scholarly journals Unmutated Immunoglobulin M Can Protect Mice from Death by Influenza Virus Infection

2003 ◽  
Vol 197 (12) ◽  
pp. 1779-1785 ◽  
Author(s):  
Yuichi Harada ◽  
Masamichi Muramatsu ◽  
Toshikatsu Shibata ◽  
Tasuku Honjo ◽  
Kazumichi Kuroda
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Neutralizing Antibodies ◽  
Somatic Hypermutation ◽  
Secondary Infection ◽  
Lethal Dose ◽  
Influenza Virus Infection ◽  
Immunoglobulin M ◽  
Secondary Infections ◽  
Significant Difference

To elucidate the role of class switch recombination (CSR) and somatic hypermutation (SHM) in virus infection, we have investigated the influence of the primary and secondary infections of influenza virus on mice deficient of activation-induced cytidine deaminase (AID), which is absolutely required for CSR and SHM. In the primary infection, AID deficiency caused no significant difference in mortality but did cause difference in morbidity. In the secondary infection with a lethal dose of influenza virus, both AID−/− and AID+/− mice survived completely. However, AID−/− mice could not completely block replication of the virus and their body weights decreased severely whereas AID+/− mice showed almost complete prevention from the reinfection. Depletion of CD8+ T cells by administration of an anti-CD8 monoclonal antibody caused slightly severer body weight loss but did not alter the survival rate of AID−/− mice in secondary infection. These results indicate that unmutated immunoglobulin (Ig)M alone is capable of protecting mice from death upon primary and secondary infections. Because the titers of virus-neutralizing antibodies were comparable between AID−/− and AID+/− mice at the time of the secondary infection, a defect of AID−/− mice in protection of morbidity might be due to the absence of either other Ig classes such as IgG, high affinity antibodies with SHM, or both.

scholarly journals A non-neutralizing antibody broadly protects against influenza virus infection by engaging effector cells

2021 ◽  
Vol 17 (8) ◽  
pp. e1009724
Author(s):  
Yi-An Ko ◽  
Yueh-Hsiang Yu ◽  
Yen-Fei Wu ◽  
Yung-Chieh Tseng ◽  
Chia-Lin Chen ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Protective Efficacy ◽  
Lethal Dose ◽  
Influenza Virus Infection ◽  
Neutralizing Antibody ◽  
H1n1 Influenza ◽  
Influenza A Viruses

Hemagglutinin (HA) is the immunodominant protein of the influenza virus. We previously showed that mice injected with a monoglycosylated influenza A HA (HAmg) produced cross-strain-reactive antibodies and were better protected than mice injected with a fully glycosylated HA (HAfg) during lethal dose challenge. We employed a single B-cell screening platform to isolate the cross-protective monoclonal antibody (mAb) 651 from mice immunized with the HAmg of A/Brisbane/59/2007 (H1N1) influenza virus (Bris/07). The mAb 651 recognized the head domain of a broad spectrum of HAs from groups 1 and 2 influenza A viruses and offered prophylactic and therapeutic efficacy against A/California/07/2009 (H1N1) (Cal/09) and Bris/07 infections in mice. The antibody did not possess neutralizing activity; however, antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis mediated by natural killer cells and alveolar macrophages were important in the protective efficacy of mAb 651. Together, this study highlighted the significance of effector functions for non-neutralizing antibodies to exhibit protection against influenza virus infection.

scholarly journals Potency of an Inactivated Influenza Vaccine against a Challenge with A/Swine/Missouri/A01727926/2015 (H4N6) in Mice for Pandemic Preparedness

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 768
Author(s):  
Hirotaka Hayashi ◽  
Norikazu Isoda ◽  
Enkhbold Bazarragchaa ◽  
Naoki Nomura ◽  
Keita Matsuno ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Neutralizing Antibodies ◽  
Influenza Pandemic ◽  
Influenza Virus Infection ◽  
Cross Reactivity ◽  
Influenza Viruses ◽  
Pandemic Preparedness ◽  
Antigenic Relation ◽  
High Immunogenicity

H4 influenza viruses have been isolated from birds across the world. In recent years, an H4 influenza virus infection has been confirmed in pigs. Pigs play an important role in the transmission of influenza viruses to human hosts. Therefore, it is important to develop a new vaccine in the case of an H4 influenza virus infection in humans, considering that this virus has a different antigenicity from seasonal human influenza viruses. In this study, after selecting vaccine candidate strains based on their antigenic relation to one of the pig isolates, A/swine/Missouri/A01727926/2015 (H4N6) (MO/15), an inactivated whole-particle vaccine was prepared from A/swan/Hokkaido/481102/2017 (H4N6). This vaccine showed high immunogenicity in mice, and the antibody induced by the vaccine showed high cross-reactivity to the MO/15 virus. This vaccine induced sufficient neutralizing antibodies and mitigated the effects of an MO/15 infection in a mouse model. This study is the first to suggest that an inactivated whole-particle vaccine prepared from an influenza virus isolated from wild birds is an effective countermeasure in case of a future influenza pandemic caused by the H4 influenza virus.

