scholarly journals A Novel Gene Delivery Vector of Agonistic Anti-Radioprotective 105 Expressed on Cell Membranes Shows Adjuvant Effect for DNA Immunization Against Influenza

2020 ◽  
Vol 11 ◽  
Author(s):  
Tatsuya Yamazaki ◽  
Mrityunjoy Biswas ◽  
Kouyu Kosugi ◽  
Maria Nagashima ◽  
Masanori Inui ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Intracellular Signaling ◽  
Transmembrane Domain ◽  
Lethal Dose ◽  
Influenza Virus Infection ◽  
Target Antigen ◽  
Dna Immunization ◽  
Adjuvant Effect ◽  
Specific Antibodies

Radioprotective 105 (RP105) (also termed CD180) is an orphan and unconventional Toll-like receptor (TLR) that lacks an intracellular signaling domain. The agonistic anti-RP105 monoclonal antibody (mAb) can cross-link RP105 on B cells, resulting in the proliferation and activation of B cells. Anti-RP105 mAb also has a potent adjuvant effect, providing higher levels of antigen-specific antibodies compared to alum. However, adjuvanticity is required for the covalent link between anti-RP105 mAb and the antigen. This is a possible obstacle to immunization due to the link between anti-RP105 mAb and some antigens, especially multi-transmembrane proteins. We have previously succeeded in inducing rapid and potent recombinant mAbs in mice using antibody gene-based delivery. To simplify the covalent link between anti-RP105 mAb and antigens, we generated genetic constructs of recombinant anti-RP105 mAb (αRP105) bound to the transmembrane domain of the IgG-B cell receptor (TM) (αRP105-TM), which could enable the anti-RP105 mAb to link the antigen via the cell membrane. We confirmed the expression of αRP105-TM and the antigen hemagglutinin, which is a membrane protein of the influenza virus, on the same cell. We also found that αRP105-TM could activate splenic B cells, including both mature and immature cells, depending on the cell surface RP105 in vitro. To evaluate the adjuvanticity of αRP105-TM, we conducted DNA immunization in mice with the plasmids encoding αRP105-TM and hemagglutinin, followed by challenge with an infection of a lethal dose of an influenza virus. We then obtained partially but significantly hemagglutinin-specific antibodies and observed protective effects against a lethal dose of influenza virus infection. The current αRP105-TM might provide adjuvanticity for a vaccine via a simple preparation of the expression plasmids encoding αRP105-TM and of that encoding the target antigen.

scholarly journals Broad Hemagglutinin-Specific Memory B Cell Expansion by Seasonal Influenza Virus Infection Reflects Early-Life Imprinting and Adaptation to the Infecting Virus

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Brenda L. Tesini ◽  
Preshetha Kanagaiah ◽  
Jiong Wang ◽  
Megan Hahn ◽  
Jessica L. Halliley ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Virus Infection ◽  
B Cell ◽  
Specific Antibody ◽  
Early Life ◽  
Influenza Virus Infection ◽  
Memory B Cells ◽  
Specific Memory ◽  
Original Antigenic Sin

ABSTRACTMemory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutinin-specific antibody production and changes in the size and character of hemagglutinin-reactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection “imprints” for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus.IMPORTANCERapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs). Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalk-reactive, as well as to head-reactive, MBCs. Our findings provide experimental support for the role of MBCs in maintaining imprinting effects and suggest a mechanism by which imprinting might confer heterosubtypic protection against avian influenza viruses. It will be important to compare our findings to the situation after influenza vaccination.

scholarly journals Preexisting immunity shapes distinct antibody landscapes after influenza virus infection and vaccination in humans

2020 ◽  
Vol 12 (573) ◽  
pp. eabd3601
Author(s):  
Haley L. Dugan ◽  
Jenna J. Guthmiller ◽  
Philip Arevalo ◽  
Min Huang ◽  
Yao-Qing Chen ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Virus Infection ◽  
Natural Infection ◽  
Influenza Virus Infection ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Protective Antibody ◽  
The Impact ◽  
Neutralizing Epitopes

