scholarly journals Type I Interferon Induction and Exhaustion during Viral Infection: Plasmacytoid Dendritic Cells and Emerging COVID-19 Findings

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1839
Author(s):  
Trever T. Greene ◽  
Elina I. Zuniga
Keyword(s):  
Dendritic Cells ◽  
Viral Infection ◽  
Opportunistic Infections ◽  
Type I Interferon ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Induction ◽  
Infection Models ◽  
Ongoing Infection ◽  
Increased Susceptibility

Type I Interferons (IFN-I) are a family of potent antiviral cytokines that act through the direct restriction of viral replication and by enhancing antiviral immunity. However, these powerful cytokines are a caged lion, as excessive and sustained IFN-I production can drive immunopathology during infection, and aberrant IFN-I production is a feature of several types of autoimmunity. As specialized producers of IFN-I plasmacytoid (p), dendritic cells (DCs) can secrete superb quantities and a wide breadth of IFN-I isoforms immediately after infection or stimulation, and are the focus of this review. Notably, a few days after viral infection pDCs tune down their capacity for IFN-I production, producing less cytokines in response to both the ongoing infection and unrelated secondary stimulations. This process, hereby referred to as “pDC exhaustion”, favors viral persistence and associates with reduced innate responses and increased susceptibility to secondary opportunistic infections. On the other hand, pDC exhaustion may be a compromise to avoid IFN-I driven immunopathology. In this review we reflect on the mechanisms that initially induce IFN-I and subsequently silence their production by pDCs during a viral infection. While these processes have been long studied across numerous viral infection models, the 2019 coronavirus disease (COVID-19) pandemic has brought their discussion back to the fore, and so we also discuss emerging results related to pDC-IFN-I production in the context of COVID-19.

scholarly journals IRF family proteins and type I interferon induction in dendritic cells

Cell Research ◽  
2006 ◽  
Vol 16 (2) ◽  
pp. 134-140 ◽  
Author(s):  
Prafullakumar Tailor ◽  
Tomohiko Tamura ◽  
Keiko Ozato
Keyword(s):  
Dendritic Cells ◽  
Type I Interferon ◽  
Type I ◽  
Interferon Induction

Type I Interferon Induction Pathway, but Not Released Interferon, Participates in the Maturation of Dendritic Cells Induced by Negative‐Strand RNA Viruses

2003 ◽  
Vol 187 (7) ◽  
pp. 1126-1136 ◽  
Author(s):  
Carolina B. López ◽  
Adolfo García‐Sastre ◽  
Bryan R. G. Williams ◽  
Thomas M. Moran
Keyword(s):  
Dendritic Cells ◽  
Type I Interferon ◽  
Rna Viruses ◽  
Type I ◽  
Negative Strand ◽  
Interferon Induction

scholarly journals M27 Expressed by Cytomegalovirus Counteracts Effective Type I Interferon Induction of Myeloid Cells but Not of Plasmacytoid Dendritic Cells

2014 ◽  
Vol 88 (23) ◽  
pp. 13638-13650 ◽  
Author(s):  
M. Doring ◽  
I. Lessin ◽  
T. Frenz ◽  
J. Spanier ◽  
A. Kessler ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Type I Interferon ◽  
Myeloid Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Interferon Induction

scholarly journals Type I interferons link skin-associated dysbiotic commensal bacteria to pathogenic inflammation and angiogenesis in rosacea

2021 ◽  
Author(s):  
Alessio Mylonas ◽  
Heike Hawerkamp ◽  
Yichen Wang ◽  
Olivier Demaria ◽  
Stephan Meller ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Type I Interferon ◽  
Plasmacytoid Dendritic Cells ◽  
Commensal Bacteria ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Interferon Production ◽  
Microbial Dysbiosis ◽  
Fluctuating Course

