Intestinal epithelial cells (IECs) are the primary target of enteric viruses. Their infection by viruses leads to the upregulation of both type I and type III interferons (IFNs). These IFNs then act in an autocrine and paracrine manner to protect IECs from viral propagation. To date, whether both IFNs use similar signaling pathways and whether these 2 cytokines can act synergistically to protect against viral infection remain unclear. Using human IECs depleted of either the type I or type III IFN receptor, we found that both signal transduction pathways are interconnected and influence each other at the level of interferon-stimulated gene (ISG) expression and efficiency of antiviral protection. Precisely, in human IECs, the presence of a functional type III IFN receptor negatively regulates type I IFN signaling and activity, whereas the presence of type I IFN receptor positively reinforces type III IFN signaling and function. We propose that this complex crosstalk allows for a preferential type III IFN-mediated protection of human intestinal cells.
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References
1.
AnkN, IversenMB, BartholdyC, StaeheliP, HartmannR, JensenUB, Dagnaes-HansenF, ThomsenAR, ChenZ, HaugenH, KlucherK, PaludanSR. 2008. An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity. J Immunol, 180(4):2474–2485.
2.
ArnoldMM, BarroM, PattonJT. 2013a. Rotavirus NSP1 mediates degradation of interferon regulatory factors through targeting of the dimerization domain. J Virol, 87(17):9813–9821.
3.
ArnoldMM, SenA, GreenbergHB, PattonJT. 2013b. The battle between rotavirus and its host for control of the interferon signaling pathway. PLoS Pathog, 9(1):e1003064.
BhushalS, WolfsmüllerM, SelvakumarTA, KemperL, WirthD, HornefMW, HauserH, KösterM. 2017. Cell polarization and epigenetic status shape the heterogeneous response to type III interferons in intestinal epithelial cells. Front Immunol, 8:671.
6.
BlazekK, EamesHL, WeissM, ByrneAJ, PerocheauD, PeaseJE, DoyleS, McCannF, WilliamsRO, UdalovaIA. 2015. IFN-λ resolves inflammation via suppression of neutrophil infiltration and IL-1β production. J Exp Med, 212(6):845–853.
7.
BolenCR, DingS, RobekMD, KleinsteinSH. 2014. Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression. Hepatology, 59(4):1262–1272.
8.
BroggiA, TanY, GranucciF, ZanoniI. 2017. IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function. Nat Immunol, 18(10):1084–1093.
9.
DumoutierL, LejeuneD, HorS, FickenscherH, RenauldJ-C. 2003. Cloning of a new type II cytokine receptor activating signal transducer and activator of transcription (STAT)1, STAT2 and STAT3. Biochem J, 370 (Pt 2): 391–396.
10.
François-NewtonV, Magno de Freitas AlmeidaG, Payelle-BrogardB, MonneronD, Pichard-GarciaL, PiehlerJ, PellegriniS, UzéG. 2011. USP18-based negative feedback control is induced by type I and type III interferons and specifically inactivates interferon α response. PLoS One, 6(7):e22200.
HoffmannH-H, SchneiderWM, RiceCM. 2015. Interferons and viruses: an evolutionary arms race of molecular interactions. Trends Immunol, 36(3):124–138.
13.
IsaacsJ, LindenmannJ, AndrewsCH. 1957. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci, 147(927):258–267.
14.
JilgN, LinW, HongJ, SchaeferEA, WolskiD, MeixongJ, GotoK, BrisacC, ChusriP, FuscoDN, ChevaliezS, LutherJ, KumthipK, UrbanTJ, PengLF, LauerGM, ChungRT. 2014. Kinetic differences in the induction of interferon stimulated genes by interferon-α and interleukin 28B are altered by infection with hepatitis C virus. Hepatology, 59(4):1250–1261.
15.
KlinkhammerJ, SchnepfD, YeL, SchwaderlappM, GadHH, HartmannR, GarcinD, MahlakõivT, StaeheliP. 2018. IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission. ELife, 7:1–18. DOI: 10.7554/eLife.33354.
16.
KotenkoSV, DurbinJE. 2017. Contribution of type III interferons to antiviral immunity: location, location, location. J Biol Chem, 292(18):7295–7303.
17.
KotenkoSV, GallagherG, BaurinVV, Lewis-AntesA, ShenM, ShahNK, LangerJA, SheikhF, DickensheetsH, DonnellyRP. 2003. IFN-Λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol, 4(1):69–77.
18.
KotenkoSV, KrauseCD, IzotovaLS, PollackBP, WuW, PestkaS. 1997. Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J, 16(19):5894–5903.
19.
LavoieTB, KalieE, Crisafulli-CabatuS, AbramovichR, DiGioiaG, MoolchanK, PestkaS, SchreiberG. 2011. Binding and activity of all human alpha interferon subtypes. Cytokine, 56(2):282–289.
20.
LinJ-D, FengN, SenA, BalanM, TsengH-C, McElrathC, SmirnovSV, PengJ, YasukawaLL, DurbinRK, DurbinJE, GreenbergHB, KotenkoSV. 2016. Distinct roles of type I and type III interferons in intestinal immunity to homologous and heterologous rotavirus infections. PLoS Pathog, 12(4):e1005600.
21.
MahlakõivT, HernandezP, GronkeK, DiefenbachA, StaeheliP. 2015. Leukocyte-derived IFN-α/β and epithelial IFN-λ constitute a compartmentalized mucosal defense system that restricts enteric virus infections. PLoS Pathog, 11(4):e1004782.
