Type III IFNs Are Commonly Induced by Bacteria-Sensing TLRs and Reinforce Epithelial Barriers during Infection

Odendall, Charlotte; Voak, Andrew A.; Kagan, Jonathan C.

doi:10.4049/jimmunol.1700250

Cited by 87 publications

(84 citation statements)

References 55 publications

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“…In these experiments, we found that canonical activation of NF‐kB via RELA/p65 is essential for poly(I:C)‐induced IFN‐lambda secretion in primary human infant AECs, as previously reported in transformed BEAS‐2B cells 38 . We also observed that IL1β elicited RELA/p65 activation and IFN‐lambda production, which is in line with previously described induction of IFN lambda by non‐viral canonical activators of NF‐kB such as LPS or bacterial stimuli 41 . Notably, the finding that a pro‐inflammatory signal such as IL1β is sufficient to induce IFN‐lambda secretion in the human infant AEC is novel and physiologically relevant.…”

Section: Discussionsupporting

confidence: 91%

Innate IFN‐lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life

Salka

Arroyo

Chorvinsky

et al. 2020

Clin Experimental Allergy

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Introduction IFN lambda (type III‐IFN‐λ1) is a molecule primarily produced by epithelial cells that provides an important first‐line defence against viral respiratory infections and has been linked to the pathogenesis of viral‐induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN‐lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections. Methods IFN‐lambda protein levels were quantified: (a) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n = 8 donors); and (b) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n = 138) and in uninfected controls (n = 74). In vivo IFN‐lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters. Results Our in vitro experiments showed that the poly(I:C)‐induced innate production of IFN lambda in human infant AECs is regulated by (a) p38‐MAPK/NF‐kB dependent mechanism; and (b) exposure to pro‐inflammatory signals such as IL1β. Our in vivo studies demonstrated that (a) infants (<18 months) had higher virus‐induced IFN‐lambda airway secretion; (b) subjects with RSV infection showed the highest IFN‐lambda airway levels; and (c) individuals with the highest virus‐induced IFN‐lambda levels (>90th percentile) had higher viral loads and were more likely to have respiratory sick visits within 12 months of discharge (OR = 5.8). Conclusion IFN‐lambda responses to dsRNA in the human infant airway epithelium are regulated by p38‐MAPK and NF‐kB signalling. High in vivo IFN‐lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children.

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Section: Discussionsupporting

confidence: 91%

Innate IFN‐lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life

Salka

Arroyo

Chorvinsky

et al. 2020

Clin Experimental Allergy

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“…Stimulation of plasma membrane toll-like receptor (TLR) (such as TLR2 and TLR5), both in myeloid and epithelial cells, selectively induces IFN-λ, and not type I IFN, mRNA expression. Moreover, activation of TLR5 has recently been proved to be essential for the induction of IFN-λ upon Salmonella encounter ( 9 ). Also, cells of epithelial lineage, both in the gut ( 12 ) and in the liver ( 13 ), preferentially produce IFN-λ over type I IFNs in response to viral ligands.…”

Section: Introductionmentioning

confidence: 99%

Interferon (IFN)-λ Takes the Helm: Immunomodulatory Roles of Type III IFNs

2017

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Type III interferons (IFNs) (or IFN-λ) are the latest addition to the IFN family. Even though they share little protein homology with type I IFN, both exhibit remarkable functional similarities: each can be induced in response to viral infections, and both lead to Janus kinases (JAK) and signal transducer and activator of transcription (STAT) activation. The JAK/STAT pathway induces antiviral responses and IFN-stimulated gene transcription. However, despite the similarities in their effector functions with type I IFNs, IFN-λ also has a non-redundant role in protecting barrier organs: epithelial cells preferentially produce IFN-λ rather than type I IFNs; and interferon lambda receptor 1 (IFNLR1), the specific receptor for IFN-λ, is highly expressed on cells of epithelial lineage. Thus far, IFN-λ has been considered mainly as an epithelial cytokine, which restricts viral replication in epithelial cells and constitutes an added layer of protection at mucosal sites. However, it is now increasingly recognized that IFNLR1 is expressed broadly, and that immune cells such as neutrophils and dendritic cells also respond to IFN-λ. Moreover, in many in vivo models, IFN-λ modulates immune cell functions and thereby configures itself less as a cytokine that is only specific to the epithelium, and more as a cytokine that directly controls the inflammatory response at mucosal sites. Here, we critically review the recent literature on immune modulatory roles for IFN-λ, and distinguish between the direct and indirect effects of this IFN on immune cell functions in different inflammatory settings.

