Immunosuppression in the Management of Presumed Non-infective Uveitis; Are We Sure What We are Treating? Notes on the Antimicrobial Properties of the Systemic Immunosuppressants

REFERENCES

• Forrester JV, Kuffova L, Dick AD. Autoimmunity, autoinflammation, and infection in uveitis. Am J Ophthalmol. 2018;189:77–85. doi:10.1016/j.ajo.2018.02.019.
   PubMed Web of Science ®Google Scholar
• Zhang L. Oral Campylobacter species: initiators of a subgroup of inflammatory bowel disease? World J Gastroenterol. 2015;21:9239–9244. doi:10.3748/wjg.v21.i10.2937.
   PubMed Web of Science ®Google Scholar
• Liu F, Ma R, Riordan SM, et al. Azathioprine, mercaptopurine, and 5-aminosalicylic acid affect the growth of IBD-associated Campylobacter species and other enteric microbes. Front Microbiol. 2017;8:527.
   PubMed Web of Science ®Google Scholar
• Antoniani D, Rossi E, Rinaldo S, et al. The immunosuppressive drug azathioprine inhibits biosynthesis of the bacterial signal molecule cyclic-di-GMP by interfering with intracellular nucleotide pool availability. Appl Microbiol Biotechnol. 2013;97:7325–7336. doi:10.1007/s00253-013-4875-0.
   PubMed Web of Science ®Google Scholar
• Shin SJ, Collins MT. Thiopurine drugs azathioprine and 6-mercaptopurine inhibit Mycobacterium paratuberculosis growth in vitro. Antimicrob Agents Chemother. 2008;52:418–426. doi:10.1128/AAC.00678-07.
   PubMed Web of Science ®Google Scholar
• Krishnan MY, Manning EJB, Collins MT. Effects of interactions of antibacterial drugs with each other and with 6-mercaptopurine on in vitro growth of Mycobacterium avium subspecies paratuberculosis. J Antimicrob Chemother. 2009;64:1018–1023. doi:10.1093/jac/dkp339.
   PubMed Web of Science ®Google Scholar
• Shiraki K, Ishibashi M, Okuno T, et al. Immunosuppressive dose of azathioprine inhibits replication of human cytomegalovirus in vitro. Arch Virol. 1991;117:165–171.
   PubMed Web of Science ®Google Scholar
• Wong GV, Hersh EM, McMaster PR. Treatment of a presumed case of sympathetic ophthalmia with methotrexate. Arch Ophthalmol. 1966;76:66–76. doi:10.1001/archopht.1966.03850010068014.
   PubMedGoogle Scholar
• Kruszewska H, Zareba T, Tyski S. Examination of antimicrobial activity of selected non-antibiotic products. Acta Poloniae Pharm. 2010;67:773–776.
   Web of Science ®Google Scholar
• de Smet MD, Vancs VS, Kohler D, Solomon D, Chan CC. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. Br J Ophthalmol. 1999;83:448–451. doi:10.1136/bjo.83.4.448.
   PubMed Web of Science ®Google Scholar
• Shanley JD, Debs RJ. The folate antagonist, methotrexate, is a potent inhibitor of murine and human cytomegalovirus in vitro. Antiviral Res. 1989;11:99–106.
   PubMed Web of Science ®Google Scholar
• Beck S, Zhu Z, Oliveira MF. et al. Mechanism of action of methotrexate against Zika virus. Viruses. 2019;11:E338. doi:10.3390/v11040338.
   PubMed Web of Science ®Google Scholar
• Warnock DW, Johnson EM, Burke J, Pracharktam R. Effect of methotrexate alone and in combination with antifungal drugs on the growth of Candida albicans. J Antimicrob Chemother. 1989;23:837–847. doi:10.1093/jac/23.6.837.
   PubMed Web of Science ®Google Scholar
• Warnock DW, Oliver DA, Cheung MM, Zurick NJ. Effect of methotrexate on the germination and growth of Aspergillus fumigatus and Aspergillus flavus strains. J Antimicrob Chemother. 1992;29:375–381. doi:10.1093/jac/29.4.375.
