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3. Group 2 ITI Consensus Report: Technological developments in implant prosthetics

Author

Derksen, W., primary, Joda, T., additional, Chantler, J., additional, Fehmer, V., additional, Gallucci, G. O., additional, Gierthmuehlen, P. C., additional, Ioannidis, A., additional, Karasan, D., additional, Lanis, A., additional, Pala, K., additional, Pjetursson, B. E., additional, Roccuzzo, M., additional, Sailer, I., additional, Strauss, F. J., additional, Sun, T. C., additional, Wolfart, S., additional, and Zitzmann, N. U., additional

Published
2023
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5. Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors.

Author

Boby, M.L., Fearon, D., Ferla, M., Filep, M., Koekemoer, L., Robinson, M.C., Chodera, J.D., Lee, A.A., London, N., Delft, A. von, Delft, F. von, Achdout, H., Aimon, A., Alonzi, D.S., Arbon, R., Aschenbrenner, J.C., Balcomb, B.H., Bar-David, E., Barr, H., Ben-Shmuel, A., Bennett, J., Bilenko, V.A., Borden, B., Boulet, P., Bowman, G.R., Brewitz, L., Brun, J., Bvnbs, S., Calmiano, M., Carbery, A., Carney, D.W., Cattermole, E., Chang, E., Chernyshenko, E., Clyde, A., Coffland, J.E., Cohen, G., Cole, J.C., Contini, A., Cox, L., Croll, T.I., Cvitkovic, M., Jonghe, S. De, Dias, A., Donckers, K., Dotson, D.L., Douangamath, A., Duberstein, S., Dudgeon, T., Dunnett, L.E., Eastman, P., Erez, N., Eyermann, C.J., Fairhead, M., Fate, G., Fedorov, O., Fernandes, R.S., Ferrins, L., Foster, R., Foster, H., Fraisse, L., Gabizon, R., García-Sastre, A., Gawriljuk, V.O., Gehrtz, P., Gileadi, C., Giroud, C., Glass, W.G., Glen, R.C., Glinert, I., Godoy, A.S., Gorichko, M., Gorrie-Stone, T., Griffen, E.J., Haneef, A., Hassell Hart, S, Heer, J., Henry, M., Hill, M., Horrell, S., Huang, Q.Y.J., Huliak, V.D., Hurley, M.F.D., Israely, T., Jajack, A., Jansen, J, Jnoff, E., Jochmans, D., John, T., Kaminow, B., Kang, L., Kantsadi, A.L., Kenny, P.W., Kiappes, J.L., Kinakh, S.O., Kovar, B., Krojer, T., La, V.N.T., Laghnimi-Hahn, S., Lefker, B.A., Levy, H., Lithgo, R.M., Logvinenko, I.G., Lukacik, P., Macdonald, H.B., MacLean, E.M., Makower, L.L., Malla, T.R., Marples, P.G., Matviiuk, T., McCorkindale, W., McGovern, B.L., Melamed, S., Melnykov, K.P., Michurin, O., Miesen, P., Mikolajek, H., Milne, B.F., Minh, D., Morris, A., Morris, G.M., Morwitzer, M.J., Moustakas, D., Mowbray, C.E., Nakamura, A.M., Neto, J.B., Neyts, J., Nguyen, L, Noske, G.D., Oleinikovas, V., Oliva, G., Overheul, G.J., Owen, C.D., Pai, R., Pan, J., Paran, N., Payne, A.M., Perry, B., Pingle, M., Pinjari, J., Politi, B., Powell, A., Pšenák, V., Pulido, I., Puni, R., Rangel, V.L., Reddi, R.N., Rees, P., Reid, S.P., Reid, L., Resnick, E., Ripka, E.G., Robinson, R.P., Rodriguez-Guerra, J., Rosales, R., Rufa, D.A., Saar, K., Saikatendu, K.S., Salah, E., Schaller, D., Scheen, J., Schiffer, C.A., Schofield, C.J., Shafeev, M., Shaikh, A., Shaqra, A.M., Shi, J., Shurrush, K., Singh, S., Sittner, A., Sjö, P., Skyner, R., Smalley, A., Smeets, B., Smilova, M.D., Solmesky, L.J., Spencer, J., Strain-Damerell, C., Swamy, V., Tamir, H., Taylor, J.C., Tennant, R.E., Thompson, W., Thompson, A., Tomásio, S., Tomlinson, C.