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  • 1
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    Bacterial neuraminidase C reverts neuraminidase A and B mediated suppression of anti-influenza immunity and aggravates the disease in influenza with pneumococcal superinfection
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 93.7-93.7
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 93.7-93.7
    Abstract: Bacterial superinfection aggravates the disease of influenza virus infection. Streptococcus pneumoniae is a frequently encountered bacterial pathogen. Superinfection with neuraminidase (Nan) C deficient wild type pneumococcus, which expresses NanA and NanB only, suppressed antigen-specific anti-influenza immunity, with impaired viral clearance. There was augmented TGF-β activation in the lung-infiltrating influenza hemagglutinin (HA)-specific CD4+ T cells. Mice suffered from exacerbated disease and died with higher virus loads in the lung. We modified this wild type strain with NanC insertion. This modified strain expresses all neuraminidases A, B and C. Superinfection with this NanC inserted pneumococcus reverted the immune-suppressive effect of the wild type pneumococcus with NanA and NanB only. There were augmented inflammatory cytokines IFN-γ and TNF-α production and suppressed TGF-β activation in the lung-infiltrating influenza HA-specific CD4+ T cells. The pro-inflammatory response enhanced viral clearance. Even the virus eradication is enhanced, the mice actually suffered from even more severe disease. Our results demonstrated the important role of NanC-mediated inflammation in the disease of severe influenza with pneumococcal superinfection.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.93.7
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
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  • 2
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    Relatively preserved functional capacity with standard COVID-19 vaccine regimen in People Living with HIV asymptomatic or with mild immunodeficiency
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 159.07-159.07
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 159.07-159.07
    Abstract: People living with HIV (PLWH) are at a higher risk of sever disease with SARS-CoV-2 virus infection. COVID-19 vaccines are effective in most PLWH, with significant reduction in the risk of severe disease or death when the standard 2-shot regimen is taken. However, suboptimal immune response to the standard course of vaccination is a concern for PLWH, especially for those with moderate to severe immunodeficiency. An additional dose is recommended as part of the extended primary series. In Taiwan, this additional dose is endorsed even for asymptomatic or mild immunodeficiency with CD4 counts & gt;200/mm 3and suppressed virology. We aimed to investigate the immune responses with the additional dose in PLWH asymptomatic or with mild immunodeficiency. We collected peripheral blood mononuclear cells (PBMC) from 72 PLWH asymptomatic or with mild immunodeficiency and from 362 non-HIV subjects, after two and three shots respectively. Two shots elicited lower responses in PLWH, although the difference was statistically insignificant. They have comparable levels of neutralizing and anti-S antibodies and comparable effector CD4+ and CD8+ T cell responses. The 3 rdshot boosted the SARS-CoV-2 immunity significantly more in PLWH compared to the non-HIV people. Upon in vitro stimulation with extracted Wuhan strain SARS-CoV-2 proteins, CD8+ T cells from PLWH after 3 shots has more durable effector responses than the non-HIV controls with extended time of stimulation. This subtle difference between PLWH and non-HIV people implied immune exhaustion with two shots in non-HIV people. Slightly compromised immunity in PLWH indeed preserved the functional capacity for further response to the 3 rdshot or natural infection. The Research Center for Emerging Viral Infections receives support from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), Taiwan and NSTC 111-2634-F-182-001 from the National Science and Technology Council, Taiwan. This work was supported by Projects CMRPG3M1811 (CTH) from the Medical Research Project Fund, Chang Gung Memorial Hospital, Taiwan.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.159.07
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 3
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    Host antigen modulated anti-influenza immunity with antigen level dependent distinct mechanisms of severe influenza
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 1_Supplement ( 2018-05-01), p. 60.10-60.10
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 1_Supplement ( 2018-05-01), p. 60.10-60.10
