The intestinal microbial metabolite nicotinamide n-oxide prevents herpes simplex encephalitis via activating mitophagy in microglia

References

• Marcocci ME, Napoletani G, Protto V, Kolesova O, Piacentini R, Li Puma DD, Lomonte P, Grassi C, Palamara AT, De Chiara G, et al. Herpes simplex virus-1 in the brain: the dark side of a sneaky infection. Trends Microbiol. 2020;28(10):808–25. doi:10.1016/j.tim.2020.03.003.
   PubMed Web of Science ®Google Scholar
• Duarte LF, Farías MA, Álvarez DM, Bueno SM, Riedel CA, González PA. Herpes simplex virus type 1 infection of the central nervous system: insights into proposed interrelationships with neurodegenerative disorders. Front Cell Neurosci. 2019;13:46. doi:10.3389/fncel.2019.00046.
   PubMed Web of Science ®Google Scholar
• Piret J, Boivin G. Immunomodulatory strategies in herpes simplex virus encephalitis. Clin Microbiol Rev. 2020;33(2):e00105–19. doi:10.1128/CMR.00105-19.
   PubMed Web of Science ®Google Scholar
• Lundberg P, Ramakrishna C, Brown J, Tyszka JM, Hamamura M, Hinton DR, Kovats S, Nalcioglu O, Weinberg K, Openshaw H, et al. The immune response to herpes simplex virus type 1 infection in susceptible mice is a major cause of central nervous system pathology resulting in fatal encephalitis. J Virol. 2008;82(14):7078–7088. doi:10.1128/JVI.00619-08.
   PubMed Web of Science ®Google Scholar
• Wang Y, Jia J, Wang Y, Li F, Song X, Qin S, Wang Z, Kitazato K, Wang Y. Roles of HSV-1 infection-induced microglial immune responses in CNS diseases: friends or foes? Crit Rev Microbiol. 2019;45(5–6):581–594. doi:10.1080/1040841X.2019.1660615.
   PubMed Web of Science ®Google Scholar
• Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, Segal D, Sancho-Shimizu V, Lorenzo L, Puel A, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–1527. doi:10.1126/science.1139522.
   PubMed Web of Science ®Google Scholar
• Sancho-Shimizu V, Pérez de Diego R, Lorenzo L, Halwani R, Alangari A, Israelsson E, Fabrega, S, Cardon A, Maluenda J, Tatematsu M, et al. Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J Clin Invest. 2011;121(12):4889–4902. doi:10.1172/JCI59259.
   PubMed Web of Science ®Google Scholar
• Pérez de Diego R, Sancho-Shimizu V, Lorenzo L, Puel A, Plancoulaine S, Picard C, Herman M, Cardon A, Durandy A, Bustamante J, et al. Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity. 2010;33(3):400–411. doi:10.1016/j.immuni.2010.08.014.
   PubMed Web of Science ®Google Scholar
• Andersen LL, Mørk N, Reinert LS, Kofod-Olsen E, Narita R, Jørgensen SE, Skipper KA, Höning K, Gad HH, Østergaard L, et al. Functional IRF3 deficiency in a patient with herpes simplex encephalitis. J Exp Med. 2015;212(9):1371–1379.
   PubMed Web of Science ®Google Scholar
• Lafaille FG, Pessach IM, Zhang S-Y, Ciancanelli MJ, Herman M, Abhyankar A, Ying S-W, Keros S, Goldstein PA, Mostoslavsky G, et al. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Nature. 2012;491(7426):769–773. doi:10.1038/nature11583.
   PubMed Web of Science ®Google Scholar
• Reinert LS, Lopušná K, Winther H, Sun C, Thomsen MK, Nandakumar R, Mogensen TH, Meyer M, Vægter C, Nyengaard JR, et al. Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS. Nat Commun. 2016;7(1):13348. doi:10.1038/ncomms13348.
   PubMed Web of Science ®Google Scholar
• Reinert LS, Rashidi AS, Tran DN, Katzilieris-Petras G, Hvidt AK, Gohr M, Fruhwürth S, Bodda C, Thomsen MK, Vendelbo MH, et al. Brain immune cells undergo cGAS/STING-dependent apoptosis during herpes simplex virus type 1 infection to limit type I IFN production. J Clin Invest. 2021;131(1):e136824. doi:10.1172/JCI136824.
