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How Computational Models Enable Mechanistic Insights into Virus Infection

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Influenza Virus

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1836))

Abstract

An implicit aim in cellular infection biology is to understand the mechanisms how viruses, microbes, eukaryotic parasites, and fungi usurp the functions of host cells and cause disease. Mechanistic insight is a deep understanding of the biophysical and biochemical processes that give rise to an observable phenomenon. It is typically subject to falsification, that is, it is accessible to experimentation and empirical data acquisition. This is different from logic and mathematics, which are not empirical, but built on systems of inherently consistent axioms. Here, we argue that modeling and computer simulation, combined with mechanistic insights, yields unprecedented deep understanding of phenomena in biology and especially in virus infections by providing a way of showing sufficiency of a hypothetical mechanism. This ideally complements the necessity statements accessible to empirical falsification by additional positive evidence. We discuss how computational implementations of mathematical models can assist and enhance the quantitative measurements of infection dynamics of enveloped and non-enveloped viruses and thereby help generating causal insights into virus infection biology.

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References

  1. Eigen M (1971) Self-organization of matter and the evolution of biological macromolecules. Naturwissenschaften 58(10):465–523

    Article  CAS  PubMed  Google Scholar 

  2. Domingo E, Sabo D, Taniguchi T, Weissmann C (1978) Nucleotide sequence heterogeneity of an RNA phage population. Cell 13(4):735–744

    Article  CAS  PubMed  Google Scholar 

  3. Domingo E, Martinez-Salas E, Sobrino F, de la Torre JC, Portela A, Ortin J, Lopez-Galindez C, Perez-Brena P, Villanueva N, Najera R et al (1985) The quasispecies (extremely heterogeneous) nature of viral RNA genome populations: biological relevance--a review. Gene 40(1):1–8

    Article  CAS  PubMed  Google Scholar 

  4. Liu AP, Fletcher DA (2009) Biology under construction: in vitro reconstitution of cellular function. Nat Rev Mol Cell Biol 10(9):644–650. https://doi.org/10.1038/nrm2746

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Pollard TD, Cooper JA (2009) Actin, a central player in cell shape and movement. Science 326(5957):1208–1212. https://doi.org/10.1126/science.1175862

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Pollard TD (2017) Nine unanswered questions about cytokinesis. J Cell Biol 216:3007. https://doi.org/10.1083/jcb.201612068

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Boianelli A, Nguyen VK, Ebensen T, Schulze K, Wilk E, Sharma N, Stegemann-Koniszewski S, Bruder D, Toapanta FR, Guzman CA, Meyer-Hermann M, Hernandez-Vargas EA (2015) Modeling influenza virus infection: a roadmap for influenza research. Viruses 7(10):5274–5304. https://doi.org/10.3390/v7102875

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Chertow DS, Memoli MJ (2013) Bacterial coinfection in influenza: a grand rounds review. JAMA 309(3):275–282. https://doi.org/10.1001/jama.2012.194139

    Article  PubMed  CAS  Google Scholar 

  9. Leimer N, Rachmuhl C, Palheiros Marques M, Bahlmann AS, Furrer A, Eichenseher F, Seidl K, Matt U, Loessner MJ, Schuepbach RA, Zinkernagel AS (2015) Nonstable Staphylococcus aureus small-Colony variants are induced by low pH and sensitized to antimicrobial therapy by Phagolysosomal Alkalinization. J Infect Dis 213:305. https://doi.org/10.1093/infdis/jiv388

    Article  PubMed  CAS  Google Scholar 

  10. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K (2003) Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289:179–186

    Article  PubMed  Google Scholar 

  11. Johnson NP, Mueller J (2002) Updating the accounts: global mortality of the 1918–1920 “Spanish” influenza pandemic. Bull Hist Med 76(1):105–115

    Article  PubMed  Google Scholar 

  12. Taubenberger JK, Reid AH, Fanning TG (2005) Capturing a killer flu virus. Sci Am 292(1):48–57

    Article  PubMed  Google Scholar 

  13. Greber UF, Way M (2006) A superhighway to virus infection. Cell 124(4):741–754. https://doi.org/10.1016/j.cell.2006.02.018

    Article  PubMed  CAS  Google Scholar 

  14. Brandenburg B, Zhuang X (2007) Virus trafficking – learning from single-virus tracking. Nat Rev Microbiol 5(3):197–208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Smith GA, Enquist LW (2002) Break ins and break outs: viral interactions with the cytoskeleton of mammalian cells. Annu Rev Cell Dev Biol 18:135–161