Abstract Rosacea is a common chronic inflammatory skin disease that is characterized by a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with high density of B. oleronius and increased activity of the serine protease kallikrein 5, which cleaves cathelicidin antimicrobial peptide, have been recognized as key pathogenic triggers in rosacea. However, how these events are linked to the hallmarks of the disease remains unknown. Here, we show that type I interferons produced by plasmacytoid dendritic cells represent the pivotal link between dysbiosis, an aberrant immune response, and neovascularization in rosacea. In fact, compared to other commensal bacteria, B. oleronius is highly susceptible and preferentially killed by cathelicidin antimicrobial peptides leading to enhanced generation of complexes with DNA. DNA from skin-associated microbiota but not from host cells is required for cathelicidin-induced activation of plasmacytoid dendritic cells and type I-interferon production, which is further amplified by B. oleronius. Moreover, kallikrein 5 cleaves cathelicidin into peptides with heightened DNA binding and type I interferon-inducing capacities, further facilitating type I interferon production within the skin. In turn, type I interferons induce IL22 whilst simultaneously rendering endothelial cells responsive through upregulation of the IL22-receptor, and thereby driving drive neoangiogenesis. These findings unravel novel pathomechanisms, which directly link several hallmarks of rosacea to the killing of dysbiotic commensal bacteria and the induction of a pathogenic type-I interferon-TH17/22 pathway.

scholarly journals The Feedback Phase of Type I Interferon Induction in Dendritic Cells Requires Interferon Regulatory Factor 8

Immunity ◽  
2007 ◽  
Vol 27 (2) ◽  
pp. 228-239 ◽  
Author(s):  
Prafullakumar Tailor ◽  
Tomohiko Tamura ◽  
Hee Jeong Kong ◽  
Toru Kubota ◽  
Mayumi Kubota ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Type I Interferon ◽  
Interferon Regulatory Factor ◽  
Type I ◽  
Regulatory Factor ◽  
Interferon Induction ◽  
Feedback Phase

scholarly journals HIV Blocks Interferon Induction in Human Dendritic Cells and Macrophages by Dysregulation of TBK1

2015 ◽  
Vol 89 (13) ◽  
pp. 6575-6584 ◽  
Author(s):  
Andrew N. Harman ◽  
Najla Nasr ◽  
Alexandra Feetham ◽  
Ani Galoyan ◽  
Abdullateef A. Alshehri ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Signaling Pathway ◽  
Sendai Virus ◽  
Type I Interferons ◽  
Target Cells ◽  
Type I ◽  
Accessory Proteins ◽  
Principal Mechanism ◽  
Interferon Induction ◽  
Hiv 1

ABSTRACTDendritic cells (DCs) and macrophages are present in the tissues of the anogenital tract, where HIV-1 transmission occurs in almost all cases. These cells are both target cells for HIV-1 and represent the first opportunity for the virus to interfere with innate recognition. Previously we have shown that both cell types fail to produce type I interferons (IFNs) in response to HIV-1 but that, unlike T cells, the virus does not block IFN induction by targeting IFN regulatory factor 3 (IRF3) for cellular degradation. Thus, either HIV-1 inhibits IFN induction by an alternate mechanism or, less likely, these cells fail to sense HIV-1. Here we show that HIV-1 (but not herpes simplex virus 2 [HSV-2] or Sendai virus)-exposed DCs and macrophages fail to induce the expression of all known type I and III IFN genes. These cells do sense the virus, and pattern recognition receptor (PRR)-induced signaling pathways are triggered. The precise stage in the IFN-inducing signaling pathway that HIV-1 targets to block IFN induction was identified; phosphorylation but not K63 polyubiquitination of TANK-binding kinase 1 (TBK1) was completely inhibited. Two HIV-1 accessory proteins, Vpr and Vif, were shown to bind to TBK1, and their individual deletion partly restored IFN-β expression. Thus, the inhibition of TBK1 autophosphorylation by binding of these proteins appears to be the principal mechanism by which HIV-1 blocks type I and III IFN induction in myeloid cells.IMPORTANCEDendritic cells (DCs) and macrophages are key HIV target cells. Therefore, definition of how HIV impairs innate immune responses to initially establish infection is essential to design preventative interventions, especially by restoring initial interferon production. Here we demonstrate how HIV-1 blocks interferon induction by inhibiting the function of a key kinase in the interferon signaling pathway, TBK1, via two different viral accessory proteins. Other viral proteins have been shown to target the general effects of TBK1, but this precise targeting between ubiquitination and phosphorylation of TBK1 is novel.

PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

2008 ◽  
Vol 31 (4) ◽  
pp. 13
Author(s):  
Martin Hyrcza ◽  
Mario Ostrowski ◽  
Sandy Der
Keyword(s):  
Dendritic Cells ◽  
Influenza Virus ◽  
Hiv Infection ◽  
Gene Transcription ◽  
Sendai Virus ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I ◽  
Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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