   PubMed Web of Science ®Google Scholar
• Uyar O, Laflamme N, Piret J, Venable M-C, Carbonneau J, Zarrouk K, Rivest S, Boivin G. An early microglial response is needed to efficiently control herpes simplex virus encephalitis. J Virol. 2020;94(23):e01428–20. doi:10.1128/JVI.01428-20.
   PubMed Web of Science ®Google Scholar
• Winkler ES, Thackray LB. A long-distance relationship: the commensal gut microbiota and systemic viruses. Curr Opin Virol. 2019;37:44–51. doi:10.1016/j.coviro.2019.05.009.
   PubMed Web of Science ®Google Scholar
• Bradley KC, Finsterbusch K, Schnepf D, Crotta S, Llorian M, Davidson S, Fuchs SY, Staeheli P, Wack A. Microbiota-driven tonic interferon signals in lung stromal cells protect from influenza virus infection. Cell Rep. 2019;28(1):245–256. doi:10.1016/j.celrep.2019.05.105.
   PubMed Web of Science ®Google Scholar
• Steed AL, Christophi GP, Kaiko GE, Sun L, Goodwin VM, Jain U, Esaulova E, Artyomov MN, Morales DJ, Holtzman MJ, et al. The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science. 2017;357(6350):498–502. doi:10.1126/science.aam5336.
   PubMed Web of Science ®Google Scholar
• Abt MC, Osborne L, Monticelli L, Doering T, Alenghat T, Sonnenberg G, Paley M, Antenus M, Williams K, Erikson J, et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity. 2012;37(1):158–170. doi:10.1016/j.immuni.2012.04.011.
   PubMed Web of Science ®Google Scholar
• Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci U S A. 2011;108(13):5354–5359. doi:10.1073/pnas.1019378108.
   PubMed Web of Science ®Google Scholar
• Grayson MH, Camarda LE, Hussain SA, Zemple SJ, Hayward M, Lam V, Hunter DA, Santoro JL, Rohlfing M, Cheung DS, et al. Intestinal microbiota disruption reduces regulatory T cells and increases respiratory viral infection mortality through increased IFNg production. Front Immunol. 2018;9:7–9. doi:10.3389/fimmu.2018.00007.
   PubMed Web of Science ®Google Scholar
• Jiang TT, Shao TY, Ang WXG, Kinder JM, Turner LH, Pham G, Whitt J, Alenghat T, Way SS. Commensal fungi recapitulate the protective benefits of intestinal bacteria. Cell Host Microbe. 2017;22(6):809–816.e4. doi:10.1016/j.chom.2017.10.013.
   PubMed Web of Science ®Google Scholar
• Chou -H-H, Chien W-H, Wu -L-L, Cheng C-H, Chung C-H, Horng J-H, Ni Y-H, Tseng H-T, Wu D, Lu X, et al. Age-related immune clearance of hepatitis B virus infection requires the establishment of gut microbiota. Proc Natl Acad Sci U S A. 2015;112(7):2175–2180. doi:10.1073/pnas.1424775112.
   PubMed Web of Science ®Google Scholar
• Kim M, Kim CH. Regulation of humoral immunity by gut microbial products. Gut Microbes. 2017;8(4):392–399. doi:10.1080/19490976.2017.1299311.
   PubMed Web of Science ®Google Scholar
• Levy M, Blacher E, Elinav E. Microbiome, metabolites and host immunity. Curr Opin Microbiol. 2017;35:8–15. doi:10.1016/j.mib.2016.10.003.
   PubMed Web of Science ®Google Scholar
• Oh JE, Kim B-C, Chang D-H, Kwon M, Lee SY, Kang D, Kim JY, Hwang I, Yu J-W, Nakae S, et al. Dysbiosis-induced IL-33 contributes to impaired antiviral immunity in the genital mucosa. Proc Natl Acad Sci U S A. 2016;113(6):E762–71. doi:10.1073/pnas.1518589113.