scholarly journals MyD88 Signaling Is Indispensable for Primary Influenza A Virus Infection but Dispensable for Secondary Infection

2010 ◽  
Vol 84 (24) ◽  
pp. 12713-12722 ◽  
Author(s):  
Sang-Uk Seo ◽  
Hyung-Joon Kwon ◽  
Joo-Hye Song ◽  
Young-Ho Byun ◽  
Baik Lin Seong ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A ◽  
Protective Efficacy ◽  
Secondary Infection ◽  
Influenza Virus Infection ◽  
Lethal Challenge ◽  
Influenza A Virus Infection ◽  
Myd88 Signaling ◽  
Deficient Mice

ABSTRACT Recent studies have revealed that innate immunity is involved in the development of adaptive immune responses; however, its role in protection is not clear. In order to elucidate the exact role of Toll-like receptor (TLR) or RIG-I-like receptor (RLR) signaling on immunogenicity and protective efficacy against influenza A virus infection (A/PR/8/34 [PR8]; H1N1), we adapted several innate signal-deficient mice (e.g., TRIF−/−, MyD88−/−, MyD88−/− TRIF−/−, TLR3−/− TLR7−/−, and IPS-1−/−). In this study, we found that MyD88 signaling was required for recruitment of CD11b+ granulocytes, production of early inflammatory cytokines, optimal proliferation of CD4 T cells, and production of Th1 cytokines by T cells. However, PR8 virus-specific IgG and IgA antibody levels in both systemic and mucosal compartments were normal in TLR- and RLR-deficient mice. To further assess the susceptibility of these mice to influenza virus infection, protective efficacy was determined after primary or secondary lethal challenge. We found that MyD88−/− and MyD88−/− TRIF−/− mice were more susceptible to primary influenza virus infection than the B6 mice but were fully protected against homologous (H1N1) and heterosubtypic (H5N2) secondary infection when primed with a nonlethal dose of PR8 virus. Taken together, these results show that MyD88 signaling plays an important role for resisting primary influenza virus infection but is dispensable for protection against a secondary lethal challenge.

scholarly journals TIV Vaccination Modulates Host Responses to Influenza Virus Infection that Correlate with Protection against Bacterial Superinfection

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 113 ◽  
Author(s):  
Choi ◽  
Christopoulou ◽  
Saelens ◽  
García-Sastre ◽  
Schotsaert
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Vaccination ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Neutralizing Antibody ◽  
Host Responses ◽  
Host Immune Responses ◽  
Bacterial Superinfection

Background: Influenza virus infection predisposes to secondary bacterial pneumonia. Currently licensed influenza vaccines aim at the induction of neutralizing antibodies and are less effective if the induction of neutralizing antibodies is low and/or the influenza virus changes its antigenic surface. We investigated the effect of suboptimal vaccination on the outcome of post-influenza bacterial superinfection. Methods: We established a mouse vaccination model that allows control of disease severity after influenza virus infection despite inefficient induction of virus-neutralizing antibody titers by vaccination. We investigated the effect of vaccination on virus-induced host immune responses and on the outcome of superinfection with Staphylococcus aureus. Results: Vaccination with trivalent inactivated virus vaccine (TIV) reduced morbidity after influenza A virus infection but did not prevent virus replication completely. Despite the poor induction of influenza-specific antibodies, TIV protected from mortality after bacterial superinfection. Vaccination limited loss of alveolar macrophages and reduced levels of infiltrating pulmonary monocytes after influenza virus infection. Interestingly, TIV vaccination resulted in enhanced levels of eosinophils after influenza virus infection and recruitment of neutrophils in both lungs and mediastinal lymph nodes after bacterial superinfection. Conclusion: These observations highlight the importance of disease modulation by influenza vaccination, even when suboptimal, and suggest that influenza vaccination is still beneficial to protect during bacterial superinfection in the absence of complete virus neutralization.

scholarly journals Bacterial Outer Membrane Vesicles Provide Broad-Spectrum Protection against Influenza Virus Infection via Recruitment and Activation of Macrophages

2019 ◽  
Vol 11 (4) ◽  
pp. 316-329 ◽  
Author(s):  
Eun-Hye Bae ◽  
Sang Hwan Seo ◽  
Chang-Ung Kim ◽  
Min Seong Jang ◽  
Min-Suk Song ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Protective Effect ◽  
Outer Membrane ◽  
Lethal Dose ◽  
Influenza Virus Infection ◽  
Outer Membrane Vesicles ◽  
Type I ◽  
Wide Range ◽  
Bacterial Outer Membrane

