Immunological Bioinformatics Ole Lund Challenges of the immune system Outside Infection with microbe A Vaccine Infection Allergen -> with allergy microbe B Peptide Transplant drugs ations Time Creation Creation of self of an immune system/ Tolerance to self Autoimmunity (break of tolerance.
Download ReportTranscript Immunological Bioinformatics Ole Lund Challenges of the immune system Outside Infection with microbe A Vaccine Infection Allergen -> with allergy microbe B Peptide Transplant drugs ations Time Creation Creation of self of an immune system/ Tolerance to self Autoimmunity (break of tolerance.
Immunological Bioinformatics Ole Lund Challenges of the immune system Outside Infection with microbe A Vaccine Infection Allergen -> with allergy microbe B Peptide Transplant drugs ations Time Creation Creation of self of an immune system/ Tolerance to self Autoimmunity (break of tolerance to self) Inside Cancer Infectious Diseases •More than 400 microbial agents are associated with disease •Licensed vaccines in the United states for 22 microbial agents •Vaccines for 36 pathogens have been developed •Immunological Bioinformatics may be used to •Identify immunogenic regions in pathogens •These regions may be used as in rational vaccine design •Which pathogens to focus on? Infectious diseases may be ranked based on •Impact on health •Dangerousness •Economic impact Deaths from infectious diseases in the world in 2002 www.who.int/entity/whr/2004/annex/topic/en/annex_2_en.pdf Immune system •Innate – fast… •Addaptive – remembers… •Cellular •Cytotoxic T lymphocytes (CTL) •Helper T lymphocytes (HTL) •Humoral •B lymphocytes Figure by Eric A.J. Reits Peptide (epitope) bound to MHC Figure by Anne Mølgaard, peptide (KVDDTFYYV) used as vaccine by Snyder et al. J Virol 78, 7052-60 (2004). Informatics in biology • 70’ Little computing power – Analytical solutions • 80’ Computers, few data – Simulations of molecular/cellular dynamics • 90’ More data – Sequence and structure – Searching biological databases – Prediction of features by data driven methods – Analysis of gene expression data >polymerase“ MERIKELRDLMSQSRTREILTKTTVDHMAIIKKYTSGRQEKNPALRMKWMMAMKYPITAD KRIMEMIPERNEQGQTLWSKTNDAGSDRVMVSPLAVTWWNRNGPTTSTVHYPKVYKTYFE KVERLKHGTFGPVHFRNQVKIRRRVDINPGHADLSAKEAQDVIMEVVFPNEVGARILTSE SQLTITKEKKEELQDCKIAPLMVAYMLERELVRKTRFLPVAGGTSSVYIEVLHLTQGTCW EQMYTPGGEVRNDDVDQSLIIAARNIVRRATVSADPLASLLEMCHSTQIGGIRMVDILRQ NPTEEQAVDICKAAMGLRISSSFSFGGFTFKRTNGSSVKKEEEVLTGNLQTLKIKVHEGY EEFTMVGRRATAILRKATRRLIQLIVSGRDEQSIAEAIIVAMVFSQEDCMIKAVRGDLNF ... Immune Epitope Database (IEDB) Peters B, et al. Immunogenetics. 