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“…We propose that PneumotypeBalanced is primarily associated with lung homeostasis, because it is characterized by a diverse bacterial community, with a moderate bacterial and viral load, and shows a human gene expression profile leaning towards immune modulation and peripheral immune tolerance. A striking characteristic of PneumotypeBalanced was also the clear association with high expression of Interferon-λ receptor 1 (IFNLR1), which suggests a link between the bacterial community and the maintenance of the epithelial barrier integrity (Odendall et al, 2017) and antiviral defense (Broggi et al, 2020). Moreover, PneumotypeBalanced showed down-regulation of Interleukin-1 receptor antagonist (IL1RN), produced in response to pro-inflammatory cytokines (Arend et al, 1998) and up-regulation of Interleukin-10 (IL-10), a tolerogenic cytokine (Ng et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…We identified 6 of the 31 genes to have a particularly high predictive power IFNLR1, MRC1, IL10, IL1RN, LY96, IDO (Importance score >10; 99% Confidence Interval, Figure 4B). IFNLR1 encodes interferon lambda receptor 1, which is involved in antiviral defence and epithelial barrier integrity (Odendall et al, 2017). This gene was up-regulated in samples with Pneumotypebalanced compared to the other three pneumotypes ( Figure 4C).…”

Section: Bacterial Pneumotypes Are Linked To Distinct Host Gene Exprementioning

confidence: 96%

A prevalent and culturable microbiota links ecological balance to clinical stability of the human lung after transplantation

Das

Bernasconi

Koutsokera

et al. 2020

Preprint

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There is accumulating evidence that the lower airway microbiota impacts lung health.However, the link between microbial community composition and lung homeostasis remains elusive. We combined amplicon sequencing and culturomics to characterize the viable bacterial community in 234 longitudinal bronchoalveolar lavage samples from 64 lung transplant recipients and established links to viral loads, host gene expression, lung function, and transplant health. We find that the lung microbiota post-transplant can be categorized into four distinct compositional states, 'pneumotypes'. The predominant 'balanced' pneumotype was characterized by a diverse bacterial community with moderate viral loads, and host gene expression profiles suggesting immune tolerance. The other three pneumotypes were characterized by being either microbiota-depleted, or dominated by potential pathogens, and were linked to increased immune activity, lower respiratory function, and increased risks of infection and rejection. Collectively, our findings establish a link between the lung microbial ecosytem, human lung function, and clinical stability post-transplant. Graphical abstract2015), we found that Bacteroidetes and Firmicutes followed by Proteobacteria and Actinobacteria are the most abundant phyla in the post-transplant lung (Figure 1B).Prevalence analysis across all BALF samples showed that the community composition is highly variable with only 22 OTUs shared by ≥50% of the samples (Figure S1B, Dataset S3).However, these 22 OTUs constituted 42 % of the total number of normalized reads, indicating that they are predominant members of the post-transplant lung microbiota (Figure 1C, Figure S1C, Table S2, Dataset S3). They belonged to the genera Prevotella7, Streptococcus, Porphyromonas and Rothia, the majority of which are also prevailing community members in completion of the clinical dataset, Julie Pernot for technical assistance, and the transplant patients for allowing their clinical data and BALF samples to be used for clinical research.

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Type III IFNs Are Commonly Induced by Bacteria-Sensing TLRs and Reinforce Epithelial Barriers during Infection

Cited by 87 publications

References 55 publications

Innate IFN‐lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life

Innate IFN‐lambda responses to dsRNA in the human infant airway epithelium and clinical regulatory factors during viral respiratory infections in early life

Interferon (IFN)-λ Takes the Helm: Immunomodulatory Roles of Type III IFNs

A prevalent and culturable microbiota links ecological balance to clinical stability of the human lung after transplantation

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