    Article  CAS  PubMed  Google Scholar 

  16. Radtke K, Dohner K, Sodeik B (2006) Viral interactions with the cytoskeleton: a hitchhiker's guide to the cell. Cell Microbiol 8(3):387–400

    Article  CAS  PubMed  Google Scholar 

  17. Burckhardt CJ, Greber UF (2009) Virus movements on the plasma membrane support infection and transmission between cells. PLoS Pathog 5(11):e1000621. https://doi.org/10.1371/journal.ppat.1000621

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Mothes W, Sherer NM, Jin J, Zhong P (2010) Virus cell-to-cell transmission. J Virol 84(17):8360–8368. doi:JVI.00443-10 [pii]. https://doi.org/10.1128/JVI.00443-10

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Florian PE, Rouille Y, Ruta S, Nichita N, Roseanu A (2016) Recent advances in human viruses imaging studies. J Basic Microbiol 56:591. https://doi.org/10.1002/jobm.201500575

    Article  PubMed  Google Scholar 

  20. Wang IH, Suomalainen M, Andriasyan V, Kilcher S, Mercer J, Neef A, Luedtke NW, Greber UF (2013) Tracking viral genomes in host cells at single-molecule resolution. Cell Host Microbe 14(4):468–480. https://doi.org/10.1016/j.chom.2013.09.004

    Article  PubMed  CAS  Google Scholar 

  21. Sakin V, Hanne J, Dunder J, Anders-Osswein M, Laketa V, Nikic I, Krausslich HG, Lemke EA, Muller B (2017) A versatile tool for live-cell imaging and super-resolution nanoscopy studies of HIV-1 Env distribution and mobility. Cell Chem Biol 24(5):635–645 e635. https://doi.org/10.1016/j.chembiol.2017.04.007

    Article  PubMed  CAS  Google Scholar 

  22. Peng K, Muranyi W, Glass B, Laketa V, Yant SR, Tsai L, Cihlar T, Muller B, Krausslich HG (2014) Quantitative microscopy of functional HIV post-entry complexes reveals association of replication with the viral capsid. eLife 3:e04114. https://doi.org/10.7554/eLife.04114

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sbalzarini IF, Koumoutsakos P (2005) Feature point tracking and trajectory analysis for video imaging in cell biology. J Struct Biol 151(2):182–195

    Article  CAS  PubMed  Google Scholar 

  24. Helmuth JA, Burckhardt CJ, Koumoutsakos P, Greber UF, Sbalzarini IF (2007) A novel supervised trajectory segmentation algorithm identifies distinct types of human adenovirus motion in host cells. J Struct Biol 159(3):347–358. https://doi.org/10.1016/j.jsb.2007.04.003

    Article  PubMed  Google Scholar 

  25. Engelke MF, Burckhardt CJ, Morf MK, Greber UF (2011) The dynactin complex enhances the speed of microtubule-dependent motions of adenovirus both towards and away from the nucleus. Viruses 3(3):233–253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Burckhardt CJ, Suomalainen M, Schoenenberger P, Boucke K, Hemmi S, Greber UF (2011) Drifting motions of the adenovirus receptor CAR and immobile integrins initiate virus uncoating and membrane lytic protein exposure. Cell Host Microbe 10(2):105–117. https://doi.org/10.1016/j.chom.2011.07.006

    Article  PubMed  CAS  Google Scholar 

  27. Ewers H, Smith AE, Sbalzarini IF, Lilie H, Koumoutsakos P, Helenius A (2005) Single-particle tracking of murine polyoma virus-like particles on live cells and artificial membranes. Proc Natl Acad Sci U S A 102(42):15110–15115

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Yamauchi Y, Boukari H, Banerjee I, Sbalzarini IF, Horvath P, Helenius A (2011) Histone deacetylase 8 is required for centrosome cohesion and influenza a virus entry. PLoS Pathog 7(10):e1002316. https://doi.org/10.1371/journal.ppat.1002316

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Helmuth JA, Burckhardt CJ, Greber UF, Sbalzarini IF (2009) Shape reconstruction of subcellular structures from live cell fluorescence microscopy images. J Struct Biol 167(1):1–10. https://doi.org/10.1016/j.jsb.2009.03.017

    Article  PubMed  CAS  Google Scholar 

  30. Helmuth JA, Paul G, Sbalzarini IF (2010) Beyond co-localization: inferring spatial interactions between sub-cellular structures from microscopy images. BMC Bioinformatics 11:372. https://doi.org/10.1186/1471-2105-11-372

