Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection
Mihai G Netea, Evangelos J Giamarellos-Bourboulis, Jorge Domínguez-Andrés, Nigel Curtis, Reinout van Crevel, Frank L van de Veerdonk, Marc Bonten, Mihai G Netea, Evangelos J Giamarellos-Bourboulis, Jorge Domínguez-Andrés, Nigel Curtis, Reinout van Crevel, Frank L van de Veerdonk, Marc Bonten
Abstract
SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.
Copyright © 2020 Elsevier Inc. All rights reserved.
Figures
References
- Arts R.J.W., Moorlag S.J.C.F.M., Novakovic B., Li Y., Wang S.-Y., Oosting M., Kumar V., Xavier R.J., Wijmenga C., Joosten L.A.B. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018;23:89–100.e5.
- Benn C.S., Netea M.G., Selin L.K., Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013;34:431–439.
- Channappanavar R., Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 2017;39:529–539.
- Dayal D., Gupta S. Connecting BCG Vaccination and COVID-19: Additional Data. MedRxiv. 2020 doi: 10.1101/2020.04.07.20053272.
- Floc’h F., Werner G.H. Increased resistance to virus infections of mice inoculated with BCG (Bacillus calmette-guérin) Ann. Immunol. (Paris) 1976;127:173–186.
- Freyne B., Marchant A., Curtis N. BCG-associated heterologous immunity, a historical perspective: intervention studies in animal models of infectious diseases. Trans. R. Soc. Trop. Med. Hyg. 2015;109:52–61.
- Giamarellos-Bourboulis E.J., Netea M.G., Rovina N., Akinosoglou K., Antoniadou A., Antonakos N., Damoraki G., Gkavogianni T., Adami M.E., Katsaounou P. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020 doi: 10.1016/j.chom.2020.04.009. Published online April 17, 2020.
- Glowacka I., Bertram S., Müller M.A., Allen P., Soilleux E., Pfefferle S., Steffen I., Tsegaye T.S., He Y., Gnirss K. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J. Virol. 2011;85:4122–4134.
- Goodridge H.S., Ahmed S.S., Curtis N., Kollmann T.R., Levy O., Netea M.G., Pollard A.J., van Crevel R., Wilson C.B. Harnessing the beneficial heterologous effects of vaccination. Nat. Rev. Immunol. 2016;16:392–400.
- Green C.M., Fanucchi S., Fok E.T., Moorlag S.J.C.F.M., Dominguez-Andres J., Negishi Y., Joosten L.A.B., Netea M.G., Mhlanga M.M. COVID-19: A model correlating BCG vaccination to protection from mortality implicates trained immunity. MedRxiv. 2020 doi: 10.1101/2020.04.10.20060905.
- Hatherill M., Geldenhuys H., Pienaar B., Suliman S., Chheng P., Debanne S.M., Hoft D.F., Boom W.H., Hanekom W.A., Johnson J.L. Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine. 2014;32:3982–3988.
- Higgins J.P.T., Soares-Weiser K., López-López J.A., Kakourou A., Chaplin K., Christensen H., Martin N.K., Sterne J.A.C., Reingold A.L. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ. 2016;355:i5170.
- Huang K.J., Su I.J., Theron M., Wu Y.C., Lai S.K., Liu C.C., Lei H.Y. An interferon-γ-related cytokine storm in SARS patients. J. Med. Virol. 2005;75:185–194.
- Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
- Ishihara C., Mizukoshi N., Iida J., Kato K., Yamamoto K., Azuma I. Suppression of Sendai virus growth by treatment with N alpha-acetylmuramyl-L-alanyl-D-isoglutaminyl-N epsilon-stearoyl-L-lysine in mice. Vaccine. 1987;5:295–301.
- Kleinnijenhuis J., Quintin J., Preijers F., Joosten L.A.B., Ifrim D.C., Saeed S., Jacobs C., van Loenhout J., de Jong D., Stunnenberg H.G. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl. Acad. Sci. USA. 2012;109:17537–17542.
- Kuba K., Imai Y., Rao S., Gao H., Guo F., Guan B., Huan Y., Yang P., Zhang Y., Deng W. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med. 2005;11:875–879.
- Kumaki Y., Salazar A.M., Wandersee M.K., Barnard D.L. Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol® (Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model. Antiviral Res. 2017;139:1–12.
- Machiels B., Dourcy M., Xiao X., Javaux J., Mesnil C., Sabatel C., Desmecht D., Lallemand F., Martinive P., Hammad H. A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 2017;18:1310–1320.
- Miller A., Reandelar M.J., Fasciglione K., Roumenova V., Li Y., Otazu G.H. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. MedRxiv. 2020 doi: 10.1101/2020.03.24.20042937.
- Mitroulis I., Ruppova K., Wang B., Chen L.S., Grzybek M., Grinenko T., Eugster A., Troullinaki M., Palladini A., Kourtzelis I. Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity. Cell. 2018;172:147–161.e12.
- Moorlag S.J.C.F.M., Arts R.J.W., van Crevel R., Netea M.G. Non-specific effects of BCG vaccine on viral infections. Clin. Microbiol. Infect. 2019;25:1473–1478.
