Innate immunity is the first responder to anything abnormal. One of the branches of innate immunity is type I interferon, or IFNI. Originally, IFNI was discovered as a potent antiviral tool that is employed by all types of cells in response to viral infection (; ; ). Scientists unravel a complex self-regulating network of external and internal receptors, signal kinases, and transcription factors by decoding the molecular mechansms involved in activation of IFNI response. Further biochemical studies reveal the multiple roles of IFNI, including regulation of cell death, inflammation, cell differentiation, transformation and neoplasia, the impact on the level of organism on tissue integrity, vascular and neuronal connectivity, and general health status (). After establishing clinical -omics technologies, disproportional IFNI activation was connected to a number of autoinflammatory disorders, the most prominent of which are grouped into the family of type I interferonopathy (). Analysis of type I interferonopathy disorders uncovers another role of IFNI signaling – it is deeply involved in the quality control of host RNA. The majority of mutations which activate spontaneous IFNI response belong to the groups of RNA and DNA metabolic enzymes (). Mutation and miscommunication between RNA and DNA quality control systems resulted in leakages of toxic RNA/DNA intermediates, which are detecting by Pattern Recognition Receptors (PRRs, including TLR3, RIG-I, cGAS) and mounting a chronic IFNI response leading to pathologies ().Therefore, the cell uses the same set of tools for detecting viral infection and mis-spliced or mis-folded self RNA molecules.
In this Research topic, we investigate what else can do IFNI, aiming to analyze non-canonic aspects of the IFNI signaling. For example, human nuclear protein Ku70, involved in DNA non-homologous and joining pathway, also is involved in innate immunity response as DNA sensor, according to the study by Sui et al. This is not the first nuclear DNA enzyme revealing its cytosolic activity as the sensor of foreign nucleic acid. Similarly, POLA1 and other components of DNA polymerase alpha complex (), as well as topoisomerase complexes GINSs and MCMs act as a modulator of immune response () (; ) (; ).
Another research article from Yang, et al. presents results from studying the potential role of ZAP and TRIM25 proteins in recognition of viral RNA and transcription intervening. Their data suggest that ZAP RNA binding activity acts through specific recognition of CpG dinucleotides in viral RNA. Additionally, RNA binding by ZAP and interaction with TRIM25 may represent two distinct determinants for ZAP antiviral activity in varying viral contexts. This pattern – differential activity which depends on the context, is well illustrated by the review article of the role of IFNI in Falconi anemia pathogenesis (Landelouci et al.). Fanconi Anemia (FA) is a genome instability syndrome caused by mutations in one of the 23 repair genes of the Fanconi pathway. This heterogeneous disease is characterized by congenital abnormalities, premature aging, and bone marrow failure. A defect in one of its proteins prevents functional DNA repair, leading to the accumulation of DNA breaks and genome instability. Abnormal DNA pattern triggers cGAS sensor leading to type I interferon response, exacerbating pathogenesis of the disease (Landelouci et al.). A more systemic view on the interferon pathway and its interaction with cellular metabolism can be found in the review article of Kano et al., summarizing cGAS and other PRRs in developing inflammatory diseases. Innate immunity also can be activated by allergens. In the original research article, Hu et al. showed that Dermatophagoides microceras allergen acts through an LPS-sensing pattern, activating the secretion of universal pro-inflammatory markers IL-6 and IL-8. Given a recent hypothesis connecting allergies to anti-venom immune response (), such interwinding of innate immune signaling and dust mite allergen sensing is intriguing.
Altogether, innate immunity and interferon signaling are versatile tools, developed by cells early in Evolution. Its wide number of cross-connection with the entire metabolism of cells and tissues make it the universal first responder to any problem that cell is facing: from infection to abnormal host metabolism.
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References
1
CottineauJ.KottemanM. C.LachF. P.KangY. H.VélyF.DeenickE. K.et al. (2017). Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J. Clin. Invest.127 (5), 1991–2006. doi: 10.1172/JCI90727
2
FarrarJ. D. (2014). Type I interferon in immunity. Reference Module in Biomedical Sciences (Elsevier)1–8. doi: 10.1016/B978-0-12-801238-3.00120-3
3
GineauL.CognetC.KaraN.LachF. P.DunneJ.VeturiU.et al. (2012). Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J. Clin. Invest.122 (3), 821–832. doi: 10.1172/JCI61014
4
HughesC. R.GuastiL.MeimaridouE.ChuangC.-H.SchimentiJ. C.KingP. J.et al. (2012). MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J. Clin. Invest.122 (3), 814–820. doi: 10.1172/JCI60224
5
JensenK.NealA. L.OwensR.WarrenJ.. (1963). Interferon responses of chick embryo fibroblasts to nucleus acids and related compounds. Nature200 (4905), 433–435. doi: 10.1038/200433a0
6
LiuQ.ChiS.DmytrukK.DmytrukO.TanS.. (2022). Coronaviral infection and interferon response: The virus-host arms race and COVID-19. Viruses14 (7), 1349. doi:Â 10.3390/v14071349
7
MaceE. M.PaustS.ConteM. I.BaxleyR. M.SchmitM. M.PatilS. L.et al. (2020). Human NK cell deficiency as a result of biallelic mutations in MCM10. J. Clin. Invest.130 (10), 5272–5286. doi: 10.1172/jci134966
8
McNabF.Mayer-BarberK.SherA.WackA.O’GarraA.. (2015). Type I interferons in infectious disease. Nat. Rev. Immunol.15 (2), 87–103. doi: 10.1038/nri3787
9
MeytsI.CasanovaJ.-L. (2016). A human inborn error connects the α’s. Nat. Immunol.17 (5), 472–474. doi: 10.1038/ni.3420
10
PalmN. W.RosensteinR. K.MedzhitovR. (2012). Allergic host defences. Nature484 (7395), 465–472. doi: 10.1038/nature11047
11
RotemZ.CoxR. A.IsaacsA. (1963). Inhibition of virus multiplication by foreign nucleic acid. Nature197, 564–566. doi: 10.1038/197564a0
12
StarokadomskyyP.GemelliT.RiosJ. J.XingC.WangR. C.LiH.et al. (2016). DNA Polymerase-α regulates the activation of type I interferons through cytosolic RNA : DNA synthesis. Nat. Immunol.17 (5), 495–504. doi: 10.1038/ni.3409
13
StarokadomskyyP.Perez-reyesA. E.BursteinE.. (2019). NK cell defects in X-linked pigmentary reticulate disorder. JCI Insight4 (21), e125688. doi:Â 10.1172/jci.insight.125688
14
StarokadomskyyP.Perez-reyesA. E.BursteinE. (2021). Immune dysfunction in mendelian disorders of POLA1 deficiency. J. Clin. Immunol41(2), 285–93. doi: 10.1007/s10875-020-00953-w
Summary
Keywords
interferon, Ifni, pattern recognition receptor (PRR), type I interferonopathy, RIG-I antiviral, cGAS sensor
Citation
Starokadomskyy P (2022) Editorial: Pattern-recognition receptors: Genetics, immunity, pathology. Front. Cell. Infect. Microbiol. 12:991898. doi: 10.3389/fcimb.2022.991898
Received
12 July 2022
Accepted
26 August 2022
Published
20 September 2022
Volume
12 - 2022
Edited and reviewed by
Amal O Amer, The Ohio State University, United States
Updates
Copyright
© 2022 Starokadomskyy.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Petro Starokadomskyy, petro.starokadomskyy@utsouthwestern.edu
This article was submitted to Microbes and Innate Immunity, a section of the journal Frontiers in Cellular and Infection Microbiology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.