus ◽

Influenza B ◽

B Virus ◽

Anti Inflammatory

Influenza B virus (IBV) is one of the main pathogens of the annual influenza epidemic, and the disease burden is significant, especially among children and young teenagers. In this study, the antiviral and anti-inflammatory effects of a traditional Chinese medicine prescription, the Lianhua-Qingwen capsule, were evaluated. Our results showed that Lianhua-Qingwen capsule can inhibit both Victoria and Yamagata lineages, and the 50% inhibitive concentrations ranged from 0.228 ± 0.150 to 0.754 ± 0.161 mg/mL. The time course results demonstrated that IBV yields were reduced with treatment at 0–4 h after infection, and the mechanistic research verified that Lianhua-Qingwen capsule has hemagglutination inhibition activity against B/Guangzhou/0215/2012 but not A/California/04/2009. In addition to antiviral activity, Lianhua-Qingwen capsule can also inhibit excessive expression of RANTES, IL-6, IL-8, IP-10, TNF-α, MCP-1, MIP-1β, and IFN-λ at the mRNA level and prevent a severe inflammatory response. The in vivo results confirmed that orally administered Lianhua-Qingwen capsule (100–400 mg/kg/day) does not reduce IBV-induced lung viral load and mortality in mice. However, the pathological change in lungs was alleviated, and there were fewer inflammatory cells in the lungs of Lianhua-Qingwen capsule treated mice than those in controls. Further research confirmed that the combination treatment of 200 mg/kg/day of Lianhua-Qingwen capsule with 2 mg/kg/day of oseltamivir significantly reduced IBV infection over the individual administration of either alone in vivo. Our findings prove that Lianhua-Qingwen capsule could be used as an assistant medicine to enhance the effect of oseltamivir against influenza B virus infection.

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TMPRSS2 Independency for Haemagglutinin Cleavage In Vivo Differentiates Influenza B Virus from Influenza A Virus

Scientific Reports ◽

10.1038/srep29430 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 10

Author(s):

Kouji Sakai ◽

Yasushi Ami ◽

Noriko Nakajima ◽

Katsuhiro Nakajima ◽

Minori Kitazawa ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Influenza B Virus ◽

Influenza B ◽

B Virus

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Characterization of Influenza B Virus Variants with Reduced Neuraminidase Inhibitor Susceptibility

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01081-18 ◽

2018 ◽

Vol 62 (11) ◽

Cited By ~ 10

Author(s):

R. Farrukee ◽

A. E. Zarebski ◽

J. M. McCaw ◽

J. D. Bloom ◽

P. C. Reading ◽

...

Keyword(s):

Treatment Options ◽

Transmission Efficiency ◽

Enzyme Function ◽

Influenza B Virus ◽

Influenza B ◽

Virus Infections ◽

Wild Type ◽

B Virus ◽

Na Substitution

ABSTRACT Treatment options for influenza B virus infections are limited to neuraminidase inhibitors (NAIs), which block the neuraminidase (NA) glycoprotein on the virion surface. The development of NAI resistance would therefore result in a loss of antiviral treatment options for influenza B virus infections. This study characterized two contemporary influenza B viruses with known resistance-conferring NA amino acid substitutions, D197N and H273Y, detected during routine surveillance. The D197N and H273Y variants were characterized in vitro by assessing NA enzyme activity and affinity, as well as replication in cell culture compared to those of NAI-sensitive wild-type viruses. In vivo studies were also performed in ferrets to assess the replication and transmissibility of each variant. Mathematical models were used to analyze within-host and between-host fitness of variants relative to wild-type viruses. The data revealed that the H273Y variant had NA enzyme function similar to that of its wild type but had slightly reduced replication and transmission efficiency in vivo. The D197N variant had impaired NA enzyme function, but there was no evidence of reduction in replication or transmission efficiency in ferrets. Our data suggest that the influenza B virus variant with the H273Y NA substitution had a more notable reduction in fitness compared to wild-type viruses than the influenza B variant with the D197N NA substitution. Although a D197N variant is yet to become widespread, it is the most commonly detected NAI-resistant influenza B virus in surveillance studies. Our results highlight the need to carefully monitor circulating viruses for the spread of influenza B viruses with the D197N NA substitution.

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Characterization of influenza B virus variants with reduced neuraminidase inhibitor susceptibility

10.1101/334201 ◽

2018 ◽

Author(s):

R Farrukee ◽

AE Zarebski ◽

JM McCaw ◽

JD Bloom ◽

PC Reading ◽

...

Keyword(s):

Antiviral Treatment ◽

Treatment Options ◽

Transmission Efficiency ◽

Enzyme Function ◽

Influenza B Virus ◽

Influenza B ◽

Wild Type ◽

B Virus ◽

Na Substitution

AbstractTreatment options for influenza B virus infections are limited to neuraminidase inhibitors (NAIs) which block the neuraminidase (NA) glycoprotein on the virion surface. The development of NAI resistance would therefore result in a loss of antiviral treatment options for influenza B infections. This study characterized two contemporary influenza B viruses with known resistance-conferring NA amino acid substitutions, D197N and H273Y, detected during routine surveillance. The D197N and H273Y variants were characterized in vitro by assessing NA enzyme activity and affinity, as well as replication in cell culture compared to NAI-sensitive wild-type viruses. In vivo studies were also performed in ferrets to assess the replication and transmissibility of each variant. Mathematical models were used to analyse within-host and between-host fitness of variants relative to wild-type viruses. The data revealed that the H273Y variant had similar NA enzyme function relative to its wild-type but had slightly reduced replication and transmission efficiency in vivo. The D197N variant had impaired NA enzyme function but there was no evidence of reduction in replication or transmission efficiency in ferrets. Our data suggest that the influenza B variant with H273Y NA substitution had a more notable reduction in fitness compared to wild-type viruses than the influenza B variant with the D197N NA substitution. Although a D197N variant is yet to become widespread, it is the most commonly detected NAI-resistant influenza B virus in surveillance studies. Our results highlight the need to carefully monitor circulating viruses for the spread of influenza B viruses with the D197N NA substitution.

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