    Abstract: Some healthy individuals suffer from severe disease and even mortality with the same strain of influenza virus that causes self-limited illnesses in the majority of people. This fact exemplifies the importance of host factors in influenza disease manifestation. Our C3-HA transgenic mice express hemagglutinin (HA) as a self-antigen that is identical to the HA of PR8 influenza virus. Compared to wild type mice, C3-HA mice incurred severe disease with PR8, but not with HA-mismatched influenza virus. Self-HA in C3-HA mice altered the immune response to the infection and impaired clearance of the influenza virus. However, different mechanisms contribute for exacerbated disease in C3-HA mice with different level of HA. In C3-HALow mice, low-level self-HA modulated HA specific immunity upon infection with less clonotypic expansion, T-bet induction and effector cytokines IFN-γ and TNF-α production of both HA-specific CD4+ and CD8+ T cells on day 4- post infection. The T cell activation status contracted further on day 7- post infection. Impaired immunity resulted in delayed virus clearance leading to severe disease and death. In C3-HAHigh mice, high-level self-HA also modulated impaired immunity and virus clearance on day 4- post infection. In contrast to further reduction on day 7- post infection in C3-HALow mice, the HA specific T cell immunity was higher on day 7- than day 4- post infection in C3-HAHigh mice. The boosted HA specific immunity resulted in severe disease with autoimmunity as a predominant feature in pathology. Our animal model exemplified the complicated interaction between cross-reactive self-antigen and influenza virus with severe disease as the results of antigen level dependent distinct mechanisms.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.200.Supp.60.10
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
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  • 4
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    Role of IL-17-EGFR axis in alleviated lung inflammation and recovery during the late phase of acute influenza virus infection
    The American Association of Immunologists ; 2021
    In:  The Journal of Immunology Vol. 206, No. 1_Supplement ( 2021-05-01), p. 103.33-103.33
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 206, No. 1_Supplement ( 2021-05-01), p. 103.33-103.33
    Abstract: Influenza hemagglutinin (HA)-specific T-Cell-Receptor (TCR) transgenic mice sustain the influenza virus infection of an inoculum size which is fatal in wild type mice. There is a prominent IL-17 response of the HA-specific TCR transgenic CD4+ T cells in late phase of infection in the transgenic mice. We have demonstrated that the late phase IL-17 response is a de novo response of naïve T cells under guidance of the Th1 cells with influenza viral neuraminidase-activated TGF-β. There is also a late phase up-regulation of epidermal growth factor receptor (EGFR) on the transgenic CD4+ T cells in the lungs. EGFR inhibition with Gefitinib resulted in impaired sustainability of the infection of the transgenic mice. They suffered from profound body weight loss and severe disease with significant mortality. IL-17-induced EGFR-mediated signaling cascade has been documented in skin stem cells that are involved in wound healing. We will further dissect the role of this cascade in alleviation of lung inflammation and recovery from the disease during the late phase of acute influenza virus infection.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.206.Supp.103.33
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2021
    detail.hit.zdb_id: 1475085-5
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  • 5
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    Rapamycin adjuvant and exacerbation of severe influenza in an experimental mouse model
    Springer Science and Business Media LLC ; 2017
    In:  Scientific Reports Vol. 7, No. 1 ( 2017-06-23)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2017-06-23)
    Abstract: Influenza virus infection often causes severe disease and acute respiratory distress syndrome. It is a common belief that overwhelming immune response contributes to the severe illness. Physicians and researchers have put forth immune modulation as salvage therapy for better recovery. However, empiric corticosteroid failed in both humans and animal models. Reported success with Rapamycin in humans prompted a comprehensive animal study and mechanistic dissection. Here we report the effect of Rapamycin alone or in combination with Oseltamivir for severe influenza in BALB/c mice. We found that Rapamycin had no antiviral effect against H1N1, H3N2 and novel-H1N1 influenza viruses in vitro . Rapamycin alone aggravated the severe disease of PR8 H1N1 influenza virus infection in mice. Timely Oseltamivir anti-viral therapy abolished the disease. Delayed Oseltamivir treatment could not prevent severe illness and Rapamycin adjuvant was associated with exacerbated disease. Rapamycin adjuvant suppressed influenza hemagglutinin antigen-specific T cell immunity and impaired virus clearance from the lungs. It also resulted in intensified lung pathology with increased intra-alveolar edema and hyaline deposition. Rapamycin may work as the salvage therapy for severe influenza but it is very difficult to define the appropriate window for such treatment to take effect.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-017-04365-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2615211-3
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  • 6