2005 57:326-36, PLoS Biol. 2005 3:e91. Data driven predictions List of peptides that have a given biological feature YMNGTMSQV GILGFVFTL ALWGFFPVV ILKEPVHGV ILGFVFTLT LLFGYPVYV GLSPTVWLS WLSLLVPFV FLPSDFFPS CVGGLLTMV FIAGNSAYE Mathematical model (neural network, hidden Markov model) Search databases for other biological sequences with the same feature/property >polymerase“ MERIKELRDLMSQSRTREILTKTTVDHMAIIKKYTSGRQEKNPALRMKWMMAMKYPITAD KRIMEMIPERNEQGQTLWSKTNDAGSDRVMVSPLAVTWWNRNGPTTSTVHYPKVYKTYFE KVERLKHGTFGPVHFRNQVKIRRRVDINPGHADLSAKEAQDVIMEVVFPNEVGARILTSE SQLTITKEKKEELQDCKIAPLMVAYMLERELVRKTRFLPVAGGTSSVYIEVLHLTQGTCW EQMYTPGGEVRNDDVDQSLIIAARNIVRRATVSADPLASLLEMCHSTQIGGIRMVDILRQ NPTEEQAVDICKAAMGLRISSSFSFGGFTFKRTNGSSVKKEEEVLTGNLQTLKIKVHEGY EEFTMVGRRATAILRKATRRLIQLIVSGRDEQSIAEAIIVAMVFSQEDCMIKAVRGDLNF ... Prediction algorithms MHC binding data Prediction algorithms Genome scans Antigen Discovery Lauemøller et al., 2000 Influenza A virus (A/Goose/Guangdong/1/96(H5N1)) >Segment 1 Genome agcaaaagcaggtcaattatattcaatatggaaagaataaaagaactaagagatctaatg tcgcagtcccgcactcgcgagatactaacaaaaaccactgtggatcatatggccataatc aagaaatacacatcaggaagacaagagaagaaccctgctctcagaatgaaatggatgatg gcaatgaaatatccaatcacagcagacaagagaataatggagatgattcctgaaaggaat and 13350 other nucleotides on 8 segments Proteins 9mer peptides >polymerase“ MERIKELRD MERIKELRDLMSQSRTREILTKTTVDHMAIIKKYTSGRQEKNPALRMKWMMAMKYPITAD ERIKELRDL KRIMEMIPERNEQGQTLWSKTNDAGSDRVMVSPLAVTWWNRNGPTTSTVHYPKVYKTYFE RIKELRDLM KVERLKHGTFGPVHFRNQVKIRRRVDINPGHADLSAKEAQDVIMEVVFPNEVGARILTSE IKELRDLMS SQLTITKEKKEELQDCKIAPLMVAYMLERELVRKTRFLPVAGGTSSVYIEVLHLTQGTCW KELRDLMSQ EQMYTPGGEVRNDDVDQSLIIAARNIVRRATVSADPLASLLEMCHSTQIGGIRMVDILRQ ELRDLMSQS NPTEEQAVDICKAAMGLRISSSFSFGGFTFKRTNGSSVKKEEEVLTGNLQTLKIKVHEGY LRDLMSQSR EEFTMVGRRATAILRKATRRLIQLIVSGRDEQSIAEAIIVAMVFSQEDCMIKAVRGDLNF RDLMSQSRT ... DLMSQSRTR LMSQSRTRE and 9 other proteins and 4376 other 9mers MHC Class I pathway Finding the needle in the haystack 1/200 peptides make to the surface Figure by Eric A.J. Reits Figure by Anne Mølgaard Why we do bioinformatics: Data driven vs. ab initio methods Limitations of Ab initio predictions of peptide binding to MHC class II molecules. Zhang H, Wang P, Papangelopoulos N, Xu Y, Sette A, Bourne PE, Lund O, Ponomarenko J, Nielsen M, Peters B. PLoS One. 2010 Feb 17;5(2):e9272. Good performance can be obtained from few data points Lundegaard C, Nielsen M, Lamberth K, Worning P, Sylvester-Hvid C, Buus S, Brunak S, Lund O. 2004. MHC Class I Epitope Binding Prediction Trained on Small Data Sets. In ICARIS 2004. (eds. G. Nicosia, V. Cutello, P.J. Bentley, and J.I. Timmis), Catania, Sicily. The Bio in Bioinformatics • Data driven computer science methods (NNs, HMMs, Gibbs samplers etc.) have poor performance on protein datasets • To give good performance they must • Be combined with information on amino acid similarities (Dayhoff and followers) • Take data set size into account Human