Toll-like receptor dual-acting agonists are potent inducers of PBMC-produced cytokines that inhibit hepatitis B virus production in primary human hepatocytes.

Culture Media, Conditioned / pharmacology Cytokines / metabolism DNA, Circular / metabolism Drug Delivery Systems Hep G2 Cells Hepatitis B virus / physiology Hepatitis B, Chronic / virology Hepatocytes / virology Humans Immunity, Innate / drug effects Interferon-alpha / metabolism Leukocytes, Mononuclear / metabolism Toll-Like Receptors / agonists Virus Replication / drug effects

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
29 07 2020
Historique:
received: 28 01 2020
accepted: 09 07 2020
entrez: 31 7 2020
pubmed: 31 7 2020
medline: 14 1 2021
Statut: epublish

Résumé

Recombinant interferon-α (IFN-α) treatment functionally cures chronic hepatitis B virus (HBV) infection in some individuals and suppresses virus replication in hepatocytes infected in vitro. We studied the antiviral effect of conditioned media (CM) from peripheral blood mononuclear cells (PBMCs) stimulated with agonists of Toll-like receptors (TLRs) 2, 7, 8 and 9. We found that CM from PBMCs stimulated with dual-acting TLR7/8 (R848) and TLR2/7 (CL413) agonists were more potent drivers of inhibition of HBe and HBs antigen secretion from HBV-infected primary human hepatocytes (PHH) than CM from PBMCs stimulated with single-acting TLR7 (CL264) or TLR9 (CpG-B) agonists. Inhibition of HBV in PHH did not correlate with the quantity of PBMC-produced IFN-α, but it was a complex function of multiple secreted cytokines. More importantly, we found that the CM that efficiently inhibited HBV production in freshly isolated PHH via various cytokine repertoires and mechanisms did not reduce covalently closed circular (ccc)DNA levels. We confirmed our data with a cell culture model based on HepG2-NTCP cells and the plasmacytoid dendritic cell line GEN2.2. Collectively, our data show the importance of dual-acting TLR agonists inducing broad cytokine repertoires. The development of poly-specific TLR agonists provides novel opportunities towards functional HBV cure.

Identifiants

DOI: 10.1038/s41598-020-69614-7 PMID: 32728070 PMC: PMC7392756
pubmed: 32728070
doi: 10.1038/s41598-020-69614-7
pii: 10.1038/s41598-020-69614-7
pmc: PMC7392756
doi:

Substances chimiques

Culture Media, Conditioned 0
Cytokines 0
DNA, Circular 0
Interferon-alpha 0
Toll-Like Receptors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