   PubMed Web of Science ®Google Scholar
• Fang P, Kazmi SA, Jameson KG, Hsiao EY. The microbiome as a modifier of neurodegenerative disease risk. Cell Host Microbe. 2020;28(2):201–222. doi:10.1016/j.chom.2020.06.008.
   PubMed Web of Science ®Google Scholar
• Erny D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, Keren-Shaul H, Mahlakoiv T, Jakobshagen K, Buch T, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965–977. doi:10.1038/nn.4030.
   PubMed Web of Science ®Google Scholar
• Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17(1):131–143. doi:10.1038/nn.3599.
   PubMed Web of Science ®Google Scholar
• Chiu IM, Morimoto EA, Goodarzi H, Liao J, O’Keeffe S, Phatnani H, Muratet M, Carroll M, Levy S, Tavazoie S, et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 2013;4(2):385–401. doi:10.1016/j.celrep.2013.06.018.
   PubMed Web of Science ®Google Scholar
• Thangaraj A Periyasamy P, Liao K, Bendi VS, Callen S, Pendyala G, Buch S. HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy. Autophagy. 2018;14(9):1596–1619. doi:10.1080/15548627.2018.1476810.
   PubMed Web of Science ®Google Scholar
• Thangaraj A, Periyasamy P, Guo M-L, Chivero ET, Callen S, Buch S. Mitigation of cocaine-mediated mitochondrial damage, defective mitophagy and microglial activation by superoxide dismutase mimetics. Autophagy. 2020;16(2):289–312. doi:10.1080/15548627.2019.1607686.
   PubMed Web of Science ®Google Scholar
• Fang EF, Hou Y, Lautrup S, Jensen MB, Yang B, SenGupta T, Caponio D, Khezri R, Demarest TG, Aman Y, et al. NAD(+) augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat Commun. 2019;10(1):5284. doi:10.1038/s41467-019-13172-8.
   PubMedGoogle Scholar
• Yildiz S, Mazel-Sanchez B, Kandasamy M, Manicassamy B, Schmolke M. Influenza A virus infection impacts systemic microbiota dynamics and causes quantitative enteric dysbiosis. Microbiome. 2018;6(1):9. doi:10.1186/s40168-017-0386-z.
   PubMedGoogle Scholar
• Zhong H, Wang Y, Shi Z, Zhang L, Ren H, He W, Zhang Z, Zhu A, Zhao J, Xiao F, et al. Characterization of respiratory microbial dysbiosis in hospitalized COVID-19 patients. Cell Discov. 2021;7(1):23. doi:10.1038/s41421-021-00257-2.
   PubMed Web of Science ®Google Scholar
• Labarta-Bajo L, Gramalla-Schmitz A, Gerner RR, Kazane KR, Humphrey G, Schwartz T, Sanders K, Swafford A, Knight R, Raffatellu M, et al. CD8 T cells drive anorexia, dysbiosis, and blooms of a commensal with immunosuppressive potential after viral infection. Proc Natl Acad Sci U S A. 2020;117(40):24998–25007. doi:10.1073/pnas.2003656117.
   PubMed Web of Science ®Google Scholar
• Bonaz B, Bazin T, Pellissier S. The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci. 2018;12:49. doi:10.3389/fnins.2018.00049.
   PubMed Web of Science ®Google Scholar
• Paola B, Conti J, Zatta V, Russo V, Scarpa M, Kotsafti A, Porzionato A, De Caro R, Scarpa M, Fassan M, et al. Persistent herpes simplex virus type 1 infection of enteric neurons triggers CD8+ T cell response and gastrointestinal neuromuscular dysfunction. Front Cell Infect Microbiol. 2021;11:615350. doi:10.3389/fcimb.2021.615350.
   PubMed Web of Science ®Google Scholar
• Brun P, Giron MC, Zoppellaro C, Bin A, Porzionato A, De Caro R, Barbara G, Stanghellini V, Corinaldesi R, Zaninotto G, et al. Herpes simplex virus type 1 infection of the rat enteric nervous system evokes small-bowel neuromuscular abnormalities. Gastroenterology. 2010;138(5):1790–1801. doi:10.1053/j.gastro.2010.01.036.