MHC: ~1000 variants distributed over 12 types Peptide: up to 209 variants Figure by Anne Mølgaard, peptide (KVDDTFYYV) used as vaccine by Snyder et al. J Virol 78, 7052-60 (2004). Arms race between humans and microbes Recognize HLA molecules In Humans Peptides from microbes Escape HLA polymorphism! B0807 A6601 B4058 A3401 B5124 B2728 B4411 B0729 A0265 B3526 A3602 A0254 B4038 B1302 B0714 B3902 B0826 B7804 B3509 B4404 B4808 A2907 A1109 A2313 B4018 B4046 B0818 B5103 A2606 A0209 A2444 B5101 B1502 A6803 A2441 B4804 A0268 B1803 B5106 B4103 A3404 A0220 B3537 B5203 B4445 B0805 B2702 A0304 B4021 B1303 A2503 B3926 B0718 A3306 A3015 A7407 B4431 B3558 B0706 B4403 A0106 B5806 B5109 B1578 B0806 B4430 B1308 B3935 A0278 B5126 B0710 B0817 B1527 B3912 B0811 A6820 B1510 A2314 A3013 A0216 A6808 A6815 A7408 A2909 B1566 B1536 A2428 B4446 A6602 B5704 B1809 A0252 B5134 B1534 B1550 B9507 B0724 B5604 B1538 B4418 B0739 B4406 A2312 A3004 A2426 B1513 B5002 B3801 B1525 B3927 A3107 A2433 B0734 B3530 B1539 B4505 A3201 B7805 B3933 B2714 A0302 A1114 B4905 B1504 B4437 A0222 B4102 B5139 B5138 A0317 B3505 B7802 B1575 A2504 A2454 A3006 B4015 B4441 B4606 A1102 A6817 B5602 A6826 B5703 B4104 A2430 B5512 B3702 B4701 A3308 B1544 B1570 B3549 B4408 B3923 A3209 A2414 B9509 B5611 B4427 B4031 A2601 A0289 B0803 B4432 B4016 B3561 A3007 B1813 A2902 B2724 A2309 A3307 B1574 A2446 B5130 B3811 B5606 B4402 A1110 A0235 B5306 A0214 B4061 A2455 A0285 A0255 B1503 B4105 B5801 A0205 A3301 A0112 A2904 B8101 B1511 A6825 B5121 A2429 B4433 B3922 B0728 A2627 B4407 B8301 B1818 B8102 B1592 B1535 A0307 A0204 B4810 B0725 B0733 B1553 A2914 B1540 B4805 A0316 A0206 A3108 B5708 B4420 B0727 A2439 B2715 A0239 A0256 B3535 B4002 B4429 B5116 B4208 B5507 B3551 A7410 B1585 B3536 A0244 B4057 A2418 B0720 B0703 B1583 B1554 B3503 A0103 B5603 A2901 A2621 B1301 B5114 A0269 B4814 B4605 B5402 B4033 A1120 B5508 B2719 B5131 B4054 A6604 A2447 B3901 B1564 B5608 A0271 A6810 B9505 B1509 B2730 A2437 B1556 B5520 A3103 B4813 B4803 B1820 A0318 A2415 B1530 A0110 B0711 B5115 B4004 B3934 A3102 B2710 B2725 B6701 B4435 B1815 B4108 A0219 A0262 B0825 B4029 B6702 A1103 A2406 B4201 B2705 B1405 B8201 B0822 B4030 B3805 B5307 A2903 B5514 B3557 B0708 B3909 A3001 B0740 B4415 B1586 A6603 B1599 A2620 B5510 B5206 A7411 A0310 A6901 A2405 B5129 A3405 A2602 A6805 A0308 B1807 B1572 B3928 B1515 B5110 A2407 B2713 A3303 A3012 B4604 B4812 A0272 A6824 B0723 A6812 B5133 A2427 B1588 B3929 A3111 A3205 B3907 A0102 B1573 B1521 A6819 B3930 B4037 B0730 B4007 B0801 B1315 A2413 B5201 B3563 B5901 A2417 A2408 B5601 B4422 B4501 B3547 B5804 A0319 B3513 A1113 A2608 B1545 A2456 A2419 B1587 B5208 B3524 A0250 B7803 A0212 B4023 B5102 A0259 B0810 B3707 B0702 A1104 B4056 B4034 B0827 B3517 B1821 A1119 A0305 A2906 B1811 A6827 A2301 B2720 B3550 B4013 B4008 B4503 