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bykov YS, Cortese M, Briggs JA, Bartenschlager R (2016) Correlative light and electron microscopy methods for the study of virus-cell interactions. FEBS Lett 590(13):1877–1895. https://doi.org/10.1002/1873-3468.12153

    Article  PubMed  CAS  Google Scholar 

  32. Lagache T, Lang G, Sauvonnet N, Olivo-Marin JC (2013) Analysis of the spatial organization of molecules with robust statistics. PLoS One 8(12):e80914. https://doi.org/10.1371/journal.pone.0080914

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Shivanandan A, Radenovic A, Sbalzarini IF (2013) MosaicIA: an ImageJ/Fiji plugin for spatial pattern and interaction analysis. BMC Bioinformatics 14:349. https://doi.org/10.1186/1471-2105-14-349

    Article  PubMed  PubMed Central  Google Scholar 

  34. Giesen C, Wang HA, Schapiro D, Zivanovic N, Jacobs A, Hattendorf B, Schuffler PJ, Grolimund D, Buhmann JM, Brandt S, Varga Z, Wild PJ, Gunther D, Bodenmiller B (2014) Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat Methods 11(4):417–422. https://doi.org/10.1038/nmeth.2869

    Article  PubMed  CAS  Google Scholar 

  35. Zenklusen D, Singer RH (2010) Analyzing mRNA expression using single mRNA resolution fluorescent in situ hybridization. Methods Enzymol 470:641–659. https://doi.org/10.1016/S0076-6879(10)70026-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Marsh M, Helenius A (2006) Virus entry: open sesame. Cell 124(4):729–740

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Flatt JW, Greber UF (2017) Viral mechanisms for docking and delivering at nuclear pore complexes. Semin Cell Dev Biol 68:59–71. https://doi.org/10.1016/j.semcdb.2017.05.008

    Article  PubMed  CAS  Google Scholar 

  38. Yamauchi Y, Greber UF (2016) Principles of virus uncoating: cues and the snooker ball. Traffic 17(6):569–592. https://doi.org/10.1111/tra.12387

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Sodhi A, Montaner S, Gutkind JS (2004) Viral hijacking of G-protein-coupled-receptor signalling networks. Nat Rev Mol Cell Biol 5(12):998–1012. https://doi.org/10.1038/nrm1529

    Article  PubMed  CAS  Google Scholar 

  40. Stertz S, Shaw ML (2011) Uncovering the global host cell requirements for influenza virus replication via RNAi screening. Microbes Infect 13(5):516–525. https://doi.org/10.1016/j.micinf.2011.01.012

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Franceschini A, Meier R, Casanova A, Kreibich S, Daga N, Andritschke D, Dilling S, Ramo P, Emmenlauer M, Kaufmann A, Conde-Alvarez R, Low SH, Pelkmans L, Helenius A, Hardt WD, Dehio C, von Mering C (2014) Specific inhibition of diverse pathogens in human cells by synthetic microRNA-like oligonucleotides inferred from RNAi screens. Proc Natl Acad Sci U S A 111(12):4548–4553. https://doi.org/10.1073/pnas.1402353111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Snijder B, Sacher R, Ramo P, Liberali P, Mench K, Wolfrum N, Burleigh L, Scott CC, Verheije MH, Mercer J, Moese S, Heger T, Theusner K, Jurgeit A, Lamparter D, Balistreri G, Schelhaas M, De Haan CA, Marjomaki V, Hyypia T, Rottier PJ, Sodeik B, Marsh M, Gruenberg J, Amara A, Greber U, Helenius A, Pelkmans L (2012) Single-cell analysis of population context advances RNAi screening at multiple levels. Mol Syst Biol 8:579. https://doi.org/10.1038/msb.2012.9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Mercer J, Snijder B, Sacher R, Burkard C, Bleck CK, Stahlberg H, Pelkmans L, Helenius A (2012) RNAi screening reveals proteasome- and Cullin3-dependent stages in vaccinia virus infection. Cell Rep 2(4):1036–1047. https://doi.org/10.1016/j.celrep.2012.09.003

    Article  PubMed  CAS  Google Scholar 

  44. Meier R, Franceschini A, Horvath P, Tetard M, Mancini R, von Mering C, Helenius A, Lozach PY (2014) Genome-wide small interfering RNA screens reveal VAMP3 as a novel host factor required for Uukuniemi virus late penetration. J Virol 88(15):8565–8578. https://doi.org/10.1128/Jvi.00388-14

