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Characterization of the host defense against influenza virus infection and a secondary bacterial pneumonia infection

ABSTRACT: Secondary bacterial infections (‘superinfection’) are a major reason for excessive mortality and hospitalizations during influenza virus infections. Here we present a longitudinal study of gene-expression changes in murine lungs during superinfection, with an initial influenza A virus (IAV) infection and a subsequent S. pneumonia (SP) infection. In addition to the well characterized impairment of the innate immune response, we identified superinfection-specific alterations in endothelial functions, including rapid downregulation in angiogenic activity and vascular regulators. Superinfection-specific alterations were also evident in analysis of cellular states related to the host’s immune resistance against pathogens. We found that only a few hours after secondary bacterial challenge, superinfected mice manifested an excessive induction of immune resistance, and in addition, there was a substantial rewiring of the resistance program: interferon-regulated genes are switched from positive to negative correlations with resistance, whereas genes of fatty-acid metabolism are switched from negative to positive correlations with resistance. Thus, the transcriptional resistance state is reprogrammed toward repressed interferon signaling and induced fatty acid metabolism. Our findings suggest new insights into the remodeling of the host defense upon superinfection, providing promising targets for future therapeutic interventions.

ORGANISM(S): Mus musculus

PROVIDER: GSE206534 | GEO | 2024/03/06

REPOSITORIES: GEO

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Project description:Miao2010 - Innate and adaptive immune responses to primary Influenza A Virus infection This model is described in the article: Quantifying the early immune response and adaptive immune response kinetics in mice infected with influenza A virus. Miao H, Hollenbaugh JA, Zand MS, Holden-Wiltse J, Mosmann TR, Perelson AS, Wu H, Topham DJ. J. Virol. 2010 Jul; 84(13): 6687-6698 Abstract: Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is approximately 1.2 days, and the half-life of free infectious IAV is approximately 4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is approximately 0.5 days, and the average half-life of free infectious virus is approximately 1.8 min. During the adaptive phase, model fitting confirms that CD8(+) CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity. This model is hosted on BioModels Database and identified by: BIOMD0000000546. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Characterization of the host defense against influenza virus infection and a secondary bacterial pneumonia infection

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