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Damage sensing through TLR9 Promotes Viral Clearance and Recovery During Influenza Infection

ABSTRACT: Toll-like receptor-9 is a pattern-recognition receptor that binds to the unmethylated CpG sequences in DNA. Its role in influenza infection is not well understood. Using mice deficient in TLR9, we demonstrated that these animals mounted a reduced inflammatory response during early infection on day 7, driven by the myeloid cells and associated cytokine responses. However, despite this diminished inflammation, TLR9-/- mice had increased viral burden on day 7 post-infection. To understand the cellular specificity and underlying mechanism of increased infection susceptibility in TLR9-/- mice, we performed single-cell RNA sequencing of lung tissues. scRNA sequencing data indicate that TLR9-/- immune cells, especially those of myeloid origin are highly susceptible to influenza infection. This susceptibility of TLR9-/- cells appeared to be independent of type I interferon signaling as the type I interferon pathway appeared the most upregulated pathway in TLR9-/- immune cells. We confirmed increased susceptibility of TLR9-/- myeloid cells using ex vivo murine alveolar macrophage and human peripheral blood monocyte cells. Despite the initial amelioration of the lung injury, the widespread infection of immune cells in TLR9-/- lungs upregulated both influenza and inflammatory responses in myeloid cells. This persistent inflammatory response manifested as the accumulation of both myeloid and lymphoid cells in the airways and increased injury markers in TLR9-/- on day 14. Elevated injury on day 14 delayed the weight loss recovery in TLR9-/- mice. Finally, we demonstrate elevated levels of TLR9 ligands during influenza infection in humans. These data demonstrate a key role of TLR9 in regulating host response to influenza infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE271505 | GEO | 2025/07/02

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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Damage sensing through TLR9 Promotes Viral Clearance and Recovery During Influenza Infection

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