- Mukherjee S., Subramaniam R., Chen H., Smith A., Keshava S., Shams H. Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia. PLoS ONE. 2017;12:e0180143.
- Nemes E., Geldenhuys H., Rozot V., Rutkowski K.T., Ratangee F., Bilek N., Mabwe S., Makhethe L., Erasmus M., Toefy A., C-040-404 Study Team Prevention of M. Tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N. Engl. J. Med. 2018;379:138–149.
- Netea M.G., Domínguez-Andrés J., Barreiro L.B., Chavakis T., Divangahi M., Fuchs E., Joosten L.A.B., van der Meer J.W.M., Mhlanga M.M., Mulder W.J.M. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 2020 doi: 10.1038/s41577-020-0285-6. Published online March 4, 2020.
- Nieuwenhuizen N.E., Kulkarni P.S., Shaligram U., Cotton M.F., Rentsch C.A., Eisele B., Grode L., Kaufmann S.H.E. The recombinant bacille Calmette-Guérin vaccine VPM1002: Ready for clinical efficacy testing. Front. Immunol. 2017;8:1147.
- Ohrui T., Nakayama K., Fukushima T., Chiba H., Sasaki H. [Prevention of elderly pneumonia by pneumococcal, influenza and BCG vaccinations] Nippon Ronen Igakkai Zasshi. 2005;42:34–36.
- Ong E.Z., Chan Y.F.Z., Leong W.Y., Lee N.M.Y., Kalimuddin S., Mohamed S., Mohideen H., Chan K.S., Tan A.T., Bertoletti A. A dynamic immune response shapes COVID-19 progression. Cell Host Microbe. 2020 doi: 10.1016/j.chom.2020.03.021. Published online April 30, 2020.
- Qin C., Zhou L., Hu Z., Zhang S., Yang S., Tao Y., Xie C., Ma K., Shang K., Wang W. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin. Infect. Dis. 2020 doi: 10.1093/cid/ciaa248. Published online March 12, 2020.
- Sheahan T., Morrison T.E., Funkhouser W., Uematsu S., Akira S., Baric R.S., Heise M.T. MyD88 is required for protection from lethal infection with a mouse-adapted SARS-CoV. PLoS Pathog. 2008;4:e1000240.
- Shi C.S., Nabar N.R., Huang N.N., Kehrl J.H. SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. Cell Death Discov. 2019;5:101.
- Shulla A., Heald-Sargent T., Subramanya G., Zhao J., Perlman S., Gallagher T. A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J. Virol. 2011;85:873–882.
- Spencer J.C., Ganguly R., Waldman R.H. Nonspecific protection of mice against influenza virus infection by local or systemic immunization with Bacille Calmette-Guérin. J. Infect. Dis. 1977;136:171–175.
- Starr S.E., Visintine A.M., Tomeh M.O., Nahmias A.J. Effects of immunostimulants on resistance of newborn mice to herpes simplex type 2 infection. Proc. Soc. Exp. Biol. Med. 1976;152:57–60.
- Suenaga T., Okuyama T., Yoshida I., Azuma M. Effect of Mycobacterium tuberculosis BCG infection on the resistance of mice to ectromelia virus infection: participation of interferon in enhanced resistance. Infect. Immun. 1978;20:312–314.
- Ter Horst R., Jaeger M., Smeekens S.P., Oosting M., Swertz M.A., Li Y., Kumar V., Diavatopoulos D.A., Jansen A.F.M., Lemmers H. Host and Environmental Factors Influencing Individual Human Cytokine Responses. Cell. 2016;167:1111–1124.e13.
- Thevarajan I., Nguyen T.H.O., Koutsakos M., Druce J., Caly L., van de Sandt C.E., Jia X., Nicholson S., Catton M., Cowie B. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat. Med. 2020;26:453–455.
- Totura A.L., Whitmore A., Agnihothram S., Schäfer A., Katze M.G., Heise M.T., Baric R.S. Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. MBio. 2015;6:e00638. e15.
- Wardhana D., Datau E.A., Sultana A., Mandang V.V., Jim E. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly. Acta Med. Indones. 2011;43:185–190.
- Wong C.K., Lam C.W.K., Wu A.K.L., Ip W.K., Lee N.L.S., Chan I.H.S., Lit L.C.W., Hui D.S.C., Chan M.H.M., Chung S.S.C., Sung J.J. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin. Exp. Immunol. 2004;136:95–103.
- Wu D., Yang X.O. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. J. Microbiol. Immunol. Infect. 2020 S1684-1182(20)30065-7.
- Xu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang C., Liu S., Zhao P., Liu H., Zhu L. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 2020;8:420–422.
- Yao Y., Jeyanathan M., Haddadi S., Barra N.G., Vaseghi-Shanjani M., Damjanovic D., Lai R., Afkhami S., Chen Y., Dvorkin-Gheva A. Induction of Autonomous Memory Alveolar Macrophages Requires T Cell Help and Is Critical to Trained Immunity. Cell. 2018;175:1634–1650.e17.
- Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z., Xiang J., Wang Y., Song B., Gu X. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–1062.
Source: PubMed