    Article  PubMed  PubMed Central  Google Scholar 

  45. Green VA, Pelkmans L (2016) A systems survey of progressive host-cell reorganization during rotavirus infection. Cell Host Microbe 20(1):107–120. https://doi.org/10.1016/j.chom.2016.06.005

    Article  PubMed  CAS  Google Scholar 

  46. Tripathi S, Pohl MO, Zhou Y, Rodriguez-Frandsen A, Wang G, Stein DA, Moulton HM, DeJesus P, Che J, Mulder LC, Yanguez E, Andenmatten D, Pache L, Manicassamy B, Albrecht RA, Gonzalez MG, Nguyen Q, Brass A, Elledge S, White M, Shapira S, Hacohen N, Karlas A, Meyer TF, Shales M, Gatorano A, Johnson JR, Jang G, Johnson T, Verschueren E, Sanders D, Krogan N, Shaw M, Konig R, Stertz S, Garcia-Sastre A, Chanda SK (2015) Meta- and orthogonal integration of influenza “OMICs” data defines a role for UBR4 in virus budding. Cell Host Microbe 18(6):723–735. https://doi.org/10.1016/j.chom.2015.11.002

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Ramo P, Drewek A, Arrieumerlou C, Beerenwinkel N, Ben-Tekaya H, Cardel B, Casanova A, Conde-Alvarez R, Cossart P, Csucs G, Eicher S, Emmenlauer M, Greber U, Hardt WD, Helenius A, Kasper C, Kaufmann A, Kreibich S, Kuhbacher A, Kunszt P, Low SH, Mercer J, Mudrak D, Muntwiler S, Pelkmans L, Pizarro-Cerda J, Podvinec M, Pujadas E, Rinn B, Rouilly V, Schmich F, Siebourg-Polster J, Snijder B, Stebler M, Studer G, Szczurek E, Truttmann M, von Mering C, Vonderheit A, Yakimovich A, Buhlmann P, Dehio C (2014) Simultaneous analysis of large-scale RNAi screens for pathogen entry. BMC Genomics 15(1):1162. https://doi.org/10.1186/1471-2164-15-1162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Staring J, von Castelmur E, Blomen VA, van den Hengel LG, Brockmann M, Baggen J, Thibaut HJ, Nieuwenhuis J, Janssen H, van Kuppeveld FJ, Perrakis A, Carette JE, Brummelkamp TR (2017) PLA2G16 represents a switch between entry and clearance of Picornaviridae. Nature 541(7637):412–416. https://doi.org/10.1038/nature21032

    Article  PubMed  CAS  Google Scholar 

  49. Elling U, Wimmer RA, Leibbrandt A, Burkard T, Michlits G, Leopoldi A, Micheler T, Abdeen D, Zhuk S, Aspalter IM, Handl C, Liebergesell J, Hubmann M, Husa AM, Kinzer M, Schuller N, Wetzel E, van de Loo N, Martinez JAZ, Estoppey D, Riedl R, Yang F, Fu B, Dechat T, Ivics Z, Agu CA, Bell O, Blaas D, Gerhardt H, Hoepfner D, Stark A, Penninger JM (2017) A reversible haploid mouse embryonic stem cell biobank resource for functional genomics. Nature 550(7674):114–118. https://doi.org/10.1038/nature24027

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Siebourg-Polster J, Mudrak D, Emmenlauer M, Ramo P, Dehio C, Greber U, Frohlich H, Beerenwinkel N (2015) NEMix: single-cell nested effects models for probabilistic pathway stimulation. PLoS Comput Biol 11(4):e1004078. https://doi.org/10.1371/journal.pcbi.1004078

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Sbalzarini IF (2013) Modeling and simulation of biological systems from image data. BioEssays 35(5):482–490. https://doi.org/10.1002/bies.201200051

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Zhao G, Perilla JR, Yufenyuy EL, Meng X, Chen B, Ning J, Ahn J, Gronenborn AM, Schulten K, Aiken C, Zhang P (2013) Mature HIV-1 capsid structure by cryo-electron microscopy and all-atom molecular dynamics. Nature 497(7451):643–646. https://doi.org/10.1038/nature12162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Schur FK, Obr M, Hagen WJ, Wan W, Jakobi AJ, Kirkpatrick JM, Sachse C, Krausslich HG, Briggs JA (2016) An atomic model of HIV-1 capsid-SP1 reveals structures regulating assembly and maturation. Science 353(6298):506–508. https://doi.org/10.1126/science.aaf9620