W.E., Tsurupa, I.S., Tumber, A., Vakonakis, I., Rij, R.P. van, Vangeel, L., Varghese, F.S., Vaschetto, M., Vitner, E.B., Voelz, V., Volkamer, A., Walsh, M.A., Ward, W., Weatherall, C., Weiss, S., White, K.M., Wild, C.F., Witt, K.D., Wittmann, M., Wright, N., Yahalom-Ronen, Y., Yilmaz, N.K., Zaidmann, D., Zhang, I., Zidane, H., Zitzmann, N., Zvornicanin, S.N., Boby, M.L., Fearon, D., Ferla, M., Filep, M., Koekemoer, L., Robinson, M.C., Chodera, J.D., Lee, A.A., London, N., Delft, A. von, Delft, F. von, Achdout, H., Aimon, A., Alonzi, D.S., Arbon, R., Aschenbrenner, J.C., Balcomb, B.H., Bar-David, E., Barr, H., Ben-Shmuel, A., Bennett, J., Bilenko, V.A., Borden, B., Boulet, P., Bowman, G.R., Brewitz, L., Brun, J., Bvnbs, S., Calmiano, M., Carbery, A., Carney, D.W., Cattermole, E., Chang, E., Chernyshenko, E., Clyde, A., Coffland, J.E., Cohen, G., Cole, J.C., Contini, A., Cox, L., Croll, T.I., Cvitkovic, M., Jonghe, S. De, Dias, A., Donckers, K., Dotson, D.L., Douangamath, A., Duberstein, S., Dudgeon, T., Dunnett, L.E., Eastman, P., Erez, N., Eyermann, C.J., Fairhead, M., Fate, G., Fedorov, O., Fernandes, R.S., Ferrins, L., Foster, R., Foster, H., Fraisse, L., Gabizon, R., García-Sastre, A., Gawriljuk, V.O., Gehrtz, P., Gileadi, C., Giroud, C., Glass, W.G., Glen, R.C., Glinert, I., Godoy, A.S., Gorichko, M., Gorrie-Stone, T., Griffen, E.J., Haneef, A., Hassell Hart, S, Heer, J., Henry, M., Hill, M., Horrell, S., Huang, Q.Y.J., Huliak, V.D., Hurley, M.F.D., Israely, T., Jajack, A., Jansen, J, Jnoff, E., Jochmans, D., John, T., Kaminow, B., Kang, L., Kantsadi, A.L., Kenny, P.W., Kiappes, J.L., Kinakh, S.O., Kovar, B., Krojer, T., La, V.N.T., Laghnimi-Hahn, S., Lefker, B.A., Levy, H., Lithgo, R.M., Logvinenko, I.G., Lukacik, P., Macdonald, H.B., MacLean, E.M., Makower, L.L., Malla, T.R., Marples, P.G., Matviiuk, T., McCorkindale, W., McGovern, B.L., Melamed, S., Melnykov, K.P., Michurin, O., Miesen, P., Mikolajek, H., Milne, B.F., Minh, D., Morris, A., Morris, G.M., Morwitzer, M.J., Moustakas, D., Mowbray, C.E., Nakamura, A.M., Neto, J.B., Neyts, J., Nguyen, L, Noske, G.D., Oleinikovas, V., Oliva, G., Overheul, G.J., Owen, C.D., Pai, R., Pan, J., Paran, N., Payne, A.M., Perry, B., Pingle, M., Pinjari, J., Politi, B., Powell, A., Pšenák, V., Pulido, I., Puni, R., Rangel, V.L., Reddi, R.N., Rees, P., Reid, S.P., Reid, L., Resnick, E., Ripka, E.G., Robinson, R.P., Rodriguez-Guerra, J., Rosales, R., Rufa, D.A., Saar, K., Saikatendu, K.S., Salah, E., Schaller, D., Scheen, J., Schiffer, C.A., Schofield, C.J., Shafeev, M., Shaikh, A., Shaqra, A.M., Shi, J., Shurrush, K., Singh, S., Sittner, A., Sjö, P., Skyner, R., Smalley, A., Smeets, B., Smilova, M.D., Solmesky, L.J., Spencer, J., Strain-Damerell, C., Swamy, V., Tamir, H., Taylor, J.C., Tennant, R.E., Thompson, W., Thompson, A., Tomásio, S., Tomlinson, C.W.E., Tsurupa, I.S., Tumber, A., Vakonakis, I., Rij, R.P. van, Vangeel, L., Varghese, F.S., Vaschetto, M., Vitner, E.B., Voelz, V., Volkamer, A., Walsh, M.A., Ward, W., Weatherall, C., Weiss, S., White, K.M., Wild, C.F., Witt, K.D., Wittmann, M., Wright, N., Yahalom-Ronen, Y., Yilmaz, N.K., Zaidmann, D., Zhang, I., Zidane, H., Zitzmann, N., and Zvornicanin, S.N.

