Dataset Information

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

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-?- 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-? neutralization enhanced local bacterial clearance in the lungs. Concomitant neutralization of IFN-? 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-? 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.

SUBMITTER: Sharma-Chawla N

PROVIDER: S-EPMC6702285 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

<i>In vivo</i> Neutralization of Pro-inflammatory Cytokines During Secondary <i>Streptococcus pneumoniae</i> Infection Post Influenza A Virus Infection.

Sharma-Chawla Niharika N Stegemann-Koniszewski Sabine S Christen Henrike H Boehme Julia D JD Kershaw Olivia O Schreiber Jens J Guzmán Carlos A CA Bruder Dunja D Hernandez-Vargas Esteban A EA

Frontiers in immunology 20190814

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 inf ...[more]

PMID: 31474978

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Project description:Background: Pneumococcal secondary infection following influenza A virus (IAV) pneumonia is a synergistic complication with high mortality. While varying invasiveness of pneumococcal serotypes is an important pathogenic factor, serotype-specifc immediate-early transcriptional responses of the IAV-perturbed alveolar epithelium have not been adressed. We comprehensively analyzed gene transcription in alveolar type II epithelial cells (AECII) isolated from mice infected with IAV and/or S. pneumoniae (S.pn.) serotypes 4, 7F and 19F. Results: IAV, 14 days post infection, rendered the lung susceptible to invasive secondary S.pn. infection with serotypes 4 and 7F but not 19F. Only secondary 7F infection induced exacerbated cytokine/chemokine responses. IAV/7F infection induced superior protein expression of type I and II interferons, acesserbated expression in IAV/serotype 4 infection. Inference of a scale-free-like ARACNE gene co-expression network revealed interferon-response network modules in AECII and network-mapping unfolded S.pn. serotype-specific transcriptional network responses/usage. Secondary S.pn. infection abrogated the IAV-induced pneumocyte proliferative configuration and preceeding IAV infection rendered the transcriptional response to 7F infection comparable to that towards serotype 4. This related especially to network genes correlating with the expression of two master regulators of interferon responses: Irf7 and Stat1. Epigenetic ATAC-seq analysis of AECII in resolved IAV infection identified enhanced expression of ARACNE network genes Hist1h2bf, Igtp, Mki67, Rasl10b, H2-Q6 and H2-Q7 to be associated with increased chromatin accessability at promoter regions. Conclusions: We show that AECII sustainably retain an IAV-associated transcriptional configuration with epigenetic involvement, that serotype-specifically affects proliferation and accelerates and enhances the AECII transcriptional response, mainly to interferons, in secondary S.pn. infection.

Dataset Information

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

Publications

<i>In vivo</i> Neutralization of Pro-inflammatory Cytokines During Secondary <i>Streptococcus pneumoniae</i> Infection Post Influenza A Virus Infection.

Similar Datasets

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