    Article  PubMed  CAS  Google Scholar 

  54. Larsson DS, Liljas L, van der Spoel D (2012) Virus capsid dissolution studied by microsecond molecular dynamics simulations. PLoS Comput Biol 8(5):e1002502. https://doi.org/10.1371/journal.pcbi.1002502

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Rapaport DC (2004) Self-assembly of polyhedral shells: a molecular dynamics study. Phys Rev E Stat Nonlinear Soft Matter Phys 70(5 Pt 1):051905. https://doi.org/10.1103/PhysRevE.70.051905

    Article  CAS  Google Scholar 

  56. Freddolino PL, Arkhipov AS, Larson SB, McPherson A, Schulten K (2006) Molecular dynamics simulations of the complete satellite tobacco mosaic virus. Structure 14(3):437–449. https://doi.org/10.1016/j.str.2005.11.014

    Article  PubMed  CAS  Google Scholar 

  57. Krishna V, Ayton GS, Voth GA (2010) Role of protein interactions in defining HIV-1 viral capsid shape and stability: a coarse-grained analysis. Biophys J 98(1):18–26. https://doi.org/10.1016/j.bpj.2009.09.049

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Arkhipov A, Freddolino PL, Schulten K (2006) Stability and dynamics of virus capsids described by coarse-grained modeling. Structure 14(12):1767–1777. https://doi.org/10.1016/j.str.2006.10.003

    Article  PubMed  CAS  Google Scholar 

  59. Kim MK, Jernigan RL, Chirikjian GS (2003) An elastic network model of HK97 capsid maturation. J Struct Biol 143(2):107–117

    Article  CAS  PubMed  Google Scholar 

  60. Zheng W, Liao JC, Brooks BR, Doniach S (2007) Toward the mechanism of dynamical couplings and translocation in hepatitis C virus NS3 helicase using elastic network model. Proteins 67(4):886–896. https://doi.org/10.1002/prot.21326

    Article  PubMed  CAS  Google Scholar 

  61. English TJ, Hammer DA (2005) The effect of cellular receptor diffusion on receptor-mediated viral binding using Brownian adhesive dynamics (BRAD) simulations. Biophys J 88(3):1666–1675. https://doi.org/10.1529/biophysj.104.047043

    Article  PubMed  CAS  Google Scholar 

  62. Szklarczyk OM, Gonzalez-Segredo N, Kukura P, Oppenheim A, Choquet D, Sandoghdar V, Helenius A, Sbalzarini IF, Ewers H (2013) Receptor concentration and diffusivity control multivalent binding of Sv40 to membrane bilayers. PLoS Comput Biol 9(11):e1003310. https://doi.org/10.1371/journal.pcbi.1003310

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Yakimovich A, Gumpert H, Burckhardt CJ, Lutschg VA, Jurgeit A, Sbalzarini IF, Greber UF (2012) Cell-free transmission of human adenovirus by passive mass transfer in cell culture simulated in a computer model. J Virol 86(18):10123–10137. https://doi.org/10.1128/JVI.01102-12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Dinh AT, Theofanous T, Mitragotri S (2005) A model for intracellular trafficking of adenoviral vectors. Biophys J 89(3):1574–1588. https://doi.org/10.1529/biophysj.105.059477

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Yakimovich A, Yakimovich Y, Schmid M, Mercer J, Sbalzarini IF, Greber UF (2016) Infectio: a generic framework for computational simulation of virus transmission between cells. mSphere 1(1):e00078-15. https://doi.org/10.1128/mSphere.00078-15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Chojnacki J, Staudt T, Glass B, Bingen P, Engelhardt J, Anders M, Schneider J, Muller B, Hell SW, Krausslich HG (2012) Maturation-dependent HIV-1 surface protein redistribution revealed by fluorescence nanoscopy. Science 338(6106):524–528. https://doi.org/10.1126/science.1226359

    Article  PubMed  CAS  Google Scholar 

  67. Sadiq SK (2016) Reaction-diffusion basis of retroviral infectivity. Philos Trans A Math Phys Eng Sci 374(2080):20160148. https://doi.org/10.1098/rsta.2016.0148

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Frank GA, Narayan K, Bess JW Jr, Del Prete GQ, Wu X, Moran A, Hartnell LM, Earl LA, Lifson JD, Subramaniam S (2015) Maturation of the HIV-1 core by a non-diffusional phase transition. Nat Commun 6:5854. https://doi.org/10.1038/ncomms6854