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    Concomitant effector and LAG-3 regulatory responses of Th1 committed cells in acute influenza
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 74.4-74.4
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 74.4-74.4
    Abstract: T-bet induced CD4+ T cells are committed to be IFN-γ competent Th1 cells. The Th1 response is essential for virus eradication, but is also a major cause of inflammation and disease aggravation in severe influenza. In our influenza hemagglutinin (HA) Ag-specific mouse experimental system, naïve CD4+ T cells respond to the infection with T-bet expression. However, they suppress cognate CD8+ T cell effector response-mediated inflammation and alleviate the disease. Here we report concomitant LAG-3 expression and IFN-γ competence in Th1 committed CD4+ T cells. LAG-3 expression increases with activation by virus as revealed by CFSE based cell division study. The Th1 committed cells with moderate LAG-3 expression produce IFN-γ and contribute to inflammation and aggravated disease. They can no longer produce IFN-γ with higher LAG-3 expression upon further activation. Th1 committed CD4+ T cells with high LAG-3 expression suppress cognate CD8+ T cells by decoupling their effector function from proliferative response, restrain lung inflammation and facilitate viral clearance. They are better than Foxp-3+HA-specific CD4+ T cells in disease amelioration. The Foxp-3+ cells suppress both effector function and proliferative response of CD8+ T cells. They moderate inflammation but impair viral clearance. Principal component analysis of genome-wide gene expression profiles further confirmed the stepwise evolution. Several regulatory function-associated genes such as Lag3, Pdcd1, Tigit, Ctla2a, Nr4a2, Klrc1, Rgs16, Sytl3, Il21, Il1r2 and Dusp4 are up-regulated graduallly as well from LAG-3Neg to LAG-3Med and LAG-3High cells.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.74.4
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
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  • 7
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    LAG-3 expressing antigen-specific CD4+ T cells attenuate lung inflammation during acute influenza virus infection
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 148.1-148.1
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 148.1-148.1
    Abstract: The host immune system responds to influenza virus infection for eradication of the virus but the immune response associated inflammation causes tissue injury and damage to the host as well. In our antigen-specific mouse model system for influenza virus infection, influenza hemagglutinin antigen-specific CD4+ T cells responded to acute infection with Th1 effector phenotype. A significant proportion of them were also with concurrent expression of LAG-3, CTLA-4, GITR or CD25. Adoptive transfer of purified LAG-3 expressing hemagglutinin antigen-specific CD4+ T cells controlled lung inflammation with acute influenza virus infection, as represented by the activation of co-transferred influenza hemagglutinin antigen-specific CD8+ T cells. Control of the inflammation by LAG-3 expressing antigen-specific Th1 CD4+ T cells was not necessarily associated with impaired capacity of virus eradication. These results reveal, besides effector function for virus eradication, subsets of CD4+ T cells activated by acute influenza virus infection also acquired regulatory function to attenuate inflammation for reducing the damage to the host. These subsets of CD4+ T cells may be employed as the practical handle for management of severe influenza disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.148.1
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
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  • 8
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    Sterilizing immunity to influenza virus infection requires local antigen-specific T cell response in the lungs
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 78.18-78.18
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 78.18-78.18
    Abstract: Pre-infection induces sterilizing immunity to homologous influenza virus challenge in ferret. In our antigen-specific experimental system, mice pre-infected with PR8 influenza virus through nasal route are likewise resistant to reinfection of the same strain of virus. The virus is cleared before establishment of effective infection. Intramuscular influenza virus injection confers protection against re-infection with facilitated virus clearance but not sterilizing immunity. Pre-infection and intramuscular injection generates comparable innate immunity and antibody response, but only pre-infection induces virus receptor reduction and antigen-specific T cell response in the lung. Pre-infection with nH1N1 influenza virus induces virus receptor reduction but not PR8 specific T cell immune response in the lung and cannot prevent infection with PR8 influenza virus. Pre-infection with PR8 virus induced PR8-specific T cell response in the lung but cannot prevent infection with nH1N1 virus either. Antigen specific T cell immunity is required for sterilizing immunity. We discuss the potential implications of these findings in vaccination strategy for effectual protection comparable to pre-infection.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.78.18
