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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
Published on: December 10, 2013
Human metapneumovirus driven IFN-β production antagonizes macrophage transcriptional induction of IL1-β in response
Simon Loevenich1,2, Nicola P Montaldo1, Arthur Wickenhagen1,3
1Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
Abstract:
Human metapneumovirus (HMPV) is a pneumovirus that may cause severe respiratory disease in humans. HMPV infection has been found to increase susceptibility to bacterial superinfections leading to increased morbidity and mortality. The molecular mechanisms underlying HMPV-mediated increase in bacterial susceptibility are poorly understood and largely understudied. Type I interferons (IFNs), while critical for antiviral defenses, may often have detrimental effects by skewing the host immune response and cytokine output of immune cells. It is currently unknown if HMPV skews the inflammatory response in human macrophages triggered by bacterial stimuli. Here we report that HMPV pre-infection impacts production of specific cytokines. HMPV strongly suppresses IL-1β transcription in response to LPS or heat-killed Pseudomonas aeruginosa and Streptococcus pneumonia, while enhancing mRNA levels of IL-6, TNF-α and IFN-β. We demonstrate that in human macrophages the HMPV-mediated suppression of IL-1β transcription requires TANK-binding kinase 1 (TBK1) and signaling via the IFN-β-IFNAR axis. Interestingly, our results show that HMPV pre-infection did not impair the LPS-stimulated activation of NF-κB and HIF-1α, transcription factors that stimulate IL-1β mRNA synthesis in human cells. Furthermore, we determined that sequential HMPV-LPS treatment resulted in accumulation of the repressive epigenetic mark H3K27me3 at the IL1B promoter. Thus, for the first time we present data revealing the molecular mechanisms by which HMPV shapes the cytokine output of human macrophages exposed to bacterial pathogens/LPS, which appears to be dependent on epigenetic reprogramming at the IL1B promoter leading to reduced synthesis of IL-1β. These results may improve current understanding of the role of type I IFNs in respiratory disease mediated not only by HMPV, but also by other respiratory viruses that are associated with superinfections.
Insights
Human metapneumovirus (HMPV) infection suppresses IL-1β production in macrophages, increasing bacterial superinfection risk. This occurs via epigenetic changes at the IL1B promoter, mediated by TBK1 and type I interferon signaling.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Human metapneumovirus (HMPV) exacerbates bacterial superinfections, increasing respiratory disease severity.
- Type I interferons (IFNs) can dysregulate immune responses during viral infections.
- Mechanisms of HMPV-induced susceptibility to bacterial infections are not well understood.
Purpose of the Study:
- Investigate how HMPV pre-infection alters human macrophage inflammatory responses to bacterial stimuli.
- Elucidate the molecular pathways involved in HMPV-mediated cytokine dysregulation.
Main Methods:
- Human macrophages were pre-infected with HMPV, then stimulated with LPS or heat-killed bacteria.
- Cytokine mRNA levels (IL-1β, IL-6, TNF-α, IFN-β) were quantified.
- NF-κB and HIF-1α activation, TBK1, IFNAR signaling, and H3K27me3 epigenetic marks at the IL1B promoter were analyzed.
Main Results:
- HMPV pre-infection suppressed IL-1β transcription but enhanced IL-6, TNF-α, and IFN-β mRNA in response to bacterial stimuli.
- Suppression of IL-1β required TBK1 and IFN-β-IFNAR signaling.
- NF-κB and HIF-1α activation remained intact.
- HMPV-LPS sequential treatment led to H3K27me3 accumulation at the IL1B promoter.
Conclusions:
- HMPV epigenetically reprograms human macrophages to suppress IL-1β production, potentially increasing susceptibility to bacterial superinfections.
- This mechanism involves TBK1, type I IFN signaling, and epigenetic modification of the IL1B promoter.
- Findings offer insights into viral-bacterial interactions in respiratory diseases.
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