   PubMed Web of Science ®Google Scholar
• Yang J, Wan Z, Wang X, Liu W, Li R. In vitro interactions between antifungals and methotrexate against Aspergillus spp. Mycopathologia. 2009;168:237–242. doi:10.1007/s11046-009-9218-4.
   PubMed Web of Science ®Google Scholar
• Odom A, Muir S, Lim E, Toffaletti DL, Perfect J, Heitman J. Calcineurin is required for virulence of Cryptococcus neoformans. Embo J. 1997;16:2576–2589. doi:10.1093/emboj/16.10.2576.
   PubMed Web of Science ®Google Scholar
• Breuder T, Hemenway CS, Movva NR, Cardenas ME, Heitman J. Calcineurin is essential in cyclosporine A- and FK506-sensitive yeast strains. Proc Natl Acad Sci. 1994;91:5372–5376. doi:10.1073/pnas.91.12.5372.
   PubMed Web of Science ®Google Scholar
• Massuda TY1, Nagashima LA, Leonello PC, et al. Cyclosporin A treatment and decreased fungal load/antigenemia in experimental murine paracoccidioidomycosis. Mycopathologia. 2011;171:161–169. doi:10.1007/s11046-010-9359-5.
   PubMed Web of Science ®Google Scholar
• Marchetti O, Entenza JM, Sanglard D, Bille J, Glauser MP, Moreillon P. Fluconazole plus cyclosporine: a fungicidal combination effective against experimental endocarditis due to Candida albicans. Antimicrob Agents Chemother. 2000;44:2932–2938. doi:10.1128/aac.44.11.2932-2938.2000.
   PubMed Web of Science ®Google Scholar
• Cordeiro Rde A, Macedo Rde B, Teixeira CE, et al. The calcineurin inhibitor cyclosporin A exhibits synergism with antifungals against Candida parapsilosis species complex. J Med Microbiol. 2014;63:936–944. doi:10.1099/jmm.0.073478-0.
   PubMed Web of Science ®Google Scholar
• Singh-Babak SD, Shekhar T, Smith AM, Giaever G, Nislow C, Cowen LE. A novel calcineurin-independent activity of cyclosporin A in Saccharomyces cerevisiae. Mol Biosyst. 2012;8:2575–2584. doi:10.1039/c2mb25107h.
   PubMedGoogle Scholar
• Firpi RJ, Zhu H, Morelli G, et al. Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation. Liver Transpl. 2006;12:51–57. doi:10.1002/lt.20532.
   PubMed Web of Science ®Google Scholar
• Firpi RJ, Soldevila-Pico C, Morelli GG, et al. The use of cyclosporine for recurrent hepatitis C after liver transplant: a randomized pilot study. Dig Dis Sci. 2010;55:196–203. doi:10.1007/s10620-009-0981-3.
   PubMed Web of Science ®Google Scholar
• Hulgan T, Donahue JP, Smeaton L, et al. Oral cyclosporin A inhibits CD4 T cell P-glycoprotein activity in HIV-infected adults initiating treatment with nucleoside reverse transcriptase inhibitors. Eur J Clin Pharmacol. 2009;65:1081–1088. doi:10.1007/s00228-009-0725-5.
   PubMed Web of Science ®Google Scholar
• McKenzie RC, Epand RM, Johnson DC. Cyclosporine A inhibits herpes simplex virus-induced cell fusion but not virus penetration into cells. Virology. 1987;159:1–9.
   PubMed Web of Science ®Google Scholar
• Gündüz K, Ozdemir O. Topical cyclosporin as an adjunct to topical acyclovir treatment in herpetic stromal keratitis. Ophthalmic Res. 1997;29:405–408. doi:10.1159/000268041.
   PubMed Web of Science ®Google Scholar
• Damaso CR, Keller SJ. Cyclosporin A inhibits vaccinia virus replication in vitro. Arch Virol. 1994;134:303–319.