22.
MakowskaZ, DuongFHT, TrincucciG, ToughDF, HeimMH. 2011. Interferon-β and interferon-λ signaling is not affected by interferon-induced refractoriness to interferon-α in vivo. Hepatology, 53(4):1171–1180.
23.
MarcelloT, GrakouiA, Barba-SpaethG, MachlinES, KotenkoSV, MacDonaldMR, RiceCM. 2006. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology, 131(6):1887–1898.
24.
MarieI, DurbinJE, LevyDE. 1998. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. EMBO J, 17(22):6660–6669.
25.
MordsteinM, KochsG, DumoutierL, RenauldJ-C, PaludanSR, KlucherK, StaeheliP. 2008. Interferon-λ contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog, 4(9):e1000151.
26.
MordsteinM, NeugebauerE, DittV, JessenB, RiegerT, FalconeV, SorgeloosF, EhlS, MayerD, KochsG, SchwemmleM, GüntherS, DrostenC, MichielsT, StaeheliP. 2010. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol, 84(11):5670–5677.
27.
NiceTJ, BaldridgeMT, McCuneBT, NormanJM, LazearHM, ArtyomovM, DiamondMS, VirginHW. 2015. Interferon-λ cures persistent murine norovirus infection in the absence of adaptive immunity. Science, 347(6219):269–273.
28.
PervolarakiK, Rastgou TalemiS, AlbrechtD, BormannF, BamfordC, MendozaJL, GarciaKC, et al.2018. Differential induction of interferon stimulated genes between type I and type III interferons is independent of interferon receptor abundance. PLoS Pathog, 14(11):e1007420.
29.
PervolarakiK, StaniferML, MünchauS, RennLA, AlbrechtD, KurzhalsS, SenísE, GrimmD, Schröder-BraunsteinJ, RabinRL, BoulantS. 2017. Type I and type III interferons display different dependency on mitogen-activated protein kinases to mount an antiviral state in the human gut. Front Immunol, 8:459.
30.
PottJ, MahlakõivT, MordsteinM, DuerrCU, MichielsT, StockingerS, StaeheliP, HornefMW. 2011. IFN-lambda determines the intestinal epithelial antiviral host defense. Proc Natl Acad Sci U S A, 108(19):7944–7949.
31.
Prokunina-OlssonL, MuchmoreB, TangW, PfeifferRM, ParkH, DickensheetsH, HergottD, Porter-GillP, MumyA, KohaarI, ChenS, BrandN, TarwayM, LiuL, SheikhF, AstemborskiJ, BonkovskyHL, EdlinBR, HowellCD, MorganTR, ThomasDL, RehermannB, DonnellyRP. 2013. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet, 45(2):164–171.
32.
SaxenaK, SimonLM, ZengX-L, BluttSE, CrawfordSE, SastriNP, KarandikarUC, AjamiNJ, ZachosNC, KovbasnjukO, DonowitzM, ConnerME, ShawCA, EstesMK. 2017. A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection. Proc Natl Acad Sci U S A, 114(4):E570–E579.
33.
SchneiderWM, ChevillotteMD, RiceCM. 2014. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol, 32:513–545.
34.
SchwerkJ, KösterM, HauserH, RohdeM, FuldeM, HornefMW, MayT. 2013. Generation of mouse small intestinal epithelial cell lines that allow the analysis of specific innate immune functions. PLoS One, 8(8):e72700.
35.
SelvakumarTA, BhushalS, KalinkeU, WirthD, HauserH, KösterM, HornefMW. 2017. Identification of a predominantly interferon-λ-induced transcriptional profile in murine intestinal epithelial cells. Front Immunol, 8:1302.
36.
SenA, SharmaA, GreenbergHB. 2017. Rotavirus degrades multiple type interferon receptors to inhibit IFN signaling and protects against mortality from endotoxin in suckling mice. J Virol, 92(1):e01394-17. DOI: 10.1128/JVI.01394-17.
37.
SheppardP, KindsvogelW, XuW, HendersonK, SchlutsmeyerS, WhitmoreTE, KuestnerR, GarriguesU, BirksC, RorabackJ, OstranderC, DongD, ShinJ, PresnellS, FoxB, HaldemanB, CooperE, TaftD, GilbertT, GrantFJ, TackettM, KrivanW, McKnightG, CleggC, FosterD, KlucherK. 2003. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol, 4(1):63–68.
38.
SommereynsC, PaulS, StaeheliP, MichielsT. 2008. IFN-lambda (IFN-λ) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLoS Pathog, 4(3):e1000017.
39.
StaniferML, KischnickC, RippertA, AlbrechtD, BoulantS. 2017. Reovirus inhibits interferon production by sequestering IRF3 into viral factories. Sci Rep, 7(1):10873.
40.
de WeerdNA, NguyenT. 2012. The interferons and their receptors-distribution and regulation. Immunol Cell Biol, 90(5):483–491.
41.
WitteK, GruetzG, VolkHD, LoomanAC, AsadullahK, SterryW, SabatR, WolkK. 2009. Despite IFN-lambda receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines. Genes Immun, 10(8):702–714.
42.
ZhouZ, HammingOJ, AnkN, PaludanSR, NielsenAL, HartmannR. 2007. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J Virol, 81(14):7749–7758.
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