Humans are repeatedly exposed to variants of influenza virus throughout their lifetime. As a result, preexisting influenza-specific memory B cells can dominate the response after infection or vaccination. Memory B cells recalled by adulthood exposure are largely reactive to conserved viral epitopes present in childhood strains, posing unclear consequences on the ability of B cells to adapt to and neutralize newly emerged strains. We sought to investigate the impact of preexisting immunity on generation of protective antibody responses to conserved viral epitopes upon influenza virus infection and vaccination in humans. We accomplished this by characterizing monoclonal antibodies (mAbs) from plasmablasts, which are predominantly derived from preexisting memory B cells. We found that, whereas some influenza infection–induced mAbs bound conserved and neutralizing epitopes on the hemagglutinin (HA) stalk domain or neuraminidase, most of the mAbs elicited by infection targeted non-neutralizing epitopes on nucleoprotein and other unknown antigens. Furthermore, most infection-induced mAbs had equal or stronger affinity to childhood strains, indicating recall of memory B cells from childhood exposures. Vaccination-induced mAbs were similarly induced from past exposures and exhibited substantial breadth of viral binding, although, in contrast to infection-induced mAbs, they targeted neutralizing HA head epitopes. Last, cocktails of infection-induced mAbs displayed reduced protective ability in mice compared to vaccination-induced mAbs. These findings reveal that both preexisting immunity and exposure type shape protective antibody responses to conserved influenza virus epitopes in humans. Natural infection largely recalls cross-reactive memory B cells against non-neutralizing epitopes, whereas vaccination harnesses preexisting immunity to target protective HA epitopes.

scholarly journals Age Dependence and Isotype Specificity of Influenza Virus Hemagglutinin Stalk-Reactive Antibodies in Humans

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Raffael Nachbagauer ◽  
Angela Choi ◽  
Ruvim Izikson ◽  
Manon M. Cox ◽  
Peter Palese ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
The Elderly ◽  
Influenza Viruses ◽  
Influenza B Virus ◽  
Enzyme Linked Immunosorbent Assay ◽  
Influenza B ◽  
Dependent Manner ◽  
Specific Antibodies

ABSTRACT Influenza remains a major global health burden. Seasonal vaccines offer protection but can be rendered less effective when the virus undergoes extensive antigenic drift. Antibodies that target the highly conserved hemagglutinin stalk can protect against drifted viruses, and vaccine constructs designed to induce such antibodies form the basis for a universal influenza virus vaccine approach. In this study, we analyzed baseline and postvaccination serum samples of children (6 to 59 months), adults (18 to 49 years), and elderly individuals (≥65 years) who participated in clinical trials with a recombinant hemagglutinin-based vaccine. We found that baseline IgG and IgA antibodies against the H1 stalk domain correlated with the ages of patients. Children generally had very low baseline titers and did not respond well to the vaccine in terms of making stalk-specific antibodies. Adults showed the highest induction of stalk-specific antibodies, but the elderly had the highest absolute antibody titers against the stalk. Importantly, the stalk antibodies measured by enzyme-linked immunosorbent assay (ELISA) showed neutralizing activity in neutralization assays and protected mice in a passive-transfer model in a stalk titer-dependent manner. Finally, we found similar patterns of stalk-specific antibodies directed against the H3 and influenza B virus hemagglutinins, albeit at lower levels than those measured against the H1 stalk. The relatively high levels of stalk-specific antibodies in the elderly patients may explain the previously reported low influenza virus infection rates in this age group. (This study has been registered at ClinicalTrials.gov under registration no. NCT00336453, NCT00539981, and NCT00395174.) IMPORTANCE The present study provides evidence that titers of broadly neutralizing hemagglutinin stalk-reactive antibodies increase with age, possibly due to repeated exposure to divergent influenza viruses. These relatively high levels of antistalk titers may be responsible for lower circulation rates of influenza viruses in older individuals. Our findings suggest that the level of antistalk antibodies is a good surrogate marker for protection against influenza virus infection. In addition, the levels of antistalk antibodies might determine the breadth of protection against different drifted strains.

scholarly journals Type I IFN Receptor Signals Directly Stimulate Local B Cells Early following Influenza Virus Infection

2006 ◽  
Vol 176 (7) ◽  
pp. 4343-4351 ◽  
Author(s):  
Elizabeth S. Coro ◽  
W. L. William Chang ◽  
Nicole Baumgarth
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Type I ◽  
Type I Ifn

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.