12767

Références

Wieland, S., Thimme, R., Purcell, R. H. & Chisari, F. V. Genomic analysis of the host response to hepatitis B virus infection. Proc. Natl. Acad. Sci. U.S.A. 101, 6669–6674. https://doi.org/10.1073/pnas.0401771101 (2004).
doi: 10.1073/pnas.0401771101 pubmed: 15100412 pmcid: 404103
Dunn, C. et al. Temporal analysis of early immune responses in patients with acute hepatitis B virus infection. Gastroenterology 137, 1289–1300. https://doi.org/10.1053/j.gastro.2009.06.054 (2009).
doi: 10.1053/j.gastro.2009.06.054 pubmed: 19591831
El-Serag, H. B. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142, 1264–1273. https://doi.org/10.1053/j.gastro.2011.12.061 (2012).
doi: 10.1053/j.gastro.2011.12.061 pubmed: 22537432 pmcid: 3338949
European Association for the Study of the Liver. Electronic address, e. e. e. & European Association for the Study of the, L. EASL. Clinical Practice guidelines on the management of hepatitis B virus infection. J. Hepatol. 67(370–398), 2017. https://doi.org/10.1016/j.jhep.2017.03.021 (2017).
doi: 10.1016/j.jhep.2017.03.021
Trepo, C., Chan, H. L. & Lok, A. Hepatitis B virus infection. Lancet 384, 2053–2063. https://doi.org/10.1016/S0140-6736(14)60220-8 (2014).
doi: 10.1016/S0140-6736(14)60220-8
Lok, A. S., Zoulim, F., Dusheiko, G. & Ghany, M. G. Hepatitis B cure: From discovery to regulatory approval. Hepatology 66, 1296–1313. https://doi.org/10.1002/hep.29323 (2017).
doi: 10.1002/hep.29323 pubmed: 28762522 pmcid: 6294322
Zoulim, F., Lebosse, F. & Levrero, M. Current treatments for chronic hepatitis B virus infections. Curr. Opin. Virol. 18, 109–116. https://doi.org/10.1016/j.coviro.2016.06.004 (2016).
doi: 10.1016/j.coviro.2016.06.004 pubmed: 27318098
Belloni, L. et al. IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J. Clin. Investig. 122, 529–537. https://doi.org/10.1172/JCI58847 (2012).
doi: 10.1172/JCI58847 pubmed: 22251702
Lucifora, J. et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 343, 1221–1228. https://doi.org/10.1126/science.1243462 (2014).
doi: 10.1126/science.1243462 pubmed: 24557838 pmcid: 6309542
Xia, Y. et al. Interferon-gamma and tumor necrosis factor-alpha produced by T cells reduce the HBV persistence form, cccDNA without cytolysis A. Gastroenterology 150, 194–205. https://doi.org/10.1053/j.gastro.2015.09.026 (2016).
doi: 10.1053/j.gastro.2015.09.026 pubmed: 26416327
Bockmann, J. H. et al. Comparative analysis of the antiviral effects mediated by type I and III Interferons in Hepatitis B virus-infected Hepatocytes. J. Infect. Dis. 220, 567–577. https://doi.org/10.1093/infdis/jiz143 (2019).
doi: 10.1093/infdis/jiz143 pubmed: 30923817
Suslov, A., Boldanova, T., Wang, X., Wieland, S. & Heim, M. H. Hepatitis B virus does not interfere with innate immune responses in the human liver. Gastroenterology 154, 1778–1790. https://doi.org/10.1053/j.gastro.2018.01.034 (2018).
doi: 10.1053/j.gastro.2018.01.034 pubmed: 29408639
Xia, Y. et al. Secreted interferon-inducible factors restrict Hepatitis B and C virus entry in vitro. J. Immunol. Res. 2017, 4828936. https://doi.org/10.1155/2017/4828936 (2017).
doi: 10.1155/2017/4828936 pubmed: 28367455 pmcid: 5358466
Park, I. H., Baek, K. W., Cho, E. Y. & Ahn, B. Y. PKR-dependent mechanisms of interferon-alpha for inhibiting hepatitis B virus replication. Mol. Cells 32, 167–172. https://doi.org/10.1007/s10059-011-1059-6 (2011).
doi: 10.1007/s10059-011-1059-6 pubmed: 21710204 pmcid: 3887671
Yan, R. et al. The Interferon-inducible protein tetherin Inhibits Hepatitis B virus virion secretion. J. Virol. 89, 9200–9212. https://doi.org/10.1128/JVI.00933-15 (2015).
doi: 10.1128/JVI.00933-15 pubmed: 26109732 pmcid: 4542364
Isorce, N. et al. Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus. Antivir. Res. 130, 36–45. https://doi.org/10.1016/j.antiviral.2016.03.008 (2016).
doi: 10.1016/j.antiviral.2016.03.008 pubmed: 26971407
Xia, Y. & Protzer, U. Control of Hepatitis B virus by cytokines. Viruses 9, 18. https://doi.org/10.3390/v9010018 (2017).
doi: 10.3390/v9010018 pmcid: 5294987