Abstract

Item does not contain fulltext, We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.

Published
2023

6. Group 2 ITI Consensus Report: Technological developments in implant prosthetics

Author

Derksen, W; https://orcid.org/0000-0002-1612-6068, Joda, T; https://orcid.org/0000-0002-1338-5419, Chantler, J; https://orcid.org/0000-0001-8527-9941, Fehmer, V, Gallucci, G O; https://orcid.org/0000-0001-6386-594X, Gierthmuehlen, P C, Ioannidis, A; https://orcid.org/0000-0002-2110-3645, Karasan, D; https://orcid.org/0000-0003-4631-2053, Lanis, A, Pala, K, Pjetursson, B E; https://orcid.org/0000-0001-8141-6427, Roccuzzo, M; https://orcid.org/0000-0002-2135-6503, Sailer, I; https://orcid.org/0000-0002-4537-7624, Strauss, F J; https://orcid.org/0000-0002-5832-7327, Sun, T C; https://orcid.org/0000-0001-8851-1152, Wolfart, S; https://orcid.org/0000-0003-2111-3250, Zitzmann, N U; https://orcid.org/0000-0002-8228-6545, Derksen, W; https://orcid.org/0000-0002-1612-6068, Joda, T; https://orcid.org/0000-0002-1338-5419, Chantler, J; https://orcid.org/0000-0001-8527-9941, Fehmer, V, Gallucci, G O; https://orcid.org/0000-0001-6386-594X, Gierthmuehlen, P C, Ioannidis, A; https://orcid.org/0000-0002-2110-3645, Karasan, D; https://orcid.org/0000-0003-4631-2053, Lanis, A, Pala, K, Pjetursson, B E; https://orcid.org/0000-0001-8141-6427, Roccuzzo, M; https://orcid.org/0000-0002-2135-6503, Sailer, I; https://orcid.org/0000-0002-4537-7624, Strauss, F J; https://orcid.org/0000-0002-5832-7327, Sun, T C; https://orcid.org/0000-0001-8851-1152, Wolfart, S; https://orcid.org/0000-0003-2111-3250, and Zitzmann, N U; https://orcid.org/0000-0002-8228-6545