   PubMed Web of Science ®Google Scholar
• Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57–69. doi:10.1038/nrn2038.
   PubMed Web of Science ®Google Scholar
• Hiscott J. Convergence of the NF-kappaB and IRF pathways in the regulation of the innate antiviral response. Cytokine Growth Factor Rev. 2007;18(5–6):483–490. doi:10.1016/j.cytogfr.2007.06.002.
   PubMed Web of Science ®Google Scholar
• Abdel-Haq R, Schlachetzki JCM, Glass CK, Mazmanian SK. Microbiome-microglia connections via the gut-brain axis. J Exp Med. 2019;216(1):41–59. doi:10.1084/jem.20180794.
   PubMed Web of Science ®Google Scholar
• Wang Y, Wang Z, Wang Y, Li F, Jia J, Song X, Qin S, Wang R, Jin F, Kitazato K, et al. The gut-microglia connection: implications for central nervous system diseases. Front Immunol. 2018;9:2325. doi:10.3389/fimmu.2018.02325.
   PubMed Web of Science ®Google Scholar
• Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao -C-C, Ardura-Fabregat A, De lima KA, Gutiérrez-Vázquez C, Hewson P, Staszewski O, et al. Microglial control of astrocytes in response to microbial metabolites. Nature. 2018;557(7707):724–728. doi:10.1038/s41586-018-0119-x.
   PubMed Web of Science ®Google Scholar
• Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, Xie Z, Chu X, Yang J, Wang H, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019;29(10):787–803. doi:10.1038/s41422-019-0216-x.
   PubMed Web of Science ®Google Scholar
• Harris SA, Harris EA. Molecular mechanisms for herpes simplex virus type 1 pathogenesis in alzheimer’s disease. Front Aging Neurosci. 2018;10:48. doi:10.3389/fnagi.2018.00048.
   PubMed Web of Science ®Google Scholar
• Jiang M, Zhang S, Yang Z, Lin H, Zhu J, Liu L, Wang W, Liu S, Liu W, Ma Y, et al. Self-recognition of an inducible host lncrna by rig-i feedback restricts innate immune response. Cell. 2018;173(4):906–919 e913. doi:10.1016/j.cell.2018.03.064.
   PubMed Web of Science ®Google Scholar
• Winkler ES, Shrihari S, Hykes BL, Handley SA, Andhey PS, Huang YJS, Swain A, Droit L, Chebrolu KK, Mack M, et al. The intestinal microbiome restricts alphavirus infection and dissemination through a bile acid-type I IFN signaling axis. Cell. 2020;182(4):901–918.e18. doi:10.1016/j.cell.2020.06.029.
   PubMed Web of Science ®Google Scholar
• Trompette A, Gollwitzer ES, Pattaroni C, Lopez-Mejia IC, Riva E, Pernot J, Ubags N, Fajas L, Nicod LP, Marsland BJ, et al. Dietary fiber confers protection against flu by shaping Ly6c- patrolling monocyte hematopoiesis and CD8+ T cell metabolism. Immunity. 2018;48(5):992–1005.e8. doi:10.1016/j.immuni.2018.04.022.
   PubMed Web of Science ®Google Scholar
• Ramakrishna C, Kujawski M, Chu H, Li L, Mazmanian SK, Cantin EM. Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis. Nat Commun. 2019;10(1):2153. doi:10.1038/s41467-019-09884-6.
   PubMedGoogle Scholar
• Yang S, Xia C, Li S, Du L, Zhang L, Zhou R. Defective mitophagy driven by dysregulation of rheb and KIF5B contributes to mitochondrial reactive oxygen species (ROS)-induced nod-like receptor 3 (NLRP3) dependent proinflammatory response and aggravates lipotoxicity. Redox Biol. 2014;3:63–71. doi:10.1016/j.redox.2014.04.001.