Hosel, M. et al. Not interferon, but interleukin-6 controls early gene expression in hepatitis B virus infection. Hepatology 50, 1773–1782. https://doi.org/10.1002/hep.23226 (2009).
doi: 10.1002/hep.23226 pubmed: 19937696
Valaydon, Z. et al. The role of tumour necrosis factor in hepatitis B infection: Jekyll and Hyde. Clin. Transl. Immunol. 5, e115. https://doi.org/10.1038/cti.2016.68 (2016).
doi: 10.1038/cti.2016.68
Lanford, R. E. et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 144, 1508–1517. https://doi.org/10.1053/j.gastro.2013.02.003 (2013).
doi: 10.1053/j.gastro.2013.02.003 pubmed: 23415804 pmcid: 3691056
Meng, Z. et al. Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection. Antivir. Res. 125, 14–24. https://doi.org/10.1016/j.antiviral.2015.11.001 (2016).
doi: 10.1016/j.antiviral.2015.11.001 pubmed: 26585244
Menne, S. et al. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B. J. Hepatol. 62, 1237–1245. https://doi.org/10.1016/j.jhep.2014.12.026 (2015).
doi: 10.1016/j.jhep.2014.12.026 pubmed: 25559326 pmcid: 4439359
Lucifora, J. et al. Direct antiviral properties of TLR ligands against HBV replication in immune-competent hepatocytes. Sci. Rep. 8, 5390. https://doi.org/10.1038/s41598-018-23525-w (2018).
doi: 10.1038/s41598-018-23525-w pubmed: 29599452 pmcid: 5876392
Niu, C. et al. Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism. J. Hepatol. 68, 922–931. https://doi.org/10.1016/j.jhep.2017.12.007 (2018).
doi: 10.1016/j.jhep.2017.12.007 pubmed: 29247725
Faure-Dupuy, S. et al. Characterization of pattern recognition receptor expression and functionality in liver primary cells and derived cell lines. J. Innate Immun. 10, 1–10. https://doi.org/10.1159/000489966 (2018).
doi: 10.1159/000489966
Janovec, V. et al. The MEK1/2-ERK pathway inhibits type I IFN production in plasmacytoid dendritic cells. Front. Immunol. 9, 364. https://doi.org/10.3389/fimmu.2018.00364 (2018).
doi: 10.3389/fimmu.2018.00364 pubmed: 29535732 pmcid: 5835309
Florentin, J. et al. HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells. Blood 120, 4544–4551. https://doi.org/10.1182/blood-2012-02-413286 (2012).
doi: 10.1182/blood-2012-02-413286 pubmed: 23053572
Bao, M. & Liu, Y. J. Regulation of TLR7/9 signaling in plasmacytoid dendritic cells. Protein Cell 4, 40–52. https://doi.org/10.1007/s13238-012-2104-8 (2013).
doi: 10.1007/s13238-012-2104-8 pubmed: 23132256
Swiecki, M. & Colonna, M. The multifaceted biology of plasmacytoid dendritic cells. Nat. Rev. Immunol. 15, 471–485. https://doi.org/10.1038/nri3865 (2015).
doi: 10.1038/nri3865 pubmed: 26160613 pmcid: 4808588
Hirsch, I., Caux, C., Hasan, U., Bendriss-Vermare, N. & Olive, D. Impaired Toll-like receptor 7 and 9 signaling: from chronic viral infections to cancer. Trends Immunol. 31, 391–397. https://doi.org/10.1016/j.it.2010.07.004 (2010).
doi: 10.1016/j.it.2010.07.004 pubmed: 20832362
Luangsay, S. et al. Expression and functionality of toll- and RIG-like receptors in HepaRG cells. J. Hepatol. 63, 1077–1085. https://doi.org/10.1016/j.jhep.2015.06.022 (2015).
doi: 10.1016/j.jhep.2015.06.022 pubmed: 26144659
Aillot, L. et al. Interaction between toll-like receptor 9-CpG oligodeoxynucleotides and Hepatitis B Virus virions leads to entry inhibition in hepatocytes and reduction of alpha interferon production by plasmacytoid dendritic cells. Antimicrob. Agents Chemother. https://doi.org/10.1128/AAC.01741-17 (2018).
doi: 10.1128/AAC.01741-17 pubmed: 29439958 pmcid: 5913918
Mullins, S. R. et al. Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies. J. Immunother. Cancer 7, 244. https://doi.org/10.1186/s40425-019-0724-8 (2019).
doi: 10.1186/s40425-019-0724-8 pubmed: 31511088 pmcid: 6739946
Surendran, N., Simmons, A. & Pichichero, M. E. TLR agonist combinations that stimulate Th type I polarizing responses from human neonates. Innate Immun. 24, 240–251. https://doi.org/10.1177/1753425918771178 (2018).
doi: 10.1177/1753425918771178 pubmed: 29673285 pmcid: 6830928
Macedo, A. B. et al. Dual TLR2 and TLR7 agonists as HIV latency-reversing agents. JCI Insight https://doi.org/10.1172/jci.insight.122673 (2018).