   PubMed Web of Science ®Google Scholar
• Shen Z, Tian Z, He H, Zhang J, Li J, Wu Y. Antiviral effects of cyclosporine A in neonatal mice with rotavirus-induced diarrhea. J Pediatr Gastroenterol Nutr. 2015;60:11–17. doi:10.1097/MPG.0000000000000493.
   PubMed Web of Science ®Google Scholar
• de Wilde AH, Zevenhoven-Dobbe JC, van der Meer Y, et al. Cyclosporin A inhibits the replication of diverse coronaviruses. J Gen Virol. 2011;92:2542–2548. doi:10.3109/03009742.2015.1013983.
   PubMed Web of Science ®Google Scholar
• Ma C, Li F, Musharrafieh R, Wang J. Discovery of cyclosporine A and its analogs as broad-spectrum anti-influenza drugs with a high in vitro genetic barrier of drug resistance. Antiviral Res. 2016;133:62–72. doi:10.1016/j.antiviral.2016.07.019.
   PubMed Web of Science ®Google Scholar
• Peel M, Scribner A. Cyclophilin inhibitors as antiviral agents. Bioorg Med Chem Lett. 2013;23:4485–4492. doi:10.1016/j.bmcl.2013.05.101.
   PubMed Web of Science ®Google Scholar
• Sugita T, Tajima M, Ito T, Saito M, Tsuboi R, Nishikawa A. Antifungal activities of tacrolimus and azole agents against the eleven currently accepted Malassezia species. J Clin Microbiol. 2005;43:2824–2829. doi:10.1128/JCM.43.6.2824-2829.2005.
   PubMed Web of Science ®Google Scholar
• Kubiça TF, Denardi LB, Azevedo MI, et al. Antifungal activities of tacrolimus in combination with antifungal agents against fluconazole-susceptible and fluconazole-resistant Trichosporon asahii isolates. Braz J Infect Dis. 2016;20:539–545. doi:10.1016/j.bjid.2016.08.008.
   PubMed Web of Science ®Google Scholar
• Denardi LB, Mario DA, Loreto ÉS, Santurio JM, Alves SH. Synergistic effects of tacrolimus and azole antifungal compounds in fluconazole-susceptible and fluconazole-resistant Candida glabrata isolates. Braz J Microbiol. 2015;46:125–129. doi:10.1590/S1517-838246120120442.
   PubMed Web of Science ®Google Scholar
• Ozawa H, Okabayashi K, Kano R, Watanabe S, Hasegawa A. Antifungal activities of the combination of tacrolimus and itraconazole against Trichophyton mentagrophytes. J Vet Med Sci. 2005;67:629–630. doi:10.1292/jvms.67.629.
   PubMed Web of Science ®Google Scholar
• Maesaki S, Marichal P, Hossain MA, Sanglard D, Vanden Bossche H, Kohno S. Synergic effects of tacrolimus and azole antifungal agents against azole-resistant Candida albicans strains. J Antimicrob Chemother. 1998;42:747–753. doi:10.1093/jac/42.6.747.
   PubMed Web of Science ®Google Scholar
• Gao L, Sun Y. In vitro interactions of antifungal agents and tacrolimus against Aspergillus biofilms. Antimicrob Agents Chemother. 2015;59:7097–7099. doi:10.1128/AAC.01510-15.
   PubMed Web of Science ®Google Scholar
• Stewart WEII, Scott WD, Sulkin SE. Relative sensitivities of viruses to different species of interferon. J Virol. 1969;4:147–153.
   PubMed Web of Science ®Google Scholar
• Sobaci G, Erdem U, Durukan AH, et al. Safety and effectiveness of interferon alpha-2a in treatment of patients with Behçet’s uveitis refractory to conventional treatments. Ophthalmology. 2010;117:1430–1435. doi:10.1016/j.ophtha.2009.11.022.
   PubMed Web of Science ®Google Scholar
• Plskova J, Greiner K, Forrester JV. Interferon-alpha as an effective treatment for noninfectious posterior uveitis and panuveitis. Am J Ophthalmol. 2007;144:55–61. doi:10.1016/j.ajo.2007.03.050.
