Advanced search
Publication Cover
Autophagy Volume 18, 2022 - Issue 7
Submit an article Journal homepage
3,019
Views
7
CrossRef citations to date
0
Altmetric
Brief Report

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

Susanna Croci1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Mary Anna Venneri3 Department of Experimental Medicine, Sapienza University of Rome, Rome, ItalyView further author information
,
Stefania Mantovani4 Division of Clinical Immunology and Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, ItalyORCID Iconhttps://orcid.org/0000-0002-5885-2842View further author information
ORCID Icon,
Chiara Fallerini1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Elisa Benetti2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Nicola Picchiotti5 DIISM-SAILAB, University of Siena, Siena, Italy;6 Department of Mathematics, University of Pavia, Pavia, ItalyView further author information
,
Federica Campolo3 Department of Experimental Medicine, Sapienza University of Rome, Rome, ItalyView further author information
,
Francesco Imperatore7 Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Core Research Laboratory, Via Fiorentina, Siena, Italy;8 Consiglio Nazionale delle Ricerche, Istituto DI Fisiologia Clinica, Siena, ItalyView further author information
,
Maria Palmieri1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Sergio Daga1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Chiara Gabbi9 Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, SwedenView further author information
,
Francesca Montagnani2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy;10 Department of Medical Sciences, Infectious and Tropical Diseases Unit, Azienda Ospedaliera Universitaria Senese, Siena, ItalyView further author information
,
Giada Beligni1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Ticiana D.J. Farias11 Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USAView further author information
,
Miriam Lucia Carriero1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Laura Di Sarno1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Diana Alaverdian1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Sigrid Aslaksen12 Department of Clinical Science, Universty of Bergen and K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, NorwayView further author information
,
Maria Vittoria Cubellis13 Department of Biology, Università Degli Studi di Napoli “Federico II”, Napoli, ItalyView further author information
,
Ottavia Spiga14 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, ItalyORCID Iconhttps://orcid.org/0000-0002-0263-7107View further author information
ORCID Icon,
Margherita Baldassarri1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Francesca Fava1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Paul J. Norman11 Division of Biomedical Informatics and Personalized Medicine, and Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USAView further author information
,
Elisa Frullanti1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Andrea M. Isidori3 Department of Experimental Medicine, Sapienza University of Rome, Rome, ItalyORCID Iconhttps://orcid.org/0000-0002-9037-5417View further author information
ORCID Icon,
Antonio Amoroso15 Department of Medical Sciences, University of Turin, Turin, Italy;16 Immunogenetics and Transplant Biology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, ItalyView further author information
,
Francesca Mari1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy;17 Genetica Medica, Azienda Ospedaliero-Universitaria Senese, ItalyView further author information
,
Simone Furini2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
,
Mario U Mondelli4 Division of Clinical Immunology and Infectious Diseases, Department of Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;18 Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, ItalyORCID Iconhttps://orcid.org/0000-0003-1811-3153View further author information
ORCID Icon,
GEN-COVID multicenter study1 Medical Genetics, University of Siena, Siena, ItalyView further author information
,
Mario Chiariello7 Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO), Core Research Laboratory, Via Fiorentina, Siena, Italy;8 Consiglio Nazionale delle Ricerche, Istituto DI Fisiologia Clinica, Siena, ItalyCorrespondence[email protected]
View further author information
,
Alessandra Renieri1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy;17 Genetica Medica, Azienda Ospedaliero-Universitaria Senese, ItalyCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0002-0846-9220View further author information
ORCID Icon &
Ilaria Meloni1 Medical Genetics, University of Siena, Siena, Italy;2 Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyView further author information
 show all
Pages 1662-1672 | Received 23 Mar 2021, Accepted 14 Oct 2021, Published online: 29 Dec 2021

References

  • Lee IH, Lee JW, Kong SW. A survey of genetic variants in SARS-CoV-2 interacting domains of ACE2, TMPRSS2 and TLR3/7/8 across populations. Infect Genet Evol. 2020;85:104507.
  • Mukherjee S, Huda S, Sinha Babu SP. Toll-like receptor polymorphism in host immune response to infectious diseases: a review. Scand J Immunol. 2019 Jul;90(1):e12771.
  • Perales-Linares R, Navas-Martin S. Toll-like receptor 3 in viral pathogenesis: friend or foe? Immunology. Immunology. 2013 Oct;140(2):153–167.