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 9
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    Online Resource
    Neuraminidase-mediated TGF-β activation facilitates evolution of protective Th17 immunity
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 78.22-78.22
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 78.22-78.22
    Abstract: The immune system responds to influenza virus infection for eradication of the virus but the associated inflammation may cause tissue damage to the host. In our antigen-specific mouse system, naïve influenza hemagglutinin (HA)-specific CD4+ T cells adoptively transferred with infection respond with Th1 phenotype and produce IFN-γ. Some of them secrete IL-17 as well. Second batch HA specific CD4+ T cells, adoptively transferred on day 4 after infection and the first transfer, respond to the infection with Th17 phenotype. They produce IL-17 but not IFN-γ. Both the Th1 and Th17 cells are activated with similar levels of ZAP-70 phosphorylation and T-bet induction. For the Th17 cells, IFN-γ deficiency is associated with excessive ROR-γt induction and altered T-bet dominance. Th17 cells display surface LAG-3 expression, suppress T cell activation in vitro and decrease lung inflammation in vivo. The evolution of Th17 cells is augmented in IL-10 deficiency, with IL-10 knockout mice as the recipients transferred with IL-10 knockout HA specific CD4+ T cells. There is increased neuraminidase-mediated TGF-β activation in this IL-10 deficient environment. Viral neuraminidase mediated TGF-β activation in the first batch of HA specific CD4+ T cells facilitates the Th17 evolution of the 2nd batch of cells. The 6.5 T cell receptor (TCR) transgenic mice of monotonous HA specific TCR repertoire respond to influenza virus infection with Th17 deviation and demonstrate survival benefit. Consecutive waves of naïve HA specific T cells from the thymus in 6.5 mice may evolve with mechanisms similar to consecutive adoptive transfers. Evolution of protective Th17 immunity is facilitated by neuraminidase-mediated TGF-β activation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.78.22
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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  • 10
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    Online Resource
    Anti-PPIL-5 antibody exacerbates disease of severe influenza in a murine experimental model
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 236.05-236.05
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 236.05-236.05
    Abstract: Respiratory viruses such as SARS-CoV2 cause serious emerging infectious diseases. Even seasonal influenza results in significant morbidity and mortality. Host immunity responds to influenza virus infection to eradicate the pathogen. However, dysregulated responses such as the cytokine storm contribute to severe disease. Mechanistic dissection of immune regulation may offer practical solutions for severe influenza. In our mouse model of severe influenza, a LAG-3 regulatory response evolves with the pro-inflammatory IFN-γ response in influenza virus hemagglutinin (HA)-specific CD4+ T cells. Adoptive transfer of LAG-3(+) IFN-γ(-) HA-specific CD4+ T cells suppressed lung inflammation without compromised virus eradication. Genomic study of LAG-3(+) IFN-γ(−) CD4+ T cells revealed up-regulation of the PPIL-5 [Peptidylprolyl isomerase (Cyclophilin)-like 5] gene. PPIL-5(+) HA-specific CD4+ T cells accumulated in the lung with time after infection. PPIL-5 protein suppressed HA-specific CD4+ T cell activation in vitro in a dose dependent manner. PPIL-5 blockade in vitro with siRNA reversed immune suppression and unleashed activation of HA-specific CD4+ T cells. PPIL-5 blockade in vivo with monoclonal anti-PPIL-5 antibodies attenuated LAG-3 and PD-1 and augmented IFN-γ responses of the lung-infiltrating HA-specific CD4+ T cells, with aggravated disease and intensified mortality of severe influenza. The HA-specific CD4+ T cells took less glucose and produced lactate with anti-PPIL-5 blockade. They adopted anaerobic glycolysis in this reverted inflammatory response. Our results suggest that PPIL-5, similar to LAG-3, is also an immune checkpoint and a possible target to be manipulated for alleviation of severe influenza. The Research Center for Emerging Viral Infections receives support from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), Taiwan and NSTC 111-2634-F-182-001 from the National Science and Technology Council, Taiwan. This work was supported by Projects MOST 111-2314-B-182-029 (AD) and MOST-105-2321-B-182A-003-MY3 (AD) from the National Science and Technology Council, Taiwan, and by CMRPG3L1671 (CTH), CMRPVVJ0052 (CTH), and CMRPG3J1771 (CYH) from the Medical Research Project Fund, Chang Gung Memorial Hospital, Taiwan.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.236.05
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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