Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

Journal of Experimental Medicine

Volumn 214, Issue 7, 2017, Pages 1949-1972

  Lamborn, Ian T ^a,b   Jing, Huie ^a   Zhang, Yu ^a   Drutman, Scott B ^d,e   Abbott, Jordan K ^c   Munir, Shirin ^a   Bade, Sangeeta ^f   Murdock, Heardley M ^a   Santos, Celia P ^a   Brock, Linda G ^a   Masutani, Evan ^a   Fordjour, Emmanuel Y ^a   McElwee, Joshua J ^g   Hughes, Jason D ^g   Nichols, Dave P ^c   Belkadi, Aziz ^h,i   Oler, Andrew J ^a   Happel, Corinne S ^a   Matthews, Helen F ^a   Abel, Laurent ^d,h,i   Collins, Peter L ^a   Subbarao, Kanta ^a   Gelfand, Erwin W ^c   Ciancanelli, Michael J ^d   Casanova, Jean Laurent ^d,h,i,j,k   Su, Helen C ^a,b   more..

^a NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

^c DEPARTMENT OF MEDICINE   (United States)

^d ROCKEFELLER UNIVERSITY   (United States)

^e MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^f Medical Science and Computing   (United States)

^g MERCK RESEARCH LABORATORIES   (United States)

^h IMAGINE INSTITUTE   (France)

ⁱ UNIVERSITÉ PARIS DESCARTES   (France)

^j HÔPITAL NECKER ENFANTS MALADES   (France)

^k HOWARD HUGHES MEDICAL INSTITUTE   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

BETA INTERFERON; DOUBLE STRANDED RNA; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERFERON INDUCED HELICASE C DOMAIN CONTAINING PROTEIN 1; INTERLEUKIN 1ALPHA; INTERLEUKIN 6; INTERLEUKIN 8; LUCIFERASE; MUTANT PROTEIN; POLYINOSINIC POLYCYTIDYLIC ACID; TUMOR NECROSIS FACTOR; ANTIVIRUS AGENT; IFIH1 PROTEIN, HUMAN; INTERFERON;

AIRWAY EPITHELIUM CELL; ANIMAL CELL; ARTICLE; CASE REPORT; CHILD; CONTROLLED STUDY; CYTOKINE PRODUCTION; FEMALE; GAIN OF FUNCTION MUTATION; GENE; GENE EXPRESSION; GENE OVEREXPRESSION; GENETIC DISORDER; HOMOZYGOSITY; HUMAN; HUMAN CELL; HUMAN RESPIRATORY SYNCYTIAL VIRUS; HUMAN RHINOVIRUS; HUMAN TISSUE; IFIH1 GENE; IMMUNOPATHOLOGY; INFECTION SENSITIVITY; INFLUENZA VIRUS; INHERITED MDA5 DEFICIENCY; INNATE IMMUNITY; INTERFERON PRODUCTION; LOSS OF FUNCTION MUTATION; LUNG FIBROBLAST; MISSENSE MUTATION; MOUSE; NONHUMAN; PRESCHOOL CHILD; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; PROTEIN MOTIF; RECURRENT INFECTION; RESPIRATORY TRACT INFECTION; RHINOVIRUS INFECTION; VIRUS REPLICATION; WILD TYPE; CELL CULTURE; DEFICIENCY; DNA MUTATIONAL ANALYSIS; DRUG EFFECTS; FIBROBLAST; GENETICS; HETEROZYGOTE; HOMOZYGOTE; HOST PATHOGEN INTERACTION; MALE; METABOLISM; MUTATION; NUCLEOTIDE SEQUENCE; PEDIGREE; PHYSIOLOGY; PICORNAVIRUS INFECTION; PROCEDURES; RECESSIVE GENE; RHINOVIRUS; VIROLOGY;

ANTIVIRAL AGENTS; BASE SEQUENCE; CELLS, CULTURED; CHILD, PRESCHOOL; DNA MUTATIONAL ANALYSIS; FEMALE; FIBROBLASTS; GENE EXPRESSION; GENES, RECESSIVE; HETEROZYGOTE; HOMOZYGOTE; HOST-PATHOGEN INTERACTIONS; HUMANS; INTERFERON-INDUCED HELICASE, IFIH1; INTERFERONS; MALE; MUTATION; PEDIGREE; PICORNAVIRIDAE INFECTIONS; RHINOVIRUS;