    Article  PubMed  CAS  Google Scholar 

  69. Mattei S, Glass B, Hagen WJ, Krausslich HG, Briggs JA (2016) The structure and flexibility of conical HIV-1 capsids determined within intact virions. Science 354(6318):1434–1437. https://doi.org/10.1126/science.aah4972

    Article  PubMed  CAS  Google Scholar 

  70. Srivastava R, You L, Summers J, Yin J (2002) Stochastic vs. deterministic modeling of intracellular viral kinetics. J Theor Biol 218(3):309–321

    Article  CAS  PubMed  Google Scholar 

  71. Konnyu B, Sadiq SK, Turanyi T, Hirmondo R, Muller B, Krausslich HG, Coveney PV, Muller V (2013) Gag-pol processing during HIV-1 virion maturation: a systems biology approach. PLoS Comput Biol 9(6):e1003103. https://doi.org/10.1371/journal.pcbi.1003103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Gazzola M, Burckhardt CJ, Bayati B, Engelke M, Greber UF, Koumoutsakos P (2009) A stochastic model for microtubule motors describes the in vivo cytoplasmic transport of human adenovirus. PLoS Comput Biol 5(12):e1000623. https://doi.org/10.1371/journal.pcbi.1000623

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Bremner KH, Scherer J, Yi J, Vershinin M, Gross SP, Vallee RB (2009) Adenovirus transport via direct interaction of cytoplasmic dynein with the viral capsid hexon subunit. Cell Host Microbe 6(6):523–535. https://doi.org/10.1016/j.chom.2009.11.006

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Labouesse C, Gabella C, Meister JJ, Vianay B, Verkhovsky AB (2016) Microsurgery-aided in-situ force probing reveals extensibility and viscoelastic properties of individual stress fibers. Sci Rep 6:23722. https://doi.org/10.1038/srep23722

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Martin-Fernandez M, Longshaw SV, Kirby I, Santis G, Tobin MJ, Clarke DT, Jones GR (2004) Adenovirus Type-5 entry and disassembly followed in living cells by FRET, fluorescence anisotropy, and FLIM. Biophys J 87(2):1316–1327

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Greber UF, Willetts M, Webster P, Helenius A (1993) Stepwise dismantling of adenovirus 2 during entry into cells. Cell 75(3):477–486. https://doi.org/10.1016/0092-8674(93)90382-Z

    Article  PubMed  CAS  Google Scholar 

  77. Nakano MY, Boucke K, Suomalainen M, Stidwill RP, Greber UF (2000) The first step of adenovirus type 2 disassembly occurs at the cell surface, independently of endocytosis and escape to the cytosol. J Virol 74(15):7085–7095

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Greber UF (2016) Virus and host mechanics support membrane penetration and cell entry. J Virol 90(8):3802–3805. https://doi.org/10.1128/JVI.02568-15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Snijder J, Reddy VS, May ER, Roos WH, Nemerow GR, Wuite GJ (2013) Integrin and defensin modulate the mechanical properties of adenovirus. J Virol 87(5):2756–2766. https://doi.org/10.1128/JVI.02516-12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Ortega-Esteban A, Condezo GN, Perez-Berna AJ, Chillon M, Flint SJ, Reguera D, San Martin C, de Pablo PJ (2015) Mechanics of viral chromatin reveals the pressurization of human adenovirus. ACS Nano 9(11):10826–10833. https://doi.org/10.1021/acsnano.5b03417

    Article  PubMed  CAS  Google Scholar 

  81. Ortega-Esteban A, Bodensiek K, San Martin C, Suomalainen M, Greber UF, de Pablo PJ, Schaap IA (2015) Fluorescence tracking of genome release during mechanical unpacking of single viruses. ACS Nano 9(11):10571–10579. https://doi.org/10.1021/acsnano.5b03020

    Article  PubMed  CAS  Google Scholar 

  82. Ortega-Esteban A, Perez-Berna AJ, Menendez-Conejero R, Flint SJ, San Martin C, de Pablo PJ (2013) Monitoring dynamics of human adenovirus disassembly induced by mechanical fatigue. Sci Rep 3:1434. https://doi.org/10.1038/srep01434

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Kusumi A, Nakada C, Ritchie K, Murase K, Suzuki K, Murakoshi H, Kasai RS, Kondo J, Fujiwara T (2005) Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. Annu Rev Biophys Biomol Struct 34:351–378