Roles of CD4+ T and B cells in influenza virus infection

2001 ◽  
Vol 1219 ◽  
pp. 311-318 ◽  
Author(s):  
Walter Gerhard ◽  
Krystyna Mozdzanowska
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
T And B Cells

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.

scholarly journals Host Genetic Variation Affects Resistance to Infection with a Highly Pathogenic H5N1 Influenza A Virus in Mice

2009 ◽  
Vol 83 (20) ◽  
pp. 10417-10426 ◽  
Author(s):  
Adrianus C. M. Boon ◽  
Jennifer deBeauchamp ◽  
Anna Hollmann ◽  
Jennifer Luke ◽  
Malak Kotb ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
H5n1 Virus ◽  
Lethal Dose ◽  
Influenza Virus Infection ◽  
Virus Titer ◽  
Influenza Viruses ◽  
Highly Pathogenic ◽  
H5n1 Influenza ◽  
Pathogenic H5n1

ABSTRACT Despite the prevalence of H5N1 influenza viruses in global avian populations, comparatively few cases have been diagnosed in humans. Although viral factors almost certainly play a role in limiting human infection and disease, host genetics most likely contribute substantially. To model host factors in the context of influenza virus infection, we determined the lethal dose of a highly pathogenic H5N1 virus (A/Hong Kong/213/03) in C57BL/6J and DBA/2J mice and identified genetic elements associated with survival after infection. The lethal dose in these hosts varied by 4 logs and was associated with differences in replication kinetics and increased production of proinflammatory cytokines CCL2 and tumor necrosis factor alpha in susceptible DBA/2J mice. Gene mapping with recombinant inbred BXD strains revealed five loci or Qivr (quantitative trait loci for influenza virus resistance) located on chromosomes 2, 7, 11, 15, and 17 associated with resistance to H5N1 virus. In conjunction with gene expression profiling, we identified a number of candidate susceptibility genes. One of the validated genes, the hemolytic complement gene, affected virus titer 7 days after infection. We conclude that H5N1 influenza virus-induced pathology is affected by a complex and multigenic host component.

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 Enhanced antiviral antibody secretion and attenuated immunopathology during influenza virus infection in nitric oxide synthase-2-deficient mice

2006 ◽  
Vol 87 (11) ◽  
pp. 3361-3371 ◽  
Author(s):  
Jerome P. Jayasekera ◽  
Carola G. Vinuesa ◽  
Gunasegaran Karupiah ◽  
Nicholas J. C. King
Keyword(s):  
Influenza Virus ◽  
B Cells ◽  
Virus Infection ◽  
Influenza A ◽  
Clinical Symptoms ◽  
Killer Cell ◽  
Influenza Virus Infection ◽  
Virus Clearance ◽  
Antiviral Antibody ◽  
Nitric Oxide Synthase 2

NOS2 gene-deficient (NOS2−/−) mice are less susceptible than wild-type (NOS2+/+) mice to infection with Influenza A virus. Virus titres in the lungs of influenza-infected NOS2−/− mice are significantly lower than those in NOS2+/+ mice, with enhanced viral clearance in NOS2−/− mice dependent on gamma interferon (IFN-γ). The current study was undertaken to ascertain the role of specific components of the immune response in promoting virus clearance in influenza-infected NOS2−/− mice. Levels of T cell- and natural killer cell-mediated cytotoxicity in the lungs of virus-infected mice were not significantly different between NOS2+/+ and NOS2−/− mice. However, virus-infected NOS2−/− mice produced higher levels of virus-specific IgG2a antibody. Furthermore, more viable B cells and plasmablasts, along with greater levels of IFN-γ, were found in NOS2−/− splenocyte cultures stimulated with B-cell mitogens. In addition to the early reduction in virus titres, clinical symptoms and proinflammatory cytokine production were attenuated in NOS2−/− mice. Thus, NOS2−/− B cells are capable of responding rapidly to influenza virus infection by proliferating and preferentially producing antibody of the IgG2a subtype. The relationship between viral load and the development of immunopathology is discussed.

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