EID: 85021862719     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20161759     Document Type: Article

References (82)

1. Arora, R., M. Kaplan, and M. Nelson. 2011. Enterovirus-specific IgG in intravenous immunoglobulin preparations. Ann. Allergy Asthma Immunol. 106:544-545. http ://dx. doi. org /10. 1016 /j. anai. 2011. 03. 007
2. Balish, A.L., J.M. Katz, and A.I. Klimov. 2013. Influenza: propagation, quantification, and storage. Curr Protoc Microbiol Chapter 15:Unit 15G 11
3. Baños-Lara, M.R., A. Ghosh, and A. Guerrero-Plata. 2013. Critical role of MDA5 in the interferon response induced by human metapneumovirus infection in dendritic cells and in vivo. J. Virol. 87:1242-1251. http ://dx.doi. org /10. 1128 /JVI. 01213-12
4. Benitez, A.A., M. Panis, J. Xue, A. Varble, J.V. Shim, A.L. Frick, C.B. López, D. Sachs, and B.R. tenOever. 2015. In Vivo RNAi Screening Identifies MDA5 as a Significant Contributor to the Cellular Defense against Influenza A Virus. Cell Reports. 11:1714-1726. http ://dx. doi. org /10.1016 /j. celrep. 2015. 05. 032
5. Bochkov, Y.A., K. Grindle, F. Vang, M.D. Evans, and J.E. Gern. 2014. Improved molecular typing assay for rhinovirus species A, B, and C. J. Clin. Microbiol. 52:2461-2471. http ://dx. doi. org /10. 1128 /JCM. 00075-14
6. Byington, C.L., K. Ampofo, C. Stockmann, F.R. Adler, A. Herbener, T. Miller, X. Sheng, A.J. Blaschke, R. Crisp, and A.T. Pavia. 2015. Community Surveillance of Respiratory Viruses Among Families in the Utah Better Identification of Germs-Longitudinal Viral Epidemiology (BIG-LoVE) Study. Clin. Infect. Dis. 61:1217-1224. http ://dx. doi. org /10. 1093 /cid /civ486
7. Casanova, J.L., M.E. Conley, S.J. Seligman, L. Abel, and L.D. Notarangelo. 2014. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. J. Exp. Med. 211:2137-2149. http ://dx. doi.org /10. 1084 /jem. 20140520
8. Case, D.A., J.T. Berryman, R.M. Betz, D.S. Cerutti, and I. Cheatham. T.E., T.A. Darden, R.E. Duke, T.J. Giese, H. Gohlke, A.W. Goetz, N. Homeyer, S. Izadi, P. Janowski, J. Kaus, A. Kovalenko, T.S. Lee, S. LeGrand, P. Li, T. Luchko, R. Luo, B. Madej, K.M. Merz, G. Monard, P. Needham, H. Nguyen, H.T. Nguyen, I. Omelyan, A. Onufriev, D.R. Roe, A. Roitberg, R. Salomon-Ferrer, C.L. Simmerling, W. Smith, J. Swails, R.C. Walker, J. Wang, R.M. Wolf, X. Wu, D.M. York, and P.A. Kollman. 2015. AMB ER 2015. In University of California, San Francisco
9. Chapgier, A., R.F. Wynn, E. Jouanguy, O. Filipe-Santos, S. Zhang, J. Feinberg, K. Hawkins, J.L. Casanova, and P.D. Arkwright. 2006. Human complete Stat-1 deficiency is associated with defective type I and II IFN responses in vitro but immunity to some low virulence viruses in vivo. J. Immunol. 176:5078-5083. http ://dx. doi. org /10. 4049 /jimmunol. 176. 8. 5078
10. Ciancanelli, M.J., S.X. Huang, P. Luthra, H. Garner, Y. Itan, S. Volpi, F.G. Lafaille, C. Trouillet, M. Schmolke, R.A. Albrecht, et al. 2015. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science. 348:448-453. http ://dx. doi. org /10.1126 /science. aaa1578
11. de Chasseval, R., and J.P. de Villartay. 1992. High level transient gene expression in human lymphoid cells by SV40 large T antigen boost. Nucleic Acids Res. 20:245-250. http ://dx. doi. org /10. 1093 /nar /20. 2. 245