   PubMed Web of Science ®Google Scholar
• Yue L, Yao H. Mitochondrial dysfunction in inflammatory responses and cellular senescence: pathogenesis and pharmacological targets for chronic lung diseases. Br J Pharmacol. 2016;173(15):2305–2318. doi:10.1111/bph.13518.
   PubMed Web of Science ®Google Scholar
• Cho DH, Kim JK, Jo EK. Mitophagy and Innate Immunity in Infection. Mol Cells. 2020;43(1):10–22. doi:10.14348/molcells.2020.2329.
   PubMed Web of Science ®Google Scholar
• Ren Z, Zhang X, Ding T, Zhong Z, Hu H, Xu Z, Deng J. Mitochondrial dynamics imbalance: a strategy for promoting viral infection. Front Microbiol. 2020;11:1992. doi:10.3389/fmicb.2020.01992.
   PubMed Web of Science ®Google Scholar
• Hui X, Zhang L, Cao L, Huang K, Zhao Y, Zhang Y, Chen X, Lin X, Chen M, and Jin M, et al. SARS-CoV-2 promote autophagy to suppress type I interferon response. Signal Transduct Target Ther. 6: 180 (2021.
   PubMed Web of Science ®Google Scholar
• Zhang L, Qin Y, Chen M. Viral strategies for triggering and manipulating mitophagy. Autophagy. 2018;14(10):1665–1673 (2018. doi:10.1080/15548627.2018.1466014.
   PubMed Web of Science ®Google Scholar
• Cutshall NS, Ursino R, Kucera KA, Latham J, Ihle NC. Nicotinamide N -Oxides as CXCR2 antagonists. Bioorg Med Chem Lett. 2001;11(14):1951–1954 (2001. doi:10.1016/S0960-894X(01)00326-2.
   PubMed Web of Science ®Google Scholar
• Blacher E, Bashiardes S, Shapiro H, Rothschild D, Mor U, Dori-Bachash M, Kleimeyer C, Moresi C, Harnik Y, Zur M, et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature. 2019;572(7770):474–480. doi:10.1038/s41586-019-1443-5.
   PubMed Web of Science ®Google Scholar
• Shats I, Williams JG, Liu J, Makarov MV, Wu X, Lih FB, Deterding LJ, Lim C, Xu X, Randall TA, et al. Bacteria boost mammalian host NAD metabolism by engaging the deamidated biosynthesis pathway. Cell Metab. 2020;31(3):564–579.e7. doi:10.1016/j.cmet.2020.02.001.
   PubMed Web of Science ®Google Scholar
• Eguchi K, Fujitani N, Nakagawa H, Miyazaki T. Prevention of respiratory syncytial virus infection with probiotic lactic acid bacterium Lactobacillus gasseri SBT2055. Sci Rep. 2019;9(1):4812. doi:10.1038/s41598-019-39602-7.
   PubMedGoogle Scholar
• Kawase M, He, F, Kubota, A, Yoda, K, Miyazawa, K, and Hiramatsu, M. Heat-killed Lactobacillus gasseri TMC0356 protects mice against influenza virus infection by stimulating gut and respiratory immune responses. FEMS Immunol Med Microbiol. 2012;64(2):280–288. doi:10.1111/j.1574-695X.2011.00903.x.
   PubMedGoogle Scholar
• Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, Costa-Mattioli M. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism spectrum disorder. Neuron. 2019;101(2):246–259.e6. doi:10.1016/j.neuron.2018.11.018.
   PubMed Web of Science ®Google Scholar
• Engevik MA, Ruan W, Esparza M, Fultz R, Shi Z, Engevik KA, Engevik AC, Ihekweazu FD, Visuthranukul C, Venable S, et al. Immunomodulation of dendritic cells by Lactobacillus reuteri surface components and metabolites. Physiol Rep. 2021;9(2):e14719. doi:10.14814/phy2.14719.
   PubMed Web of Science ®Google Scholar
• Gopinath S, Kim MV, Rakib T, Wong PW, van Zandt M, Barry NA, Kaisho T, Goodman AL, and Iwasaki A, et al. Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner. Nat Microbiol. 2018;(3):611–621. doi:10.1038/s41564-018-0138-2.
   PubMedGoogle Scholar