B3809 B5518 B2723 A0275 B4060 A0277 A0225 A0234 B3936 B5204 A6804 B3511 B2717 A0207 B0804 B5137 A3011 B5702 A2622 B5205 B4806 B5001 A1116 A0260 B1402 B4036 B1304 A2452 B1517 B4101 B2727 A2410 A3003 A0208 B5207 B5403 B3803 A2913 B4417 B5308 B4703 B5311 B0715 B3519 A2420 B3520 A2603 B4507 B4444 B1548 B3932 A1123 A1107 B5607 B1310 B5615 A3402 B0731 B4410 A0270 B1589 B3501 B3542 B0824 B3506 A3304 B2706 B5119 A0230 B1531 B3529 A0313 A2619 A0114 B3559 B5605 B0745 B0743 B4603 B1804 B3528 B5120 B4502 A3002 A2616 B4802 B1822 B7801 B4504 B5805 A0218 A0314 B4053 A6605 A2450 B1314 A2502 A2612 B1576 A0113 B1306 B1552 A3010 B1819 B3904 A2617 B3514 A0231 B3548 B1547 B9506 B5519 B0709 A2442 B3523 A2610 A0251 B4807 A6813 B5401 B4044 A6823 A0246 B4602 B1404 B3527 B4405 B1516 B1309 A1111 B1563 B5509 B1542 B4601 B5710 A2425 A1101 B0726 B2726 A2910 A3110 B9502 B2721 A0322 B5616 B3545 A0263 B5305 B1812 B3502 A6802 A3106 A2438 B5709 B0707 B3709 A4301 B3534 B1598 A2435 B3512 A2305 B4704 B8202 A3008 B4005 B4107 B1507 A2303 A7404 B5501 A0273 A3204 B3533 B5613 B5128 A6816 B4051 B0732 B4205 A0261 B1562 A0236 A0227 A3202 A2404 A6801 B1312 B5515 A2453 B3915 B3917 A0228 A3112 A2614 B0814 B4438 B1403 B4426 B3806 A3104 B2707 B5406 B4811 B3531 A0233 B1546 B3552 B4428 B0717 B3504 B3808 B1551 B4059 A7402 A2615 A2458 A0274 A2424 B0802 A7406 B5135 B1590 B4439 A2609 B2729 B4702 B1596 B0813 A7405 B5301 B4052 A6830 A2623 A6822 B4440 A0117 B3911 B4003 A0201 B0736 B3905 B3802 B5404 A2403 B3924 A2911 B5112 B3918 B4421 B5504 A2501 A2310 B0741 A3601 B0744 B1567 A0258 B1561 B3554 B3810 B5118 A3305 B5113 B1520 A6829 B0823 B5610 B4042 A0202 B5122 B4032 A2421 A2605 B4902 A2423 B4409 A3105 A0267 A2912 B3539 A0108 B4035 A0241 B4001 B4436 B4020 B4901 A1117 B4047 B3701 B4012 B5310 A2618 A0245 A0238 B3708 B2711 A0237 B3920 B4904 A8001 A3009 B1805 B5503 A3206 B3914 A2443 B1505 B1581 B1549 B5808 B4062 B1529 B3510 B5511 B1524 B2701 B5132 B1597 A7403 B4009 B5706 B3546 HLA specificity clustering A0201 A0101 A6802 B0702 Coverage of HLA alleles Supertype Selected allele A1 A*0101 A2 A*0201 A3 A*1101 A24 A*2401 A26 (new*) A*2601 B7 B*0702 B8 (new*) B*0801 B27 B*2705 B39(new*) B*3901 B44 B*4001 B58 B*5801 B62 B*1501 Clustering in: O Lund et al., Immunogenetics. 2004 55:797-810 Class II MHC binding Human MHC II: ~1000 variants • MHC class II binds peptides in the class II antigen presentation pathway • Binds peptides of length 9-18 (even whole proteins can bind!) • Binding cleft is open • Binding core is 9 aa Peptide: up to 209 variants Pan predictions – interpolation between both ligands and receptors Nielsen M, Lundegaard C, Blicher T, Lamberth K, Harndahl M, Justesen S, Roder G, Peters B, Sette A, Lund O, Buus S., NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS ONE. 2007 