12. Delaloye, J., T. Roger, Q.G. Steiner-Tardivel, D. Le Roy, M. Knaup Reymond, S. Akira, V. Petrilli, C.E. Gomez, B. Perdiguero, J. Tschopp, et al. 2009. Innate immune sensing of modified vaccinia virus Ankara (MVA) is mediated by TLR2-TLR6, MDA-5 and the NALP3 inflammasome. PLoS Pathog. 5:e1000480. http ://dx. doi. org /10. 1371 /journal. ppat.1000480
13. Deschamps, M., G. Laval, M. Fagny, Y. Itan, L. Abel, J.L. Casanova, E. Patin, and L. Quintana-Murci. 2016. Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes. Am. J. Hum. Genet. 98:5-21. http ://dx. doi. org /10. 1016 /j. ajhg.2015. 11. 014
14. Dittmann, M., H.H. Hoffmann, M.A. Scull, R.H. Gilmore, K.L. Bell, M. Ciancanelli, S.J. Wilson, S. Crotta, Y. Yu, B. Flatley, et al. 2015. A serpin shapes the extracellular environment to prevent influenza A virus maturation. Cell. 160:631-643. http ://dx. doi. org /10. 1016 /j. cell. 2015. 01. 040
15. Eilertson, K.E., J.G. Booth, and C.D. Bustamante. 2012. SnIPRE: selection inference using a Poisson random effects model. PLOS Comput. Biol. 8:e1002806. http ://dx. doi. org /10. 1371 /journal. pcbi. 1002806
16. Errett, J.S., M.S. Suthar, A. McMillan, M.S. Diamond, and M. Gale Jr. 2013. The essential, nonredundant roles of RIG-I and MDA5 in detecting and controlling West Nile virus infection. J. Virol. 87:11416-11425. http ://dx.doi. org /10. 1128 /JVI. 01488-13
17. Galama, J.M., M. Gielen, and C.M. Weemaes. 2000. Enterovirus antibody titers after IVIG replacement in agammaglobulinemic children. Clin. Microbiol. Infect. 6:630-632. http ://dx. doi. org /10. 1046 /j. 1469-0691.2000. 00173. x
18. Gaunt, E.R., H. Harvala, C. McIntyre, K.E. Templeton, and P. Simmonds. 2011. Disease burden of the most commonly detected respiratory viruses in hospitalized patients calculated using the disability adjusted life year (DALY) model. J. Clin. Virol. 52:215-221. http ://dx. doi. org /10. 1016 /j.jcv. 2011. 07. 017
19. Gitlin, L., W. Barchet, S. Gilfillan, M. Cella, B. Beutler, R.A. Flavell, M.S. Diamond, and M. Colonna. 2006. Essential role of mda-5 in type I IFN responses to polyriboinosinic :polyribocytidylic acid and encephalomyocarditis picornavirus. Proc. Natl. Acad. Sci. USA. 103:8459-8464. http ://dx. doi. org /10. 1073 /pnas. 0603082103
20. Gitlin, L., L. Benoit, C. Song, M. Cella, S. Gilfillan, M.J. Holtzman, and M. Colonna. 2010. Melanoma differentiation-associated gene 5 (MDA5) is involved in the innate immune response to Paramyxoviridae infection in vivo. PLoS Pathog. 6:e1000734. http ://dx. doi. org /10. 1371 /journal. ppat.1000734
21. Global Burden of Disease Study 2013 Collaborators. 2015. Global, regional, and national incidence, prevalence, and years lived with disability for 301. acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 386:743-800. http ://dx. doi. org /10. 1016 /S0140-6736(15)60692-4
22. Grandvaux, N., X. Guan, F. Yoboua, N. Zucchini, K. Fink, P. Doyon, L. Martin, M.J. Servant, and S. Chartier. 2014. Sustained activation of interferon regulatory factor 3 during infection by paramyxoviruses requires MDA5. J. Innate Immun. 6:650-662. http ://dx. doi. org /10. 1159 /000360764
23. Greenberg, S.B. 2011. Update on rhinovirus and coronavirus infections. Semin. Respir. Crit. Care Med. 32:433-446. http ://dx. doi. org /10. 1055. /s-0031-1283283