Abstract

Objectives Group‐2 reviewed the scientific evidence in the field of «Technology». Focused research questions were: (1) additive versus subtractive manufacturing of implant restorations; (2) survival, complications, and esthetics comparing prefabricated versus customized abutments; and (3) survival of posterior implant‐supported multi‐unit fixed dental prostheses.Materials and MethodsLiterature was systematically screened, and 67 publications could be critically reviewed following PRISMA guidelines, resulting in three systematic reviews. Consensus statements were presented to the plenary where after modification, those were accepted.ResultsAdditively fabricated implant restorations of zirconia and polymers were investigated for marginal/internal adaptation and mechanical properties without clear results in favor of one technology or material. Titanium base abutments for screw‐retained implant single crowns compared to customized abutments did not show significant differences concerning 1‐year survival. PFM, veneered and monolithic zirconia implant‐supported multi‐unit posterior fixed dental prostheses demonstrated similar high 3‐year survival rates, whereas veneered restorations exhibited the highest annual ceramic fracture and chipping rates.ConclusionsFor interim tooth‐colored implant single crowns both additive and subtractive manufacturing are viable techniques. The clinical performance of additively produced restorations remains to be investigated. Implant single crowns on titanium base abutments show similar clinical performance compared to other type of abutments; however, long‐term clinical data from RCTs are needed. The abutment selection should be considered already during the planning phase. Digital planning facilitates 3D visualization of the prosthetic design including abutment selection. In the posterior area, monolithic zirconia is recommended as the material of choice for multi‐unit implant restorations to reduce technical complications.

Published
2023

7. Molecular basis of MHC I quality control in the peptide loading complex

Author

Domnick, A, Winter, C, Sušac, L, Hennecke, L, Hensen, M, Zitzmann, N, Trowitzsch, S, Thomas, C, and Tampé, R

Subjects
Quality Control, Antigen Presentation, Epitopes, HLA Antigens, Polysaccharides, Histocompatibility Antigens Class I, Humans, Endoplasmic Reticulum, Peptides, Molecular Chaperones
Abstract

Major histocompatibility complex class I (MHC I) molecules are central to adaptive immunity. Their assembly, epitope selection, and antigen presentation are controlled by the MHC I glycan through a sophisticated network of chaperones and modifying enzymes. However, the mechanistic integration of the corresponding processes remains poorly understood. Here, we determine the multi-chaperone-client interaction network of the peptide loading complex (PLC) and report the PLC editing module structure by cryogenic electron microscopy at 3.7 Å resolution. Combined with epitope-proofreading studies of the PLC in near-native lipid environment, these data show that peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan, which only becomes accessible for processing by α-glucosidase II upon loading of optimal epitopes. Our work reveals allosteric coupling between peptide-MHC I assembly and glycan processing. This inter-process communication defines the onset of an adaptive immune response and provides a prototypical example of the tightly coordinated events in endoplasmic reticulum quality control.

Published
2022

11. COVID-19 therapeutics: Challenges and directions for the future

Author

Robinson, PC, Liew, DFL, Tanner, HL, Grainger, JR, Dwek, RA, Reisler, RB, Steinman, L, Feldmann, M, Ho, L-P, Hussell, T, Moss, P, Richards, D, Zitzmann, N, Robinson, PC, Liew, DFL, Tanner, HL, Grainger, JR, Dwek, RA, Reisler, RB, Steinman, L, Feldmann, M, Ho, L-P, Hussell, T, Moss, P, Richards, D, and Zitzmann, N

Abstract

The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.

Published
2022

19. Antiviral effects of deoxynojirimycin (DNJ)-based iminosugars in dengue virus-infected primary dendritic cells

Author

Perera, N, Brun, J, Alonzi, DS, Tyrrell, BE, Miller, JL, and Zitzmann, N

Subjects
Dengue, Pharmacology, 1-Deoxynojirimycin, Macrophages, Virology, Humans, Dendritic Cells, Dengue Virus, Endoplasmic Reticulum, Antiviral Agents
Abstract

Dendritic cells (DCs) are important targets for dengue virus (DENV) infection and play a significant role in the early immune response. Antiviral effects of iminosugars against DENV in primary cells have been demonstrated previously in monocyte-derived macrophages (MDMΦs). Given the important role played by DCs in innate immune defense against DENV, the antiviral effects of three deoxynojirimycin (DNJ) derivatives (NN-DNJ, EOO-DNJ and 2THO-DNJ) and a deoxygalactonojirimycin (DGJ) negative control were evaluated in DENV-infected primary human monocyte-derived immature DCs (imDCs). DNJ- but not DGJ-derivatives elicited antiviral activity in DENV-infected imDCs, similar to that observed in MDMΦs. The DNJ-derivatives inhibited DENV secretion in a dose-dependent manner. Endoplasmic reticulum (ER) α-glucosidase I inhibition by DNJ-derived iminosugars, at concentrations of 3.16 μM, correlated with a reduction in the specific infectivity of virions that were still secreted, as well as a reduction in DENV-induced tumour necrosis factor alpha secretion. This suggests iminosugar-mediated ER α-glucosidase I inhibition may give rise to further benefits during DENV infection, beyond the reduction in viral secretion associated with ER α-glucosidase II inhibition.