Influenza A virus (IAV) poses a constant worldwide threat to human health. Although conventional vaccines are available, their protective efficacy is type or strain specific, and their production is time-consuming. For the control of an influenza pandemic in particular, agents that are immediately effective against a wide range of virus variants should be developed. Although pretreatment of various Toll-like receptor (TLR) ligands have already been reported to be effective in the defense against subsequent IAV infection, the efficacy was limited to specific subtypes, and safety concerns were also raised. In this study, we investigated the protective effect of an attenuated bacterial outer membrane vesicle ­harboring modified lipid A moiety of lipopolysaccharide (fmOMV) against IAV infection and the underlying mechanisms. Administration of fmOMV conferred significant protection against a lethal dose of pandemic H1N1, PR8, H5N2, and highly pathogenic H5N1 viruses; this broad antiviral activity was dependent on macrophages but independent of neutrophils. fmOMV induced recruitment and activation of macrophages and elicited type I IFNs. Intriguingly, fmOMV showed a more significant protective effect than other TLR ligands tested in previous reports, without exhibiting any adverse effect. These results show the potential of fmOMV as a prophylactic agent for the defense against influenza virus infection.

scholarly journals Protection and antibody responses in different strains of mouse immunized with plasmid DNAs encoding influenza virus haemagglutinin, neuraminidase and nucleoprotein

1999 ◽  
Vol 80 (10) ◽  
pp. 2559-2564 ◽  
Author(s):  
Ze Chen ◽  
Tomoki Yoshikawa ◽  
Shin-etsu Kadowaki ◽  
Yukari Hagiwara ◽  
Kazutoshi Matsuo ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Lethal Dose ◽  
Serum Antibody ◽  
Influenza Virus Infection ◽  
Antibody Responses ◽  
Significant Protection ◽  
Plasmid Dnas ◽  
Homologous Virus ◽  
Different Strains

Protection against influenza virus infection and antibody responses in mice vaccinated with plasmid DNAs encoding haemagglutinin (HA), neuraminidase (NA) and nucleoprotein (NP) were compared among BALB/c (H-2d), B10 (H-2b) and C3H (H-2k ) mice. Mice were inoculated with each DNA construct twice, 3 weeks apart, at a dose of 1 μg per mouse by particle-mediated DNA transfer (gene gun) to the epidermis. They were challenged with a lethal dose of the homologous virus 7 days after the second vaccination. NA-DNA provided significant protection in all strains of mouse, whereas HA-DNA afforded significant protection only in BALB/c mice. The serum antibody titres against NA or HA molecules in BALB/c, C3H and B10 mice were high, intermediate and low, respectively. NP-DNA failed to provide protection in any strain of mouse, and elicited low titres of anti-NP antibodies. These results suggest that NA-DNA can be used as a vaccine component to provide effective protection against influenza virus infection in various strains of mouse.

Unmutated immunoglobulin M can protect mice from death by influenza virus infection

2004 ◽  
Vol 1263 ◽  
pp. 135-140
Author(s):  
Yuichi Harada ◽  
Masamichi Muramatsu ◽  
Toshikatsu Shibata ◽  
Tasuku Honjo ◽  
Kazufumi Shimizu ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Immunoglobulin M

scholarly journals Toll-Like Receptor 7 Agonist Imiquimod in Combination with Influenza Vaccine Expedites and Augments Humoral Immune Responses against Influenza A(H1N1)pdm09 Virus Infection in BALB/c Mice

2014 ◽  
Vol 21 (4) ◽  
pp. 570-579 ◽  
Author(s):  
Anna J. X. Zhang ◽  
Can Li ◽  
Kelvin K. W. To ◽  
Hou-Shun Zhu ◽  
Andrew C. Y. Lee ◽  
...  
Keyword(s):  
Virus Infection ◽  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Geometric Mean ◽  
Lethal Dose ◽  
Influenza Virus Infection ◽  
Control Group ◽  
Immune Protection ◽  
Pdm09 Virus ◽  
Influenza A H1n1