24. Hanawa, H., P. Hematti, K. Keyvanfar, M.E. Metzger, A. Krouse, R.E. Donahue, S. Kepes, J. Gray, C.E. Dunbar, D.A. Persons, and A.W. Nienhuis. 2004. Efficient gene transfer into rhesus repopulating hematopoietic stem cells using a simian immunodeficiency virus-based lentiviral vector system. Blood. 103:4062-4069. http ://dx. doi. org /10. 1182 /blood-2004-01.-0045
25. Hasegawa, K., J.M. Mansbach, and C.A. Camargo Jr. 2014. Infectious pathogens and bronchiolitis outcomes. Expert Rev. Anti Infect. Ther. 12:817-828. http ://dx. doi. org /10. 1586 /14787210. 2014. 906901
26. Heikkinen, T., and A. Järvinen. 2003. The common cold. Lancet. 361:51-59. http ://dx. doi. org /10. 1016 /S0140-6736(03)12162-9
27. Hornak, V., R. Abel, A. Okur, B. Strockbine, A. Roitberg, and C. Simmerling. 2006. Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins. 65:712-725. http ://dx.doi. org /10. 1002 /prot. 21123
28. Israel, L., Y. Wang, K. Bulek, E. Della Mina, Z. Zhang, V. Pedergnana, M. Chrabieh, N.A. Lemmens, V. Sancho-Shimizu, M. Descatoire, et al. 2017. Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity. Cell. 168:789-800.e10. http ://dx. doi. org /10. 1016 /j. cell.2017. 01. 039
29. Itan, Y., L. Shang, B. Boisson, M.J. Ciancanelli, J.G. Markle, R. Martinez-Barricarte, E. Scott, I. Shah, P.D. Stenson, J. Gleeson, et al. 2016. The mutation significance cutoff: gene-level thresholds for variant predictions. Nat. Methods. 13:109-110. http ://dx. doi. org /10. 1038 /nmeth. 3739
30. Jaïdane, H., P. Sauter, F. Sane, A. Goffard, J. Gharbi, and D. Hober. 2010. Enteroviruses and type 1 diabetes: towards a better understanding of the relationship. Rev. Med. Virol. 20:265-280. http ://dx. doi. org /10. 1002 / rmv. 647
31. Jain, S., D.J. Williams, S.R. Arnold, K. Ampofo, A.M. Bramley, C. Reed, C. Stockmann, E.J. Anderson, C.G. Grijalva, W.H. Self, et al. CDC EPIC Study Team. 2015. Community-acquired pneumonia requiring hospitalization among U.S. children. N. Engl. J. Med. 372:835-845. http ://dx. doi. org /10. 1056 /NEJMoa1405870
32. Jin, Y.H., S.J. Kim, E.Y. So, L. Meng, M. Colonna, and B.S. Kim. 2012. Melanoma differentiation-associated gene 5 is critical for protection against Theiler's virus-induced demyelinating disease. J. Virol. 86:1531-1543. http ://dx. doi. org /10. 1128 /JVI. 06457-11
33. Jing, H., Q. Zhang, Y. Zhang, B.J. Hill, C.G. Dove, E.W. Gelfand, T.P. Atkinson, G. Uzel, H.F. Matthews, P.J. Mustillo, et al. 2014. Somatic reversion in dedicator of cytokinesis 8 immunodeficiency modulates disease phenotype. J. Allergy Clin. Immunol. 133:1667-1675. http ://dx. doi. org /10. 1016 /j. jaci. 2014. 03. 025
34. Kato, H., O. Takeuchi, S. Sato, M. Yoneyama, M. Yamamoto, K. Matsui, S. Uematsu, A. Jung, T. Kawai, K.J. Ishii, et al. 2006. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 441:101-105. http ://dx. doi. org /10. 1038 /nature04734
35. Kim, W.K., D. Jain, M.D. Sánchez, C.J. Koziol-White, K. Matthews, M.Q. Ge, A. Haczku, R.A. Panettieri Jr., M.B. Frieman, and C.B. López. 2014. Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation. Am. J. Respir. Crit. Care Med. 189:437-448. http ://dx. doi. org /10. 1164 /rccm. 201307-1338OC
36. Kingston, R.E., C.A. Chen, and H. Okayama. 2003. Calcium phosphate transfection. Curr Protoc Cell Biol Chapter 20:Unit 20 23
37. Lee, W.M., Y. Chen, W. Wang, and A. Mosser. 2015a. Growth of human rhinovirus in H1-HeLa cell suspension culture and purification of virions. Methods Mol. Biol. 1221:49-61. http ://dx. doi. org /10. 1007 /978.-1-4939-1571-2 5