Published
2022

22. Targeting ER α-glucosidase I with a single-dose iminosugar treatment protects against lethal influenza and dengue virus infections

Author

Warfield, K, Alonzi, DS, Hill, JC, Caputo, AT, Roversi, P, Kiappes, JL, Sheets, N, Duchars, M, Dwek, RA, Biggins, J, Barnard, D, Shresta, S, Treston, A, and Zitzmann, N

Abstract

Influenza and dengue viruses present a growing global threat to public health. Both viruses depend on the host endoplasmic reticulum (ER) glycoprotein folding pathway. In 2014, Sadat et al. reported two siblings with a rare genetic defect in ER alpha-glucosidase I (ER Glu I) who showed resistance to viral infections, identifying ER Glu I as a key antiviral target. Here we show that a single dose of UV-4B (the hydrochloride salt form of N-(9′-methoxynonyl)-1- deoxynojirimycin; MON-DNJ) capable of inhibiting Glu I in vivo is sufficient to prevent death in mice infected with lethal viral doses, even when treatment is started as late as 48 hours post-infection. The first crystal structure of mammalian ER Glu I will constitute the basis for the development of potent and selective inhibitors. Targeting ER Glu I with UV-4B derived compounds may alter treatment paradigms for acute viral disease through development of a single-dose therapeutic regime.

Published
2020

23. A need to raise the bar - A systematic review of temporal trends in diagnostics for Japanese encephalitis virus infection, and perspectives for future research.

Author

Bharucha, T, Shearer, FM, Vongsouvath, M, Mayxay, M, de Lamballerie, X, Newton, PN, Zitzmann, N, Gould, E, Dubot-Pérès, A, Bharucha, T, Shearer, FM, Vongsouvath, M, Mayxay, M, de Lamballerie, X, Newton, PN, Zitzmann, N, Gould, E, and Dubot-Pérès, A

Abstract

OBJECTIVE: Japanese encephalitis virus infection (JE) remains a leading cause of neurological disease in Asia, mainly involving individuals living in remote areas with limited access to treatment centers and diagnostic facilities. Laboratory confirmation is fundamental for the justification and implementation of vaccination programs. We reviewed the literature on historical developments and current diagnostic capability worldwide, to identify knowledge gaps and instill urgency to address them. METHODS: Searches were performed in Web of Science and PubMed using the term 'Japanese encephalitis' up to 13th October 2019. Studies reporting laboratory-confirmed symptomatic JE cases in humans were included, and data on details of diagnostic tests were extracted. A JE case was classified according to confirmatory levels (Fischer et al., 2008; Campbell et al., 2011; Pearce et al., 2018; Heffelfinger et al., 2017), where level 1 represented the highest level of confidence. FINDINGS: 20,212 published JE cases were identified from 205 studies. 15,167 (75%) of these positive cases were confirmed with the lowest-confidence diagnostic tests (level 3 or 4, or level 4). Only 109 (53%) of the studies reported contemporaneous testing for dengue-specific antibodies. CONCLUSION: A fundamental pre-requisite for the control of JEV is lacking - that of a simple and specific diagnostic procedure that can be adapted for point-of-care tests and readily used throughout JE-endemic regions of the world.

