Dataset Information

Macrophage Coordination of the Interferon Lambda Immune Response.

ABSTRACT: Lambda interferons (IFN-?s) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-? not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-?, uniquely positioned to bridge the gap between IFN-? producing cells and lymphocyte populations that are not intrinsically responsive to IFN-?. While CD14+ monocytes do not express the IFN-? receptor, IFNLR1, sensitivity is quickly gained upon differentiation to macrophages in vitro. IFN-? stimulates macrophage cytotoxicity and phagocytosis as well as the secretion of pro-inflammatory cytokines and interferon stimulated genes that mediate immune cell chemotaxis and effector functions. In particular, IFN-? induced CCR5 and CXCR3 chemokines, stimulating T and NK cell migration, as well as subsequent NK cell cytotoxicity. Using immunofluorescence and cell sorting techniques, we confirmed that human liver macrophages expressing CD14 and CD68 are highly responsive to IFN-? ex vivo. Together, these data highlight a novel role for macrophages in shaping IFN-? dependent immune responses both directly through pro-inflammatory activity and indirectly by recruiting and activating IFN-? unresponsive lymphocytes.

SUBMITTER: Read SA

PROVIDER: S-EPMC6878940 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Macrophage Coordination of the Interferon Lambda Immune Response.

Read Scott A SA Wijaya Ratna R Ramezani-Moghadam Mehdi M Tay Enoch E Schibeci Steve S Liddle Christopher C Lam Vincent W T VWT Yuen Lawrence L Douglas Mark W MW Booth David D George Jacob J Ahlenstiel Golo G

Frontiers in immunology 20191119

Lambda interferons (IFN-λs) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-λ not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-λ, uniquely positioned to bridge the gap between IFN-λ producing cells and lymphocyte populations that are not intrinsically responsive to IFN-λ. While CD14<sup>+</sup> monocytes do not ...[more]

PMID: 31798594

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Project description:Early interactions of influenza A virus (IAV) with respiratory epithelium might determine the outcome of infection. The study of global cellular innate immune responses often masks multiple aspects of the mechanisms by which populations of cells work as organized and heterogeneous systems to defeat virus infection, and how the virus counteracts these systems. In this study, we experimentally dissected the dynamics of IAV and human epithelial respiratory cell interaction during early infection at the single-cell level. We found that the number of viruses infecting a cell (multiplicity of infection [MOI]) influences the magnitude of virus antagonism of the host innate antiviral response. Infections performed at high MOIs resulted in increased viral gene expression per cell and stronger antagonist effect than infections at low MOIs. In addition, single-cell patterns of expression of interferons (IFN) and IFN-stimulated genes (ISGs) provided important insights into the contributions of the infected and bystander cells to the innate immune responses during infection. Specifically, the expression of multiple ISGs was lower in infected than in bystander cells. In contrast with other IFNs, IFN lambda 1 (IFNL1) showed a widespread pattern of expression, suggesting a different cell-to-cell propagation mechanism more reliant on paracrine signaling. Finally, we measured the dynamics of the antiviral response in primary human epithelial cells, which highlighted the importance of early innate immune responses at inhibiting virus spread.IMPORTANCE Influenza A virus (IAV) is a respiratory pathogen of high importance to public health. Annual epidemics of seasonal IAV infections in humans are a significant public health and economic burden. IAV also causes sporadic pandemics, which can have devastating effects. The main target cells for IAV replication are epithelial cells in the respiratory epithelium. The cellular innate immune responses induced in these cells upon infection are critical for defense against the virus, and therefore, it is important to understand the complex interactions between the virus and the host cells. In this study, we investigated the innate immune response to IAV in the respiratory epithelium at the single-cell level, providing a better understanding on how a population of epithelial cells functions as a complex system to orchestrate the response to virus infection and how the virus counteracts this system.

Dataset Information

Macrophage Coordination of the Interferon Lambda Immune Response.

Publications

Macrophage Coordination of the Interferon Lambda Immune Response.

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