38. Lee, W.M., Y. Chen, W. Wang, and A. Mosser. 2015b. Infectivity assays of human rhinovirus-A and-B serotypes. Methods Mol. Biol. 1221:71-81. http ://dx. doi. org /10. 1007 /978-1-4939-1571-2 7
39. Lee, W.M., K. Grindle, R. Vrtis, T. Pappas, F. Vang, I. Lee, and J.E. Gern. 2015c. Molecular identification and quantification of human rhinoviruses in respiratory samples. Methods Mol. Biol. 1221:25-38. http ://dx. doi. org /10. 1007 /978-1-4939-1571-2 3
40. Li, J., Y. Liu, and X. Zhang. 2010. Murine coronavirus induces type I interferon in oligodendrocytes through recognition by RIG-I and MDA5. J. Virol. 84:6472-6482. http ://dx. doi. org /10. 1128 /JVI. 00016-10
41. Li, P., B.P. Roberts, D.K. Chakravorty, and K.M. Merz Jr. 2013. Rational Design of Particle Mesh Ewald Compatible Lennard-Jones Parameters for +2 Metal Cations in Explicit Solvent. J. Chem. Theory Comput. 9:2733-2748. http ://dx. doi. org /10. 1021 /ct400146w
42. Lin, R., P. Génin, Y. Mamane, and J. Hiscott. 2000. Selective DNA binding and association with the CREB binding protein coactivator contribute to differential activation of alpha/beta interferon genes by interferon regulatory factors 3 and 7. Mol. Cell. Biol. 20:6342-6353. http ://dx. doi.org /10. 1128 /MCB. 20. 17. 6342-6353. 2000
43. Loo, Y.M., J. Fornek, N. Crochet, G. Bajwa, O. Perwitasari, L. Martinez-Sobrido, S. Akira, M.A. Gill, A. García-Sastre, M.G. Katze, and M. Gale Jr. 2008. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J. Virol. 82:335-345. http ://dx. doi. org /10. 1128 /JVI. 01080-07
44. Mäkelä, M.J., T. Puhakka, O. Ruuskanen, M. Leinonen, P. Saikku, M. Kimpimäki, S. Blomqvist, T. Hyypiä, and P. Arstila. 1998. Viruses and bacteria in the etiology of the common cold. J. Clin. Microbiol. 36:539-542
45. McCartney, S.A., L.B. Thackray, L. Gitlin, S. Gilfillan, H.W. Virgin, and M. Colonna. 2008. MDA-5 recognition of a murine norovirus. PLoS Pathog. 4:e1000108. http ://dx. doi. org /10. 1371 /journal. ppat. 1000108
46. McCartney, S.A., W. Vermi, S. Lonardi, C. Rossini, K. Otero, B. Calderon, S. Gilfillan, M.S. Diamond, E.R. Unanue, and M. Colonna. 2011. RNA sensor-induced type I IFN prevents diabetes caused by a β cell-tropic virus in mice. J. Clin. Invest. 121:1497-1507. http ://dx. doi. org /10. 1172. /JCI44005
47. McQuillan, R., A.L. Leutenegger, R. Abdel-Rahman, C.S. Franklin, M. Pericic, L. Barac-Lauc, N. Smolej-Narancic, B. Janicijevic, O. Polasek, A. Tenesa, et al. 2008. Runs of homozygosity in European populations. Am. J. Hum. Genet. 83:359-372. http ://dx. doi. org /10. 1016 /j. ajhg. 2008. 08. 007
48. Meagher, K.L., L.T. Redman, and H.A. Carlson. 2003. Development of polyphosphate parameters for use with the AMB ER force field. J. Comput. Chem. 24:1016-1025. http ://dx. doi. org /10. 1002 /jcc. 10262
49. Munir, S., C. Le Nouen, C. Luongo, U.J. Buchholz, P.L. Collins, and A. Bukreyev. 2008. Nonstructural proteins 1 and 2 of respiratory syncytial virus suppress maturation of human dendritic cells. J. Virol. 82:8780-8796. http ://dx. doi. org /10. 1128 /JVI. 00630-08
50. Nejentsev, S., N. Walker, D. Riches, M. Egholm, and J.A. Todd. 2009. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science. 324:387-389. http ://dx. doi. org /10. 1126. /science. 1167728
51. Oda, H., K. Nakagawa, J. Abe, T. Awaya, M. Funabiki, A. Hijikata, R. Nishikomori, M. Funatsuka, Y. Ohshima, Y. Sugawara, et al. 2014. Aicardi-Goutières syndrome is caused by IFIH1 mutations. Am. J. Hum. Genet. 95:121-125. http ://dx. doi. org /10. 1016 /j. ajhg. 2014. 06. 007