   PubMed Web of Science ®Google Scholar
• Deuter CM, Kötter I, Günaydin I, Stübiger N, Doycheva DG, Zierhut M. Efficacy and tolerability of interferon alpha treatment in patients with chronic cystoid macular oedema due to non-infectious uveitis. Br J Ophthalmol. 2009;93:906–913. doi:10.1136/bjo.2008.153874.
   PubMed Web of Science ®Google Scholar
• Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev. 2001;14:778–809. doi:10.1128/CMR.14.4.778-809.2001.
   PubMed Web of Science ®Google Scholar
• Boxx GM, Cheng G. The roles of Type I interferon in bacterial infection. Cell Host Microbe. 2016;19:760–769. doi:10.1016/j.chom.2016.05.016.
   PubMed Web of Science ®Google Scholar
• Uchiyama S, Keller N, Schlaepfer E, et al. Interferon α-enhanced clearance of group A streptococcus despite neutropenia. J Infect Dis. 2016;214:321–328. doi:10.1093/infdis/jiw157.
   PubMed Web of Science ®Google Scholar
• van Lieshout MH, Florquin S, Vanʼt Veer C, de Vos AF, van der Poll T. TIR-domain-containing adaptor-inducing interferon-β (TRIF) mediates antibacterial defense during Gram-negative pneumonia by inducing interferon-x03B3. J Innate Immun. 2015;7:637–646. doi:10.1159/000430913.
   PubMed Web of Science ®Google Scholar
• Florey HW, Jennings MA. Mycophenolic acid; an antibiotic from Penicillium brevicompactum dlerckx. Lancet. 1946;1(6385):46–49. doi:10.1016/s0140-6736(46)90242-5.
   PubMedGoogle Scholar
• Noto T, Sawada M, Ando K. Some biologic properties of mycophenolic acid. J Antibiotics. 1969;22:165–169. doi:10.7164/antibiotics.22.165.
   PubMed Web of Science ®Google Scholar
• Oz HS, Hughes WT. Novel anti-Pneumocystis carinii effects of the immunosuppressant mycophenolate mofetil in contrast to provocative effects of tacrolimus, sirolimus, and dexamethasone. J Infect Dis. 1997;175:901–904. doi:10.1086/513988.
   PubMed Web of Science ®Google Scholar
• Williams RH, Lively DH, DeLong DC, et al. Mycophenolic acid: antiviral and antitumor properties. J Antibiotics. 1968;21:463–464. doi:10.7164/antibiotics.21.463.
   PubMed Web of Science ®Google Scholar
• Ando K, Suzuki S, Tamura G, Arima K. Antiviral activity of mycophenolic acid. Studies on antiviral and antitumour antibiotics IV. J Antibiotics. 1968;21:649–652. doi:10.7164/antibiotics.21.649.
   PubMed Web of Science ®Google Scholar
• Smee DF, Bray M, Huggins JW. Antiviral activity and mode of action studies of ribavirin and mycophenolic acid against orthopoxviruses in vitro. Antivir Chem Chemother. 2001;12:327–335. doi:10.1177/095632020101200602.
   PubMed Web of Science ®Google Scholar
• Padalko E, Verbeken E, Matthys P, Aerts JL, De Clercq E, Neyts J. Mycophenolate mofetil inhibits the development of Coxsackie B3-virus-induced myocarditis in mice. BMC Microbiol. 2003;3:25. doi:10.1186/1471-2180-3.
   PubMedGoogle Scholar
• Livonesi MC, Moro de Sousa RL, Moraes Figueiredo LT. In vitro study of antiviral activity of mycophenolic acid on Brazilian orthobunyaviruses. Intervirology. 2007;50:204–208. doi:10.1159/000099219.
   PubMed Web of Science ®Google Scholar
• Henry SD, Metselaar HJ, Lonsdale RCB, et al. Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporine A and interferon-α. Gastroenterology. 2006;131:1452–1462. doi:10.1053/j.gastro.2006.08.027.