doi: 10.1172/jci.insight.122673 pubmed: 30282829 pmcid: 6237480
Fosdick, A. et al. Pharmacokinetic and pharmacodynamic properties of GS-9620, a novel Toll-like receptor 7 agonist, demonstrate interferon-stimulated gene induction without detectable serum interferon at low oral doses. J. Pharmacol. Exp. Ther. 348, 96–105. https://doi.org/10.1124/jpet.113.207878 (2014).
doi: 10.1124/jpet.113.207878 pubmed: 24133297
Dental, C. et al. Hepatitis C virus fails to activate NF-kappaB signaling in plasmacytoid dendritic cells. J. Virol. 86, 1090–1096. https://doi.org/10.1128/JVI.05444-11(2011) (2011).
doi: 10.1128/JVI.05444-11(2011) pubmed: 22090103
Mitchell, A. M. et al. Transmitted/founder hepatitis C viruses induce cell-type- and genotype-specific differences in innate signaling within the liver. MBio 6, e02510. https://doi.org/10.1128/mBio.02510-14 (2015).
doi: 10.1128/mBio.02510-14 pubmed: 25714713 pmcid: 4357998
Aouar, B. et al. Dual role of the tyrosine kinase Syk in regulation of toll-like receptor signaling in plasmacytoid dendritic cells. PLoS ONE 11, e0156063. https://doi.org/10.1371/journal.pone.0156063 (2016).
doi: 10.1371/journal.pone.0156063 pubmed: 27258042 pmcid: 4892542
Chaperot, L. et al. Virus or TLR agonists induce TRAIL-mediated cytotoxic activity of plasmacytoid dendritic cells. J. Immunol. 176, 248–255 (2006).
doi: 10.4049/jimmunol.176.1.248
Jurk, M. et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol. 3, 499 (2002).
doi: 10.1038/ni0602-499
Leifer, C. A. & Medvedev, A. E. Molecular mechanisms of regulation of Toll-like receptor signaling. J. Leukoc. Biol. 100, 927–941. https://doi.org/10.1189/jlb.2MR0316-117RR (2016).
doi: 10.1189/jlb.2MR0316-117RR pubmed: 27343013 pmcid: 5069093
Liu, Y. J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005).
doi: 10.1146/annurev.immunol.23.021704.115633
de Marcken, M., Dhaliwal, K., Danielsen, A. C., Gautron, A. S. & Dominguez-Villar, M. TLR7 and TLR8 activate distinct pathways in monocytes during RNA virus infection. Sci. Signal. https://doi.org/10.1126/scisignal.aaw1347 (2019).
doi: 10.1126/scisignal.aaw1347 pubmed: 31662487
Agarwal, K. et al. Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. J. Viral. Hepat. 25, 1331–1340. https://doi.org/10.1111/jvh.12942 (2018).
doi: 10.1111/jvh.12942 pubmed: 29851204
Janssen, H. L. A. et al. Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. J. Hepatol. 68, 431–440. https://doi.org/10.1016/j.jhep.2017.10.027 (2018).
doi: 10.1016/j.jhep.2017.10.027 pubmed: 29104121
Lawitz, E. et al. Safety, pharmacokinetics and pharmacodynamics of the oral toll-like receptor 7 agonist GS-9620 in treatment-naive patients with chronic hepatitis C. Antivir. Ther. 20, 699–708. https://doi.org/10.3851/IMP2845 (2015).
doi: 10.3851/IMP2845 pubmed: 25105516
Scheiermann, J. & Klinman, D. M. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer. Vaccine 32, 6377–6389. https://doi.org/10.1016/j.vaccine.2014.06.065 (2014).
doi: 10.1016/j.vaccine.2014.06.065 pubmed: 24975812 pmcid: 4252359
Laino, J. et al. Targeting of immune cells by dual TLR2/7 ligands suppresses features of allergic Th2 immune responses in mice. J. Immunol. Res. 2017, 7983217. https://doi.org/10.1155/2017/7983217 (2017).
doi: 10.1155/2017/7983217 pubmed: 29204451 pmcid: 5674512
Lubyova, B. et al. PRMT5: a novel regulator of hepatitis B virus replication and an arginine methylase of HBV core. PLoS ONE 12, e0186982. https://doi.org/10.1371/journal.pone.0186982 (2017).
doi: 10.1371/journal.pone.0186982 pubmed: 29065155 pmcid: 5655436
David, P. et al. Metabolic capacities in cultured human hepatocytes obtained by a new isolating procedure from non-wedge small liver biopsies. Hum. Exp. Toxicol. 17, 544–553. https://doi.org/10.1177/096032719801701004 (1998).
doi: 10.1177/096032719801701004 pubmed: 9821017
Gondois-Rey, F. et al. Hepatitis C virus is a weak inducer of interferon alpha in plasmacytoid dendritic cells in comparison with influenza and human herpesvirus type-1. PLoS ONE 4, e4319 (2009).
doi: 10.1371/journal.pone.0004319

