Short-lived AIM2 Inflammasome Activation Relates to Chronic MCMV Infection in BALB/c Mice

Abstract

Absent in melanoma 2 (AIM2) inflammasome is a crucial link bridging the innate host defense and the subsequent adaptive immunity when activated by exogenous double stranded DNA (dsDNA). Through establishing models of disseminated murine cytomegalovirus (MCMV) infection in BALB/c and C57BL/6 mice, we evaluated dynamic expression of AIM2 inflammasome components and its relationship with pathological damage and viral replication, trying to figure out whether AIM2 inflammasome is related to the chronic mechanism of MCMV. BALB/c and C57BL/6 mice were sacrificed on day 0, 1, 3, 7, 14 and 28 post infection. Expression levels of AIM2, pro-caspase-1, caspase-1 p20, pro-IL1β and mature IL1β in primary peritoneal macrophages (PMs) and spleens were detected by Western blotting. Contents of IL18 in the serum were detected by ELISA. Pathological examinations of livers were performed, and mRNA levels of MCMV glycoprotein B (gB) in salivary glands also assessed. Results showed that expression levels of AIM2 in PMs and spleens of C57BL/6 mice increased on day 3, even continued to day 28; caspase-1 p20 and mature IL1β increased on day 7, 14 and 28; the persistently high expression of IL18 in the serum started on day 1, showing a double peak curve. As for BALB/c mice, expression of AIM2 in PMs increased on day 1 and day 7, while contents of AIM2 in spleens increased on day 1 and day 3; caspase-1 p20 and mature IL1β merely increased 7 days fter infection. Thereafter, expression levels of AIM2, caspase-1 p20, mature IL1β and IL18 were limited; the duration of AIM2 inflammasome activation in BALB/c mice was much shorter than that in C57BL/6 mice. The severer pathological damage and more viral replications in BALB/c mice further proved the deficient antiviral immunity to MCMV. In conclusion, the activation of AIM2 inflammasome in BALB/c mice was short-lived, which is quite possibly related to the chronicity of MCMV infection.

Keywords

AIM2 / murine cytomegalovirus / BALB/c mice / C57BL/6 mice / macrophages

References

[1] HarvalaH, StewartC, MullerK, et al.. High risk of cytomegalovirus infection following solid organ transplantation despite prophylactic therapy. J Med Virol, 2013, 85(5): 893-898

[2] WujcickaWI, WilczynskiJS, NowakowskaDE. Association of SNPs from IL1A, IL1B, and IL6 Genes with Human Cytomegalovirus Infection Among Pregnant Women. Viral Immunol, 2017, 30(4): 288-297

[3] AriyantoIA, EstiasariR, WatersS, et al.. Active and Persistent Cytomegalovirus Infections Affect T Cells in Young Adult HIV Patients Commencing Antiretroviral Therapy. Viral Immunol, 2018, 31(6): 472-479

[4] CekinovicD, LisnicVJ, JonjicS. Rodent models of congenital cytomegalovirus infection. Methods Mol Biol, 2014, 1119: 289-310

[5] MorroneSR, MatyszewskiM, YuX, et al.. Assembly-driven activation of the AIM2 foreign-dsDNA sensor provides a polymerization template for downstream ASC. Nat Commun, 2015, 6: 7827

[6] CridlandJA, CurleyEZ, WykesMN, et al.. The mammalian PYHIN gene family: phylogeny, evolution and expression. BMC Evol Biol, 2012, 12: 140

[7] HornungV, AblasserA, Charrel-DennisM, et al.. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature, 2009, 458(7237): 514-518

[8] RobertsTL, IdrisA, DunnJA, et al.. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science, 2009, 323(5917): 1057-1060

[9] NeteaMG, SimonA, van de VeerdonkF, et al.. IL-1beta processing in host defense: beyond the inflammasomes. PLoS Pathog, 2010, 6(2): e1000661

[10] ZhengQ, TaoR, GaoH, et al.. HCMV-encoded UL128 enhances TNF-alpha and IL-6 expression and promotes PBMC proliferation through the MAPK/ERK pathway in vitro. Viral Immunol, 2012, 25(2): 98-105

[11] DinarelloCA, NovickD, KimS, et al.. Interleukin-18 and IL-18 binding protein. Front Immunol, 2013, 4: 289

[12] RathinamVA, JiangZ, WaggonerSN, et al.. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunol, 2010, 11(5): 395-402

[13] van de VeerdonkFL, NeteaMG, DinarelloCA, et al.. Inflammasome activation and IL-1beta and IL-18 processing during infection. Trends Immunol, 2011, 32(3): 110-116

[14] BrownMG, DokunAO, HeuselJW, et al.. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science, 2001, 292(5518): 934-937

[15] ZeleznjakJ, PopovicB, KrmpoticA, et al.. Mouse cytomegalovirus encoded immunoevasins and evolution of Ly49 receptors - Sidekicks or enemies?. Immunol Lett, 2017, 189: 40-47

[16] LuY, LiuX, HuangY, et al.. The Effects of IL10 and NK Cells on the Susceptibility to Mouse Cytomegalovirus in BALB/c Mice despite the Compensation of IFNgamma. Intervirology, 2018, 61(3): 111-122

[17] LiaoY, LiuX, HuangY, et al.. Expression pattern of CD11c on lung immune cells after disseminated murine cytomegalovirus infection. Virol J, 2017, 14(1): 132

[18] LiX, LiuL, ShuS, et al.. Cytosolic dsDNA from murine cytomegalovirus can be recognized by AIM2 inflammasome. Chin J Microbiol Immunol (Chinese), 2012, 32(1): 31-35

[19] JonjicS, KrmpoticA, ArapovicJ, et al.. Dissection of the antiviral NK cell response by MCMV mutants. Methods in molecular biology, 2008, 415: 127-149

[20] TsuchiyaK, HaraH, KawamuraI, et al.. Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. J Immunol, 2010, 185(2): 1186-1195

[21] HaraH, TsuchiyaK, NomuraT, et al.. Dependency of caspase-1 activation induced in macrophages by Listeria monocytogenes on cytolysin, listeriolysin O, after evasion from phagosome into the cytoplasm. J Immunol, 2008, 180(12): 7859-7868

[22] WeizmanOE, AdamsNM, SchusterIS, et al.. ILC1 Confer Early Host Protection at Initial Sites of Viral Infection. Cell, 2017, 171(4): 795-808 e712

[23] PopovicB, GolemacM, PodlechJ, et al.. IL-33/ST2 pathway drives regulatory T cell dependent suppression of liver damage upon cytomegalovirus infection. PLoS Pathogens, 2017, 13(4): e1006345

[24] HumphreysIR, de TrezC, KinkadeA, et al.. Cytomegalovirus exploits IL-10-mediated immune regulation in the salivary glands. J Exp Med, 2007, 204(5): 1217-1225

[25] Fernandes-AlnemriT, YuJW, DattaP, et al.. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature, 2009, 458(7237): 509-513

[26] BohmV, SimonCO, PodlechJ, et al.. The immune evasion paradox: immunoevasins of murine cytomegalovirus enhance priming of CD8 T cells by preventing negative feedback regulation. J Virol, 2008, 82(23): 11637-11650

[27] LiYH, WeiX, JiS, et al.. In vivo effects of the NLRP1/NLRP3 inflammasome pathway on latent respiratory virus infection. Int J Mol Med, 2018, 41(6): 3620-3628

[28] HuangY, LiuL, MaD, et al.. Human cytomegalovirus triggers the assembly of AIM2 inflammasome in THP-1-derived macrophages. J Med Virol, 2017, 89(12): 2188-2195