   PubMed Web of Science ®Google Scholar
• Mayer K, Reinhard T, Reis A, Voiculescu A, Sundmacher R. Synergistic antiherpetic effect of acyclovir and mycophenolate mofetil following keratoplasty in patients with herpetic eye disease: first results of a randomised pilot study. Graefes Arch Clin Exp Ophthalmol. 2003;241:1051–1054. doi:10.1007/s00417-003-0724-7.
   PubMed Web of Science ®Google Scholar
• Diamond MS, Zachariah M, Harris E. Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA. Virology. 2002;304:211–221.
   PubMed Web of Science ®Google Scholar
• Sebastian L, Madhusudana SN, Ravi V, Desai A. Mycophenolic acid inhibits replication of Japanese encephalitis virus. Chemotherapy. 2011;57:56–61. doi:10.1159/000321483.
   PubMed Web of Science ®Google Scholar
• To KK, Mok KY, Chan AS, et al. Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans. J Gen Virol. 2016;97:1807–1817. doi:10.1099/jgv.0.000512.
   PubMed Web of Science ®Google Scholar
• Cho J, Yi H, Jang EY, et al. Mycophenolic mofetil, an alternative antiviral and immunomodulator for the highly pathogenic avian influenza H5N1 virus infection. Biochem Biophys Res Commun. 2017;494:298–304. doi:10.1016/j.bbrc.2017.10.037.
   PubMed Web of Science ®Google Scholar
• Cheng KW, Cheng SC, Chen WY. et al. Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015;115:9–16. doi:10.1016/j.antiviral.2014.12.011.
   PubMed Web of Science ®Google Scholar
• Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot. 1975;28:721–726.
   PubMed Web of Science ®Google Scholar
• Kim WS, Xu L, Souw D, Fang A, Demain AL. An unexpected inhibitory effect of rapamycin against germination of spores of Bacillus brevis strain Nagano. J Antibiot. 2002;55:650–654.
   PubMed Web of Science ®Google Scholar
• Wong GK, Griffith S, Kojima I, Demain AL. Antifungal activities of rapamycin and its derivatives, prolylrapamycin, 32-desmethylrapamycin, and 32-desmethoxyrapamycin. J Antibiot. 1998;51:487–491.
   PubMed Web of Science ®Google Scholar
• Bastidas RJ, Shertz CA, Lee SC, Heitman J, Cardenas ME. Rapamycin exerts antifungal activity in vitro and in vivo against Mucor circinelloides via FKBP12-dependent inhibition of Tor. Eukaryot Cell. 2012;11:270–281. doi:10.1128/EC.05284-11.
   PubMedGoogle Scholar
• van Wanrooij EJ, Happé H, Hauer AD, et al. HIV entry inhibitor TAK-779 attenuates atherogenesis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2005;25:2642–2647. doi:10.1161/01.ATV.0000192018.90021.c0.
   PubMed Web of Science ®Google Scholar
• Di Benedetto F, Di Sandro S, De Ruvo N, et al. First report on a series of HIV patients undergoing rapamycin monotherapy after liver transplantation. Transplantation. 2010;89:733–738. doi:10.1097/TP.0b013e3181c7dcc0.
   PubMed Web of Science ®Google Scholar
• Donia M, McCubrey JA, Bendtzen K, Nicoletti F. Potential use of rapamycin in HIV infection. Br J Clin Pharmacol. 2010;70:784–793. doi:10.1111/j.1365-2125.2010.03735.x.
   PubMed Web of Science ®Google Scholar
• Fang CB, Zhou DX, Zhan SX. et al. Amelioration of experimental autoimmune uveitis by leflunomide in Lewis rats. PLoS One. 2013;8:e62071. doi:10.1371/journal.pone.0062071.