Auteurs

Vaclav Janovec (V)

Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25150, Vestec, Czech Republic.
IOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, 16610, Prague, Czech Republic.

Jan Hodek (J)

IOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, 16610, Prague, Czech Republic.

Kamila Clarova (K)

IOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, 16610, Prague, Czech Republic.

Tomas Hofman (T)

Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25150, Vestec, Czech Republic.
IOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, 16610, Prague, Czech Republic.

Pavel Dostalik (P)

Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25150, Vestec, Czech Republic.

Jiri Fronek (J)

Transplantation Surgery Department, Institute for Clinical and Experimental Medicine, 14021, Prague, Czech Republic.
Department of Anatomy, Second Faculty of Medicine, Charles University, 15006, Prague, Czech Republic.

Jaroslav Chlupac (J)

Transplantation Surgery Department, Institute for Clinical and Experimental Medicine, 14021, Prague, Czech Republic.
Department of Anatomy, Second Faculty of Medicine, Charles University, 15006, Prague, Czech Republic.

Laurence Chaperot (L)

CNRS UMR5309, Inserm U1209, CHU Grenoble Alpes, IAB, EFS, Université Grenoble Alpes, 38000, Grenoble, France.

Sarah Durand (S)

Inserm, Institut de Recherche Sur Les Maladies Virales Et Hepatiques UMRS 1110, Universite de Strasbourg, 67000, Strasbourg, France.

Thomas F Baumert (TF)

Inserm, Institut de Recherche Sur Les Maladies Virales Et Hepatiques UMRS 1110, Universite de Strasbourg, 67000, Strasbourg, France.
Pole Hepato-Digestif, Institut Hospitalo-Universitaire, Hopitaux Universitaires de Strasbourg, 67000, Strasbourg, France.

Iva Pichova (I)

IOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, 16610, Prague, Czech Republic.

Barbora Lubyova (B)

IOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, 16610, Prague, Czech Republic.

Ivan Hirsch (I)

Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25150, Vestec, Czech Republic. hirschi@natur.cuni.cz.
IOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, 16610, Prague, Czech Republic. hirschi@natur.cuni.cz.
Institute of Molecular Genetics of the Czech Academy of Sciences, 14220, Prague, Czech Republic. hirschi@natur.cuni.cz.
ORCID: 0000-0003-1701-1438

Jan Weber (J)

IOCB & Gilead Research Center, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Science, 16610, Prague, Czech Republic. weber@uochb.cas.cz.
ORCID: 0000-0002-2799-7352

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Équipement et fournitures › Milieux de culture › Milieux de culture conditionnés › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Conformation d'acide nucléique › ADN circulaire › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Systèmes de délivrance de médicaments › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Cellules HepG2 › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Virus › Virus de l'hépatite › Hepadnaviridae › Orthohepadnavirus › Virus de l'hépatite B › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Hépatite chronique › Hépatite B chronique › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Immunité innée › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interférons › Interféron de type I › Interféron alpha › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs de reconnaissance de motifs moléculaires › Récepteurs de type Toll › Toll-like receptor dual-acting agonists are...
questionsmedicales.fr › Phénomènes microbiologiques › Phénomènes physiologiques viraux › Réplication virale › Toll-like receptor dual-acting agonists are...