Does Type I Interferon Limit Protective Neutrophil Responses during Pulmonary Francisella Tularensis Infection?

Furuya, Yasubumi; Steiner, Donald J.; Metzger, Dennis W.

doi:10.3389/fimmu.2014.00355

Cited by 9 publications

(10 citation statements)

References 21 publications

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“…Although knowledge of the airway microbiome lags behind that of the gut, important characteristics of the microbial communities in the airway are beginning to emerge. Similar to the gut, the community structure of an individual’s airway microbiome is established early in life and plays a critical role in immune development [ 10 – 12 ]. Many external factors influence the airway microbiome, including mode of delivery at birth [ 13 ], breastfeeding [ 14 ], antibiotic use [ 15 , 16 ], and exposure to tobacco smoke [ 17 ] and pathogens [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Host genetic variation in mucosal immunity pathways influences the upper airway microbiome

et al. 2017

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BackgroundThe degree to which host genetic variation can modulate microbial communities in humans remains an open question. Here, we performed a genetic mapping study of the microbiome in two accessible upper airway sites, the nasopharynx and the nasal vestibule, during two seasons in 144 adult members of a founder population of European decent.ResultsWe estimated the relative abundances (RAs) of genus level bacteria from 16S rRNA gene sequences and examined associations with 148,653 genetic variants (linkage disequilibrium [LD] r 2 < 0.5) selected from among all common variants discovered in genome sequences in this population. We identified 37 microbiome quantitative trait loci (mbQTLs) that showed evidence of association with the RAs of 22 genera (q < 0.05) and were enriched for genes in mucosal immunity pathways. The most significant association was between the RA of Dermacoccus (phylum Actinobacteria) and a variant 8 kb upstream of TINCR (rs117042385; p = 1.61 × 10−8; q = 0.002), a long non-coding RNA that binds to peptidoglycan recognition protein 3 (PGLYRP3) mRNA, a gene encoding a known antimicrobial protein. A second association was between a missense variant in PGLYRP4 (rs3006458) and the RA of an unclassified genus of family Micrococcaceae (phylum Actinobacteria) (p = 5.10 × 10−7; q = 0.032).ConclusionsOur findings provide evidence of host genetic influences on upper airway microbial composition in humans and implicate mucosal immunity genes in this relationship.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-016-0227-5) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Host genetic variation in mucosal immunity pathways influences the upper airway microbiome

et al. 2017

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“…Although type I IFN production is critical for activation of the host-protective absent in melanoma 2 inflammasome during F. tularensis infection (102-104), type I IFNR-deficient mice were shown to be more resistant to intradermal infection than WT animals (108). This latter study suggests that type I IFNs can negatively regulate the accumulation of IL-17-producing cells, thereby impairing neutrophil accumulation and resistance to F. tularensis infection (108,109). However, other mechanisms may exist.…”

Section: Franciscellamentioning

confidence: 99%

“…However, other mechanisms may exist. As reviewed by Furuya et al (109), neutrophil recruitment following pulmonary F. tularensis infection is independent of IL-17, suggesting that the mechanism of action of type I IFNs operating in intradermal infection (108) is different from that in intranasal infection (110).…”

Section: Franciscellamentioning

confidence: 99%

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

Stifter¹,

Feng²

2015

The Journal of Immunology

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Type I IFNs are known to inhibit viral replication and mediate protection against viral infection. However, recent studies revealed that these cytokines play a broader and more fundamental role in host responses to infections beyond their well-established antiviral function. Type I IFN induction, often associated with microbial evasion mechanisms unique to virulent microorganisms, is now shown to increase host susceptibility to a diverse range of pathogens, including some viruses. This article presents an overview of the role of type I IFNs in infections with bacterial, fungal, parasitic, and viral pathogens and discusses the key mechanisms mediating the regulatory function of type I IFNs in pathogen clearance and tissue inflammation.

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“…The induction of type I IFN can be achieved either by membrane-anchored Toll-like receptors which recognize microbial PAMPs in the extracellular or endosomal space (4) or through cytosolic PRRs such as RIG-I (retinoic acid inducible gene I)-like receptors which allow for immune surveillance in the cytoplasm (5). Unlike its role in virus defense, induction of the type I IFN response leads to an increase of host susceptibility to intracellular pathogens such as Listeria monocytogenes (6, 7), Mycobacterium tuberculosis (8, 9), and Francisella tularensis (10).…”

Section: Introductionmentioning

confidence: 99%

The secRNome of Listeria monocytogenes Harbors Small Noncoding RNAs That Are Potent Inducers of Beta Interferon

Frantz

Teubner

Schultze

et al. 2019

mBio

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Cellular sensing of bacterial RNA is increasingly recognized as a determinant of host-pathogen interactions. The intracellular pathogen Listeria monocytogenes induces high levels of type I interferons (alpha/beta interferons [IFN-α/β]) to create a growth-permissive microenvironment during infection. We previously demonstrated that RNAs secreted by L. monocytogenes (comprising the secRNome) are potent inducers of IFN-β. We determined the composition and diversity of the members of the secRNome and found that they are uniquely enriched for noncoding small RNAs (sRNAs). Testing of individual sRNAs for their ability to induce IFN revealed several sRNAs with this property. We examined ril32, an intracellularly expressed sRNA that is highly conserved for the species L. monocytogenes and that was the most potent inducer of IFN-β expression of all the sRNAs tested in this study, in more detail. The rli32-induced IFN-β response is RIG-I (retinoic acid inducible gene I) dependent, and cells primed with rli32 inhibit influenza virus replication. We determined the rli32 motif required for IFN induction. rli32 overproduction promotes intracellular bacterial growth, and a mutant lacking rli32 is restricted for intracellular growth in macrophages. rli32-overproducing bacteria are resistant to H2O2 and exhibit both increased catalase activity and changes in the cell envelope. Comparative transcriptome sequencing (RNA-Seq) analysis indicated that ril32 regulates expression of the lhrC locus, previously shown to be involved in cell envelope stress. Inhibition of IFN-β signaling by ruxolitinib reduced rli32-dependent intracellular bacterial growth, indicating a link between induction of the interferon system and bacterial physiology. rli32 is, to the best of our knowledge, the first secreted individual bacterial sRNA known to trigger the induction of the type I IFN response. IMPORTANCE Interferons are potent and broadly acting cytokines that stimulate cellular responses to nucleic acids of unusual structures or locations. While protective when induced following viral infections, the induction of interferons is detrimental to the host during L. monocytogenes infection. Here, we identify specific sRNAs, secreted by the bacterium, with the capacity to induce type I IFN. Further analysis of the most potent sRNA, rli32, links the ability to induce RIG-I-dependent induction of the type I IFN response to the intracellular growth properties of the bacterium. Our findings emphasize the significance of released RNA for Listeria infection and shed light on a compartmental strategy used by an intracellular pathogen to modulate host responses to its advantage.

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Does Type I Interferon Limit Protective Neutrophil Responses during Pulmonary Francisella Tularensis Infection?

Cited by 9 publications

References 21 publications

Host genetic variation in mucosal immunity pathways influences the upper airway microbiome

Host genetic variation in mucosal immunity pathways influences the upper airway microbiome

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

The secRNome of Listeria monocytogenes Harbors Small Noncoding RNAs That Are Potent Inducers of Beta Interferon

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