  • Totura AL, Whitmore A, Agnihothram S, et al. Toll-Like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. mBio 2015 May 26;6(3):e00638–15.
  • Matsumoto M, Oshiumi H, Seya T. Antiviral responses induced by the TLR3 pathway. Rev Med Virol. 2011 Mar;21(2):67–77.
  • Schulz O, Diebold SS, Chen M, et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature. 2005 Feb 24;433(7028):887–892.
  • Suresh MV, Dolgachev VA, Zhang B, et al. TLR3 absence confers increased survival with improved macrophage activity against pneumonia. JCI Insight. 2019 Dec 5;4(23):e131195.
  • Ranjith-Kumar CT, Miller W, Sun J, et al. Effects of single nucleotide polymorphisms on Toll-Like receptor 3 activity and expression in cultured cells. J Biol Chem. 2007 Jun 15;282(24):17696–17705.
  • Teimouri H, Maali A. Single-nucleotide polymorphisms in host pattern-recognition receptors show association with antiviral responses against SARS-CoV-2, in-silico trial. JoMMID. 2020;8(2):65–70.
  • Dhangadamajhi G, Rout R, Cavazos-Escobar E. Association of TLR3 functional variant (rs3775291) with COVID-19 susceptibility and death: a population-scale study. Hum Cell. 2021 Feb 22;34:1–3.
  • Franco LH, Fleuri AKA, Pellison NC, et al. Autophagy downstream of endosomal Toll-Like receptor signaling in macrophages is a key mechanism for resistance to Leishmania major infection. J Biol Chem. 2017 Aug 11;292(32):13087–13096.
  • Kirkin V, McEwan DG, Novak I, et al. A role for ubiquitin in selective autophagy. Mol Cell. 2009 May 15;34(3):259–269.
  • Delgado MA, Elmaoued RA, Davis AS, et al. Toll-like receptors control autophagy. EMBO J. 2008 Apr 9;27(7):1110–1121.
  • Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011 Jan 20;469(7330):323–335.
  • Prentice E, Jerome WG, Yoshimori T, et al. Coronavirus replication complex formation utilizes components of cellular autophagy. J Biol Chem. 2004 Mar 12;279(11):10136–10141.
  • Guo L, Yu H, Gu W, et al. Autophagy negatively regulates transmissible gastroenteritis virus replication. Sci Rep. 2016 Mar 31;6: 23864.
  • Carvalho-Schneider C, Laurent E, Lemaignen A, et al. Follow-up of adults with noncritical COVID-19 two months after symptom onset. Clin Microbiol Infect. 2021 Feb;27(2):258–263.
  • Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020Apr16;181(2):271–280. e8.
  • Miao Y, Fan L, Li JY. Potential treatments for COVID-19 related cytokine storm - beyond corticosteroids. Front Immunol. 2020 Jun 16;11: 1445.
  • Shojaei S, Suresh M, Klionsky DJ, et al. Autophagy and SARS-CoV-2 infection: a possible smart targeting of the autophagy pathway. Virulence. 2020 Dec;11(1):805–810.
  • Benvenuto D, Angeletti S, Giovanetti M, et al. Evolutionary analysis of SARS-CoV-2: how mutation of non-structural protein 6 (NSP6) could affect viral autophagy. J Infect. 2020 Jul;81(1):e24–e27.
  • Jamwal S, Gautam A, Elsworth J, et al. An updated insight into the molecular pathogenesis, secondary complications and potential therapeutics of COVID-19 pandemic. Life Sci. 2020 Sep 15;257: 118105.
  • Torcia MG, Nencioni L, Clemente AM, et al. Sex differences in the response to viral infections: TLR8 and TLR9 ligand stimulation induce higher IL10 production in males. PLoS One. 2012;7(6):e39853.
  • Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019 Sep 2;216(9):2038–2056.
  • Zhang Q, Bastard P, Liu Z, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020 Oct 23;370(6515):eabd4570.
  • Enkhbayar P, Kamiya M, Osaki M, et al. Structural principles of leucine-rich repeat (LRR) proteins. Proteins. 2004 Feb 15;54(3):394–403.
  • Rothberg JM, Jacobs JR, Goodman CS, et al. slit: an extracellular protein necessary for development of midline glia and commissural axon pathways contains both EGF and LRR domains. Genes Dev. 1990 Dec;4(12A):2169–2187.
  • Kobe B, Kajava AV. The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol. 2001 Dec;11(6):725–732.