   PubMed Web of Science ®Google Scholar
• Bichler J, Benseler SM, Krumrey-Langkammerer M, Haas JP, Hügle B. Leflunomide is associated with a higher flare rate compared to methotrexate in the treatment of chronic uveitis in juvenile idiopathic arthritis. Scand J Rheumatol. 2015;44:280–283. doi:10.3109/03009742.2015.1013983.
   PubMed Web of Science ®Google Scholar
• John GT, Manivannan J, Chandy S, et al. A prospective evaluation of leflunomide therapy for cytomegalovirus disease in renal transplant recipients. Transplant Proc. 2005;37:4303–4305. doi:10.1016/j.transproceed.2005.10.116.
   PubMed Web of Science ®Google Scholar
• Liacini A, Seamone ME, Muruve DA, Tibbles LA. Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection. Transplantation. 2010;90:1450–1457. doi:10.1097/TP.0b013e3182007be2.
   PubMed Web of Science ®Google Scholar
• Rifkin LM, Minkus CL, Pursell K, Jumroendararasame C, Goldstein DA. Utility of leflunomide in the treatment of drug resistant cytomegalovirus retinitis. Ocul Immunol Inflamm. 2017;25:93–96. doi:10.3109/09273948.2015.1071406.
   PubMed Web of Science ®Google Scholar
• Graziano TS, Cuzzullin MC, Franco GC, et al. Statins and antimicrobial effects: simvastatin as a potential drug against Staphylococcus aureus biofilm. PLoS One. 2015;10:e0128098. 0128098. eCollection 2015. doi:10.1371/journal.pone.
   PubMed Web of Science ®Google Scholar
• Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555:623–628. doi:10.1038/nature25979.
   PubMed Web of Science ®Google Scholar
• Suau A, Bonnet R, Sutren M. Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut. Appl Environ Microbiol. 1999;65:4799.
   PubMed Web of Science ®Google Scholar
• Gianchecchi E, Fierabracci A. Recent advances on microbiota involvement in the pathogenesis of autoimmunity. Int J Mol Sci. 2019;20:283. doi:10.3390/ijms20020283.
   Web of Science ®Google Scholar
• Zuo T, Ng SC. The gut microbiota in the pathogenesis and therapeutics of inflammatory bowel disease. Front Microbiol. 2018;9:2247. doi:10.3389/fmicb.2018.02247.
   PubMed Web of Science ®Google Scholar
• Nakamura YK, Metea C, Karstens L, et al. Gut microbial alterations associated with protection from autoimmune uveitis. Invest Ophthalmol Vis Sci. 2016;57:3747–3758. doi:10.1167/iovs.16-19733.
   PubMed Web of Science ®Google Scholar
• Horai R, Caspi R. Microbiome and autoimmune uveitis. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.00232.
   PubMed Web of Science ®Google Scholar
• Proal AD, Marshall TG. Re-framing the theory of autoimmunity in the era of the microbiome: persistent pathogens, autoantibodies and molecular mimickry. Discovery Med. 2018;25:299–308.
   PubMed Web of Science ®Google Scholar
• Zaza G, Gassa AD, Felis G, Granata S, Torriani S, Lupo A. Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: comparison between an everolimus- and a standard tacrolimus-based regimen. PLoS One. 2017;12:e0178228. doi:10.1371/journal.pone.0178228.
   PubMed Web of Science ®Google Scholar
• Tabibian JH, Kenderian SS. The microbiome and immune regulation after transplantation. Transplantation. 2017;101:56–62. doi:10.1097/TP.0000000000001588.
   PubMed Web of Science ®Google Scholar
• Wen X, Hu X, Miao L, et al. Epigenetics, microbiota, and intraocular inflammation: new paradigms of immune regulation in the eye. Prog Retin Eye Res. 2018;64:84–95. doi:10.1016/j.preteyeres.2018.01.001.
   PubMed Web of Science ®Google Scholar
• Kirstahler P, Bjerrum SS, Friis-Møller A, et al. Genomics-based identification of microorganisms in human ocular body fluid. Sci Rep. 2018;8:4126. doi:10.1038/s41598-018-22416-4.
   PubMed Web of Science ®Google Scholar