    Article  CAS  PubMed  Google Scholar 

  84. Iizuka N, Oka M, Yamada-Okabe H, Mori N, Tamesa T, Okada T, Takemoto N, Tangoku A, Hamada K, Nakayama H, Miyamoto T, Uchimura S, Hamamoto Y (2002) Comparison of gene expression profiles between hepatitis B virus- and hepatitis C virus-infected hepatocellular carcinoma by oligonucleotide microarray data on the basis of a supervised learning method. Cancer Res 62(14):3939–3944

    PubMed  CAS  Google Scholar 

  85. Snijder B, Sacher R, Ramo P, Damm EM, Liberali P, Pelkmans L (2009) Population context determines cell-to-cell variability in endocytosis and virus infection. Nature 461(7263):520–523. https://doi.org/10.1038/nature08282

    Article  PubMed  CAS  Google Scholar 

  86. Helmuth JA, Sbalzarini IF (2009) Deconvolving active contours for fluorescence microscopy images. In: Proc. Intl. Symp. Visual Computing (ISVC), Lecture notes in computer science, vol 5875. Springer, Las Vegas, USA, pp 544–553

    Google Scholar 

  87. Saltelli A, Ratto M, Andres T, Campolongo F, Cariboni J, Gatelli D, Saisana M (2008) Global sensitivity analysis: the primer, 1st edn. Wiley Interscience, New York

    Google Scholar 

  88. Sbalzarini IF, Mezzacasa A, Helenius A, Koumoutsakos P (2005) Effects of organelle shape on fluorescence recovery after photobleaching. Biophys J 89(3):1482–1492

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Kjellström G, Taxen L (1981) Stochastic optimization in system design. IEEE Trans Circ Syst 28:702–715

    Article  Google Scholar 

  90. Thach PT (1988) The design centering problem as a D.C. programming problem. Math Program 41:229–248

    Article  Google Scholar 

  91. Asmus J, Muller CL, Sbalzarini IF (2017) Lp-adaptation: simultaneous design centering and robustness estimation of electronic and biological systems. Sci Rep 7(1):6660. https://doi.org/10.1038/s41598-017-03556-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Reddy T, Shorthouse D, Parton DL, Jefferys E, Fowler PW, Chavent M, Baaden M, Sansom MS (2015) Nothing to sneeze at: a dynamic and integrative computational model of an influenza a virion. Structure 23(3):584–597. https://doi.org/10.1016/j.str.2014.12.019

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Miao Y, Fu R, Zhou HX, Cross TA (2015) Dynamic short hydrogen bonds in histidine tetrad of full-length M2 proton channel reveal tetrameric structural heterogeneity and functional mechanism. Structure 23(12):2300–2308. https://doi.org/10.1016/j.str.2015.09.011

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Takeda M, Pekosz A, Shuck K, Pinto LH, Lamb RA (2002) Influenza a virus M2 ion channel activity is essential for efficient replication in tissue culture. J Virol 76(3):1391–1399

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Shimbo K, Brassard DL, Lamb RA, Pinto LH (1996) Ion selectivity and activation of the M2 ion channel of influenza virus. Biophys J 70(3):1335–1346. https://doi.org/10.1016/S0006-3495(96)79690-X

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Martin K, Helenius A (1991) Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import. Cell 67(1):117–130

    Article  CAS  PubMed  Google Scholar 

  97. Fontana J, Steven AC (2013) At low pH, influenza virus matrix protein M1 undergoes a conformational change prior to dissociating from the membrane. J Virol 87(10):5621–5628. https://doi.org/10.1128/JVI.00276-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Ison MG (2011) Antivirals and resistance: influenza virus. Curr Opin Virol 1(6):563–573. https://doi.org/10.1016/j.coviro.2011.09.002

    Article  PubMed  CAS  Google Scholar 

  99. Greber UF (2014) How cells tune viral mechanics--insights from biophysical measurements of influenza virus. Biophys J 106(11):2317–2321. https://doi.org/10.1016/j.bpj.2014.04.025

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Cross TA, Dong H, Sharma M, Busath DD, Zhou HX (2012) M2 protein from influenza a: from multiple structures to biophysical and functional insights. Curr Opin Virol 2(2):128–133. https://doi.org/10.1016/j.coviro.2012.01.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI (2006) Adamantane resistance among influenza a viruses isolated early during the 2005–2006 influenza season in the United States. JAMA 295(8):891–894. https://doi.org/10.1001/jama.295.8.joc60020