  • Gao T, Zhang SP, Wang JF, et al. TLR3 contributes to persistent autophagy and heart failure in mice after myocardial infarction. J Cell Mol Med. 2018 Jan;22(1):395–408.
  • Mehra MR, Ruschitzka F, Patel AN. Retraction-Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020 Jun 13;395(10240):1820.
  • Mahase E. Covid-19: WHO halts hydroxychloroquine trial to review links with increased mortality risk. BMJ 2020 May 28;369: m2126.
  • Ayele Mega T, Feyissa TM, Dessalegn Bosho D, et al. The outcome of hydroxychloroquine in patients treated for COVID-19: systematic review and meta-analysis. Can Respir J. 2020 Oct 13;2020: 4312519.
  • Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy 2021 Feb;8:1–382.
  • Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017 Sep;179:528–542. [ Epub 2017 Jul 28]. PMID: 28751651; PMCID: PMC5975367.
  • Michalakis K, Ilias I. SARS-CoV-2 infection and obesity: common inflammatory and metabolic aspects. Diabetes Metab Syndr. 2020 Jul-Aug;14(4):469–471.
  • Vomero M, Barbati C, Colasanti T, et al. Autophagy modulation in lymphocytes from COVID-19 patients: new therapeutic target in SARS-COV-2 infection. Front Pharmacol. 2020 Nov 19;11: 569849.
  • Jang CH, Choi JH, Byun MS, et al. Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology (Oxford). 2006 Jun;45(6):703–710.
  • Hayn M, Hirschenberger M, Koepke L, et al. Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities. Cell Rep. 2021 May 18;357:109126. [ Epub 2021 Apr 27]. PMID: 33974846; PMCID: PMC8078906.
  • Nahum A, Dadiac H, Batesac A, et al. The biological significance of TLR3 variant, L412F, in conferring susceptibility to cutaneous candidiasis, CMV and autoimmunity. Autoimmun Rev. 2012 Mar;11(5):341–347.
  • Aslaksen S, Wolff AB, Vigeland MD, et al. Identification and characterization of rare toll-like receptor 3 variants in patients with autoimmune Addison’s disease. J Transl Autoimmun. 2019 May 28;1:100005.
  • Wu DJ, Adamopoulos IE. Autophagy and autoimmunity. Clin Immunol. 2017Mar;176:55–62.
  • Caza TN, Talaber G, Perl A. Metabolic regulation of organelle homeostasis in lupus T cells. Clin Immunol. 2012 Sep;144(3):200–213.
  • Keller CW, Lünemann JD. Autophagy and autophagy-related proteins in CNS autoimmunity. Front Immunol. 2017 Feb 27;8: 165.
  • De Sousa E, Ligeiro D, Lérias JR, et al. Mortality in COVID-19 disease patients: correlating the association of major histocompatibility complex (MHC) with severe acute respiratory syndrome 2 (SARS-CoV-2) variants. Int J Infect Dis. 2020 Sep;98:454–459. Epub 2020 Jul 18.
  • Erichsen MM, Løvås K, Skinningsrud B, et al. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab. 2009 Dec;94(12):4882–4890.
  • Smigoc Schweiger D, Mendez A, Kunilo Jamnik S, et al. High-risk genotypes HLA-DR3-DQ2/DR3-DQ2 and DR3-DQ2/DR4-DQ8 in co-occurrence of type 1 diabetes and celiac disease. Autoimmunity. 2016 Jun;49(4):240–247.
  • Daga S, Fallerini C, Baldassarri M, et al. Employing a systematic approach to biobanking and analyzing clinical and genetic data for advancing COVID-19 research. Eur J Hum Genet. 2021 Jan;17:1–15.
  • Molnar R. Interpretable machine learning. A guide for making black box models explainable. 2020. lulu.com.
  • Tibshirani R. Regression shrinkage and selection via the Lasso. Journal of the Royal Statistical Society: Series B (Methodological). 1996;58(1):267–288.
  • Norman PJ, Hollenbach JA, Nemat-Gorgani N, et al. Defining KIR and HLA Class I genotypes at highest resolution via high-throughput sequencing. Am J Hum Genet. 2016 Aug 4;99(2):375–391.
  • Dilthey AT, Mentzer AJ, Carapito R, et al. HLA*LA-HLA typing from linearly projected graph alignments. Bioinformatics. 2019 Nov 1;35(21):4394–4396.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.