2:e796. B cell epitope predictions Humoral immunity Cartoon by Eric Reits Antibody - Antigen interaction Antigen The antibody recognizes structural properties of the surface of the antigen Fab Epitope Paratope Antibody Discontinuous B-cell epitopes An example: An epitope of the Outer Surface Protein A from Borrelia Burgdorferi (1OSP) SLDEKNSVSVDLPGEM KVLVSKEKNKDGKYDLI ATVDKLELKGTSDKNN GSGVLEGVKADKCKVK LTISDDLGQTTLEVFKE DGKTLVSKKVTSKDKS STEEKFNEKGEVSEKIIT RADGTRLEYTGIKSDGS GKAKEVLKG 1OSP, Li et al. 1997 Polyvalent vaccines • The equivalent of this in epitope based vaccines is to select epitopes in a way that that they together cover all strains. Uneven coverage, Average coverage = 2 Epitope Strain 1 Strain 2 Even coverage, Average coverage = 2 Strain 1 Strain 2 Karolinska Institute Response of 31 HIV infected patients to 184 predicted HIV epitopes Annika Karlsson Carina Perez Perez et al., JI, 2008 All HIV responsive patients respond to at least one of nine peptides Perez et al., JI, 2008 Designing diagnostic peptides • Algorithm – Select 20mer peptides conserved in all strains the diagnose should cover – Deselect all 20mer peptides that have more than 7 identical residues in any strain the diagnose should not cover – Select for epitopes etc. • Currently being tested in leporsy patients – Human TB, Cow paraTB underway Sheila Tuyet Tang, Claus Lundegaard Michel Klein, Annemieke Geluk (Leiden), Gregers Jungersen (Veterinærinst.) High throughput generation of linear B cell epitope data PepChipOmics: In situ synthesis of 10^6 different peptides on a glass slide Schafer Nielsen, Søren Buus, Massimo Andretta The parasite exports VAR2CSA to the RBC membrane which enable adhesion of parasites to CSA in the placenta IRBC Causing: Placental malaria Ali Salanti Min Sundheds Forliis - Frederik Christian von Havens Rejsejournal fra Den Arabiske Rejse 1760-1763, udgivet af Anne Haslund Hansen og Stig T. Rasmussen. Forlaget Vandkunsten, 2005. 405 s. : ill. ISBN 87-91393-10- Structural envelope of VAR2CSA with 7 domains Red blood cell membrane Ali Salanti Ali Salanti Rat sera were then tested by flow cytometry to test if IgG reacts with native VAR2CSA on VAR2CSA expressing malaria parasites: MFI 18 16 14 12 10 8 MFI 6 4 2 0 pep152 KLHconjugated pep152 KLHconjugated pep153 KLHconjugated pep153 KLHconjugated Control protein Conclusion. Both peptides induce IgG that reacts with native VAR2CSA. To do: Denature VAR2CSA and induce antibodies against linear epitopes and test on array Ali Salanti Immunonological Bioinformatics Group • • • • • • • • • • • Claus Lundegaard Morten Nielsen Mette Voldby Larsen Thomas Stranzl Massimo Andretta Leon Jessen Edita Bartaseviciute Salvatore Cosentino Jens Vindahl Kringelum Juliet Fredriksen Maria Dalby