    Article  PubMed  CAS  Google Scholar 

  102. Gleed ML, Busath DD (2015) Why bound amantadine fails to inhibit proton conductance according to simulations of the drug-resistant influenza a M2 (S31N). J Phys Chem B 119(3):1225–1231. https://doi.org/10.1021/jp508545d

    Article  PubMed  CAS  Google Scholar 

  103. Wright AK, Batsomboon P, Dai J, Hung I, Zhou HX, Dudley GB, Cross TA (2016) Differential binding of rimantadine enantiomers to influenza a M2 proton channel. J Am Chem Soc 138(5):1506–1509. https://doi.org/10.1021/jacs.5b13129

    Article  PubMed  CAS  Google Scholar 

  104. Pinto LH, Holsinger LJ, Lamb RA (1992) Influenza virus M2 protein has ion channel activity. Cell 69(3):517–528

    Article  CAS  PubMed  Google Scholar 

  105. Holsinger LJ, Lamb RA (1991) Influenza virus M2 integral membrane protein is a homotetramer stabilized by formation of disulfide bonds. Virology 183(1):32–34

    Article  CAS  PubMed  Google Scholar 

  106. Leiding T, Wang J, Martinsson J, DeGrado WF, Arskold SP (2010) Proton and cation transport activity of the M2 proton channel from influenza a virus. Proc Natl Acad Sci U S A 107(35):15409–15414. https://doi.org/10.1073/pnas.1009997107

    Article  PubMed  PubMed Central  Google Scholar 

  107. Stauffer S, Feng Y, Nebioglu F, Heilig R, Picotti P, Helenius A (2014) Stepwise priming by acidic pH and high K+ is required for efficient uncoating of influenza a virus cores after penetration. J Virol 88:13029. https://doi.org/10.1128/JVI.01430-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Chizhmakov IV, Geraghty FM, Ogden DC, Hayhurst A, Antoniou M, Hay AJ (1996) Selective proton permeability and pH regulation of the influenza virus M2 channel expressed in mouse erythroleukaemia cells. J Physiol 494(Pt 2):329–336

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Scott CC, Gruenberg J (2011) Ion flux and the function of endosomes and lysosomes: pH is just the start: the flux of ions across endosomal membranes influences endosome function not only through regulation of the luminal pH. BioEssays 33(2):103–110. https://doi.org/10.1002/bies.201000108

    Article  PubMed  CAS  Google Scholar 

  110. Suomalainen M, Greber UF (2013) Uncoating of non-enveloped viruses. Curr Opin Virol 3:27–33. https://doi.org/10.1016/j.coviro.2012.12.004

    Article  PubMed  CAS  Google Scholar 

  111. Kilcher S, Mercer J (2015) DNA virus uncoating. Virology 479-480:578. https://doi.org/10.1016/j.virol.2015.01.024

    Article  PubMed  CAS  Google Scholar 

  112. Polyansky AA, Ramaswamy R, Volynsky PE, Sbalzarini IF, Marrink SJ, Efremov RG (2010) Antimicrobial peptides induce growth of phosphatidylglycerol domains in a model bacterial membrane. J Phys Chem Lett 1(20):3108–3111. https://doi.org/10.1021/jz101163e

    Article  CAS  Google Scholar 

  113. Luisoni S, Suomalainen M, Boucke K, Tanner LB, Wenk MR, Guan XL, Grzybek M, Coskun U, Greber UF (2015) Co-option of membrane wounding enables virus penetration into cells. Cell Host Microbe 18(1):75–85. https://doi.org/10.1016/j.chom.2015.06.006

    Article  PubMed  CAS  Google Scholar 

  114. Luisoni S, Greber UF (2016) Biology of adenovirus cell entry – receptors, pathways, mechanisms. In: Curiel D (ed) Adenoviral vectors for gene therapy, 2nd edn. Academic Press, Elsevier, London, pp 27–58

    Chapter  Google Scholar 

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Authors and Affiliations

  1. Faculty of Computer Science, TU Dresden, Dresden, Germany

    Ivo F. Sbalzarini

  2. Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

    Ivo F. Sbalzarini

  3. Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland

    Urs F. Greber

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  1. Ivo F. Sbalzarini
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  2. Urs F. Greber
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Correspondence to Urs F. Greber .

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  1. School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK

    Yohei Yamauchi

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Sbalzarini, I.F., Greber, U.F. (2018). How Computational Models Enable Mechanistic Insights into Virus Infection. In: Yamauchi, Y. (eds) Influenza Virus. Methods in Molecular Biology, vol 1836. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8678-1_30

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