Published
2020

26. Structure of the catalytic domain of human endo-alpha-mannosidase MANEA in complex with GlcDMJ and hexatungstotellurate(VI) TEW

Author

Sobala, L.F., primary, Fernandes, P.Z., additional, Hakki, Z., additional, Thompson, A.J., additional, Howe, J.D., additional, Hill, M., additional, Zitzmann, N., additional, Davies, S., additional, Stamataki, Z., additional, Butters, T.D., additional, Alonzi, D.S., additional, Williams, S.J., additional, and Davies, G.J., additional

Published
2020
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27. Structure of an inactive E404Q variant of the catalytic domain of human endo-alpha-mannosidase MANEA in complex with tetrasaccharide N-glycan fragment and hexatungstotellurate(VI) TEW

Author

Sobala, L.F., primary, Fernandes, P.Z., additional, Hakki, Z., additional, Thompson, A.J., additional, Howe, J.D., additional, Hill, M., additional, Zitzmann, N., additional, Davies, S., additional, Stamataki, Z., additional, Butters, T.D., additional, Alonzi, D.S., additional, Williams, S.J., additional, and Davies, G.J., additional

Published
2020
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32. Structure of the catalytic domain of human endo-alpha-mannosidase MANEA in complex with HEPES and hexatungstotellurate(VI) TEW

Author

Sobala, L.F., primary, Fernandes, P.Z., additional, Hakki, Z., additional, Thompson, A.J., additional, Howe, J.D., additional, Hill, M., additional, Zitzmann, N., additional, Davies, S., additional, Stamataki, Z., additional, Butters, T.D., additional, Alonzi, D.S., additional, Williams, S.J., additional, and Davies, G.J., additional

Published
2020
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34. Structure of the catalytic domain of human endo-alpha-mannosidase MANEA in complex with GlcIFG, alpha-1,2-mannobiose and hexatungstotellurate(VI) TEW

Author

Sobala, L.F., primary, Fernandes, P.Z., additional, Hakki, Z., additional, Thompson, A.J., additional, Howe, J.D., additional, Hill, M., additional, Zitzmann, N., additional, Davies, S., additional, Stamataki, Z., additional, Butters, T.D., additional, Alonzi, D.S., additional, Williams, S.J., additional, and Davies, G.J., additional

Published
2020
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36. Structure of an inactive E404Q variant of the catalytic domain of human endo-alpha-mannosidase MANEA in complex with 1-methyl alpha-1,2-mannobiose

Author

Sobala, L.F., primary, Fernandes, P.Z., additional, Hakki, Z., additional, Thompson, A.J., additional, Howe, J.D., additional, Hill, M., additional, Zitzmann, N., additional, Davies, S., additional, Stamataki, Z., additional, Butters, T.D., additional, Alonzi, D.S., additional, Williams, S.J., additional, and Davies, G.J., additional

Published
2020
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37. Structure of the GH99 endo-alpha-mannanase from Bacteroides xylanisolvens in complex with cyclohexylmethyl-Glc-1,3-isofagomine

Author

Thompson, A.J., primary, Sobala, L.F., additional, Fernandes, P.Z., additional, Hakki, Z., additional, Howe, J.D., additional, Hill, M., additional, Zitzmann, N., additional, Davies, S., additional, Stamataki, Z., additional, Butters, T.D., additional, Alonzi, D.S., additional, Williams, S.J., additional, and Davies, G.J., additional

Published
2020
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49. Interferon lambda 4 impacts the genetic diversity of hepatitis C virus

Author

Ansari, M, Aranday-Cortes, E, Ip, C, Da Silva Filipe, A, Lau, S, Bamford, C, Bonsall, D, Trebes, A, Piazza, P, Sreenu, V, Cowton, V, Consortium, Stop-Hcv, Ball, J, Barnes, E, Burgess, G, Cooke, G, Dillon, J, Foster, G, Gore, C, Guha, N, Halford, R, Holmes, C, Hudson, E, Hutchinson, S, Irving, W, Khakoo, S, Klenerman, P, Martin, N, Mbisa, T, McKeating, J, McLauchlan, J, Miners, A, Murray, A, Shaw, P, Simmonds, P, Smith, S, Spencer, C, Thomson, E, Troke, P, Vickerman, P, Zitzmann, N, Bowden, R, Patel, A, Agarwal, K, Pedergnana, V, University of Oxford, University of Glasgow, University of Glascow, Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), Queen Mary University of London (QMUL), University of Nottingham, UK (UON), King's College Hospital (KCH), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), and National Institute for Health Research