ABSTRACTToll-like receptors (TLRs) of the innate immune system are known targets for enhancing vaccine efficacy. We investigated whether imiquimod, a synthetic TLR7 agonist, can expedite the immune response against influenza virus infection when combined with influenza vaccine. BALB/c mice were immunized intraperitoneally with monovalent A(H1N1)pdm09 vaccine combined with imiquimod (VCI) prior to intranasal inoculation with a lethal dose of mouse-adapted A(H1N1)pdm09 virus. For mice immunized 3 days before infection, the survival rates were significantly higher in the VCI group (60%, mean survival time[MST], 11 days) than in the vaccine-alone (30%; MST, 8.8 days), imiquimod-alone (5%; MST, 8.4 days), and phosphate-buffered saline (PBS) (0%; MST, 6.2 days) groups (P< 0.01). In the VCI group, 45 and 35% of the mice survived even when they were infected 2 days or 1 day after immunization. Virus-specific serum IgM, IgG, and neutralizing antibodies appeared earlier with higher geometric mean titers in the VCI group than in the control groups. The pulmonary viral load was significantly lower at all time points postinfection in the VCI, vaccine-alone, and imiquimod-alone groups than in the PBS control group (P< 0.05). The protection induced by VCI was specific for A(H1N1)pdm09 virus but not for A(H5N1) virus. Since imiquimod combined with RNase-treated vaccine is as protective as imiquimod combined with untreated vaccine, mechanisms other than TLR7 may operate in expediting and augmenting immune protection. Moreover, increased gamma interferon mRNA expression and IgG isotype switching, which are markers of the Th1 response induced by imiquimod, were not apparent in our mouse model. The mechanisms of imiquimod-induced immune protection deserve further study.

scholarly journals Prophylactic Administration of Bacterially Derived Immunomodulators Improves the Outcome of Influenza Virus Infection in a Murine Model

2010 ◽  
Vol 84 (6) ◽  
pp. 2983-2995 ◽  
Author(s):  
Elizabeth B. Norton ◽  
John D. Clements ◽  
Thomas G. Voss ◽  
Lucia Cárdenas-Freytag
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza A ◽  
Immune Modulation ◽  
Lethal Dose ◽  
Plaque Assay ◽  
Influenza Virus Infection ◽  
Mutant Form ◽  
Immune System Activation ◽  
Cpg Oligodeoxynucleotide

ABSTRACT Prophylactic or therapeutic immunomodulation is an antigen-independent strategy that induces nonspecific immune system activation, thereby enhancing host defense to disease. In this study, we investigated the effect of prophylactic immunomodulation on the outcome of influenza virus infection using three bacterially derived immune-enhancing agents known for promoting distinct immunological profiles. BALB/c mice were treated nasally with either cholera toxin (CT), a mutant form of the CT-related Escherichia coli heat-labile enterotoxin designated LT(R192G), or CpG oligodeoxynucleotide. Mice were subsequently challenged with a lethal dose of influenza A/PR/8/34 virus 24 h after the last immunomodulation treatment and either monitored for survival or sacrificed postchallenge for viral and immunological analysis. Treatment with the three immunomodulators prevented or delayed mortality and weight loss, but only CT and LT(R192G) significantly reduced initial lung viral loads as measured by plaque assay. Analysis performed 4 days postinfection indicated that prophylactic treatments with CT, LT(R192G), or CpG resulted in significantly increased numbers of CD4 T cells, B cells, and dendritic cells and altered costimulatory marker expression in the airways of infected mice, coinciding with reduced expression of pulmonary chemokines and the appearance of inducible bronchus-associated lymphoid tissue-like structures in the lungs. Collectively, these results suggest that, despite different immunomodulatory mechanisms, CT, LT(R192G), and CpG induce an initial inflammatory process and enhance the immune response to primary influenza virus challenge while preventing potentially damaging chemokine expression. These studies provide insight into the immunological parameters and immune modulation strategies that have the potential to enhance the nonspecific host response to influenza virus infection.

scholarly journals Contribution of  Virus-specific CD8+ Cytotoxic T Cells to Virus Clearance or Pathologic Manifestations of Influenza Virus Infection in a T Cell Receptor Transgenic Mouse Model

1998 ◽  
Vol 188 (2) ◽  
pp. 223-232 ◽  
Author(s):  
Demetrius Moskophidis ◽  
Dimitris Kioussis
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Neutralizing Antibodies ◽  
Cytotoxic T Cells ◽  
Influenza Infection ◽  
Immune Surveillance ◽  
Influenza Virus Infection ◽  
Cell Receptor ◽  
Very High Frequency ◽  
Variable Surface

The ability of influenza virus to evade immune surveillance by neutralizing antibodies (Abs) directed against its variable surface antigens provides a challenge to the development of effective vaccines. CD8+ cytotoxic T lymphocytes (CTLs) restricted by class I major histocompatibility complex molecules are important in establishing immunity to influenza virus because they recognize internal viral proteins which are conserved between multiple viral strains. In contrast, protective Abs are strain-specific. However, the precise role of effector CD8+ CTLs in protection from influenza virus infection, critical for understanding disease pathogenesis, has not been well defined. In transgenic mice with a very high frequency of antiinfluenza CTL precursors, but without protective Abs, CD8+ CTLs conferred protection against low dose viral challenge, but exacerbated viral pathology and caused mortality at high viral dose. The data suggest a dual role for CD8+ CTLs against influenza, which may present a challenge to the development of effective CTL vaccines. Effector mechanisms used by CD8+ CTLs in orchestrating clearance of virus and recovery from experimental influenza infection, or potentiation of lethal pathology, are discussed.

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