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In vivo Neutralization of Pro-inflammatory Cytokines During Secondary Streptococcus pneumoniae Infection Post Influenza A Virus Infection

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  • In vivo Neutralization of Pro-inflammatory Cytokines During Secondary Streptococcus pneumoniae Infection Post Influenza A Virus Infection

    Front Immunol. 2019 Aug 14;10:1864. doi: 10.3389/fimmu.2019.01864. eCollection 2019.
    In vivo Neutralization of Pro-inflammatory Cytokines During Secondary Streptococcus pneumoniae Infection Post Influenza A Virus Infection.

    Sharma-Chawla N1,2,3, Stegemann-Koniszewski S2,3,4, Christen H2, Boehme JD2,3, Kershaw O5, Schreiber J4, Guzmán CA6,7, Bruder D2,3, Hernandez-Vargas EA1.
    Author information

    1 Frankfurt Institute for Advanced Studies, Frankfurt am Main, Germany. 2 Immune Regulation Group, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany. 3 Infection Immunology Group, Institute of Medical Microbiology, Infection Prevention and Control, Health Immunology, Infectiology and Inflammation, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. 4 Experimental Pneumology, University Hospital of Pneumology, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. 5 Department of Veterinary Medicine, Institute of Veterinary Pathology, Free University Berlin, Berlin, Germany. 6 Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany. 7 Centre for Individualized Infection Medicine (CiiM), Hanover, Germany.

    Abstract

    An overt pro-inflammatory immune response is a key factor contributing to lethal pneumococcal infection in an influenza pre-infected host and represents a potential target for therapeutic intervention. However, there is a paucity of knowledge about the level of contribution of individual cytokines. Based on the predictions of our previous mathematical modeling approach, the potential benefit of IFN-γ- and/or IL-6-specific antibody-mediated cytokine neutralization was explored in C57BL/6 mice infected with the influenza A/PR/8/34 strain, which were subsequently infected with the Streptococcus pneumoniae strain TIGR4 on day 7 post influenza. While single IL-6 neutralization had no effect on respiratory bacterial clearance, single IFN-γ neutralization enhanced local bacterial clearance in the lungs. Concomitant neutralization of IFN-γ and IL-6 significantly reduced the degree of pneumonia as well as bacteremia compared to the control group, indicating a positive effect for the host during secondary bacterial infection. The results of our model-driven experimental study reveal that the predicted therapeutic value of IFN-γ and IL-6 neutralization in secondary pneumococcal infection following influenza infection is tightly dependent on the experimental protocol while at the same time paving the way toward the development of effective immune therapies.


    KEYWORDS:

    IFN-γ neutralization; IL-6 neutralization; Influenza Virus; Streptococcus pneumoniae; co-infection; mathematical modeling

    PMID: 31474978 PMCID: PMC6702285 DOI: 10.3389/fimmu.2019.01864
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