Subjects
Life Sciences & Biomedicine - Other Topics, hepatitis C virus, 0301 basic medicine, CLEARANCE, MESH: Selection, Genetic, viruses, IL28B, Genome-wide association study, 0601 Biochemistry and Cell Biology, medicine.disease_cause, interferon lambda 4, MESH: Genotype, 0302 clinical medicine, E2, Interferon, INFECTION, host-pathogen interactions, genetics, MESH: Hepacivirus, MESH: Genetic Variation, Biology (General), innate immunity, SCAVENGER RECEPTOR-BI, MESH: Immunologic Factors, General Neuroscience, SINGLE-NUCLEOTIDE POLYMORPHISMS, General Medicine, Acquired immune system, 3. Good health, Medicine, MESH: Viral Load, Life Sciences & Biomedicine, Viral load, medicine.drug, MESH: Antiviral Agents, MESH: Interleukins, QH301-705.5, Science, infectious disease, Hepatitis C virus, MESH: Whites, virus, Human leukocyte antigen, Biology, General Biochemistry, Genetics and Molecular Biology, Virus, 03 medical and health sciences, genomics, medicine, human, Genetic variability, GENOME-WIDE ASSOCIATION, genome-to-genome analysis, MESH: Hepatitis C, Science & Technology, MESH: Humans, General Immunology and Microbiology, FALSE DISCOVERY, microbiology, MESH: Host-Pathogen Interactions, Virology, ALPHA, 030104 developmental biology, MESH: Genome-Wide Association Study, INTERLEUKIN 28B, STOP-HCV Consortium, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

International audience; Hepatitis C virus (HCV) is a highly variable pathogen that frequently establishes chronic infection. This genetic variability is affected by the adaptive immune response but the contribution of other host factors is unclear. Here, we examined the role played by interferon lambda-4 (IFN-λ4) on HCV diversity; IFN-λ4 plays a crucial role in spontaneous clearance or establishment of chronicity following acute infection. We performed viral genome-wide association studies using human and viral data from 485 patients of white ancestry infected with HCV genotype 3a. We demonstrate that combinations of host genetic variants, which determine IFN-λ4 protein production and activity, influence amino acid variation across the viral polyprotein - not restricted to specific viral proteins or HLA restricted epitopes - and modulate viral load. We also observed an association with viral di-nucleotide proportions. These results support a direct role for IFN-λ4 in exerting selective pressure across the viral genome, possibly by a novel mechanism.

Published
2019

50. Iminosugars counteract the downregulation of the interferon gamma receptor by dengue virus

Author

Miller, J, Hill, M, Brun, J, Pountain, A, Sayce, A, and Zitzmann, N

Subjects
viruses, biochemical phenomena, metabolism, and nutrition
Abstract

The antiviral mechanism of action of iminosugars against many enveloped viruses is hypothesized to be a consequence of misfolding of viral N-linked glycoproteins through inhibition of host endoplasmic reticulum alpha-glucosidase enzymes. Iminosugar treatment of dengue virus (DENV) infection results in reduced secretion of virions and hence lower viral titres in vitro and in vivo. We investigated whether iminosugars might also affect host receptors important in DENV attachment and uptake and immune responses to DENV. Using a primary human macrophage model of DENV infection, we investigated the effects of maturation with IL-4, DENV-infection and treatment with N-butyl-1-deoxynojirimycin (NB-DNJ) or N-(9-methoxynonyl)-1-DNJ (MON-DNJ) on expression of 11 macrophage receptors. Whereas iminosugars did not affect surface expression of any of the receptors examined, DENV infection significantly reduced surface IFN gamma receptor amongst other changes to total receptor expression. This effect required infectious DENV and was reversed by iminosugar treatment. Treatment also affected signalling of the IFN gamma receptor and TNF alpha receptor. In addition, iminosugars reduced ligand binding to the carbohydrate receptor-binding domain of the mannose receptor. This work demonstrates that iminosugar treatment of primary macrophages affects expression and functionality of some key glycosylated host immune receptors important in the dengue life cycle.

Published
2019

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