52. Palmenberg, A.C., D. Spiro, R. Kuzmickas, S. Wang, A. Djikeng, J.A. Rathe, C.M. Fraser-Liggett, and S.B. Liggett. 2009. Sequencing and analyses of all known human rhinovirus genomes reveal structure and evolution. Science. 324:55-59. http ://dx. doi. org /10. 1126 /science. 1165557
53. Pavia, A.T. 2011. Viral infections of the lower respiratory tract: old viruses, new viruses, and the role of diagnosis. Clin. Infect. Dis. 52(Suppl 4):S284-S289. http ://dx. doi. org /10. 1093 /cid /cir043
54. Pichlmair, A., O. Schulz, C.P. Tan, J. Rehwinkel, H. Kato, O. Takeuchi, S. Akira, M. Way, G. Schiavo, and C. Reis e Sousa. 2009. Activation of MDA5. requires higher-order RNA structures generated during virus infection. J. Virol. 83:10761-10769. http ://dx. doi. org /10. 1128 /JVI. 00770-09
55. Poole, A., C. Urbanek, C. Eng, J. Schageman, S. Jacobson, B.P. O'Connor, J.M. Galanter, C.R. Gignoux, L.A. Roth, R. Kumar, et al. 2014. Dissecting childhood asthma with nasal transcriptomics distinguishes subphenotypes of disease. J. Allergy Clin. Immunol. 133:670-8.e12. http ://dx. doi. org /10. 1016 /j. jaci. 2013. 11. 025
56. Purcell, S., B. Neale, K. Todd-Brown, L. Thomas, M.A. Ferreira, D. Bender, J. Maller, P. Sklar, P.I. de Bakker, M.J. Daly, and P.C. Sham. 2007. PLI NK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81:559-575. http ://dx. doi. org /10. 1086. /519795
57. Retterer, K., J. Juusola, M.T. Cho, P. Vitazka, F. Millan, F. Gibellini, A. Vertino-Bell, N. Smaoui, J. Neidich, K.G. Monaghan, et al. 2016. Clinical application of whole-exome sequencing across clinical indications. Genet. Med. 18:696-704. http ://dx. doi. org /10. 1038 /gim. 2015. 148
58. Reynolds, S.D., C. Rios, A. Wesolowska-Andersen, Y. Zhuang, M. Pinter, C. Happoldt, C.L. Hill, S.W. Lallier, G.P. Cosgrove, G.M. Solomon, et al. 2016. Airway Progenitor Clone Formation Is Enhanced by Y-27632-Dependent Changes in the Transcriptome. Am. J. Respir. Cell Mol. Biol. 55:323-336. http ://dx. doi. org /10. 1165 /rcmb. 2015-0274MA
59. Rice, G.I., G.M. Forte, M. Szynkiewicz, D.S. Chase, A. Aeby, M.S. Abdel-Hamid, S. Ackroyd, R. Allcock, K.M. Bailey, U. Balottin, et al. 2013. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNA SEH2A, RNA SEH2B, RNA SEH2C, SAM HD1, and ADAR: a case-control study. Lancet Neurol. 12:1159-1169. http ://dx. doi. org /10. 1016 /S1474.-4422(13)70258-8
60. Rice, G.I., Y. del Toro Duany, E.M. Jenkinson, G.M. Forte, B.H. Anderson, G. Ariaudo, B. Bader-Meunier, E.M. Baildam, R. Battini, M.W. Beresford, et al. 2014. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46:503-509. http ://dx. doi. org /10. 1038 /ng. 2933
61. Rodero, M.P., and Y.J. Crow. 2016. Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J. Exp. Med. 213:2527-2538. http ://dx. doi. org /10. 1084 /jem. 20161596
62. Rodriguez-Calvo, T., and M.G. von Herrath. 2015. Enterovirus infection and type 1 diabetes: closing in on a link? Diabetes. 64:1503-1505. http ://dx.doi. org /10. 2337 /db14-1931
63. Roth-Cross, J.K., S.J. Bender, and S.R. Weiss. 2008. Murine coronavirus mouse hepatitis virus is recognized by MDA5 and induces type I interferon in brain macrophages/microglia. J. Virol. 82:9829-9838. http ://dx. doi. org /10. 1128 /JVI. 01199-08
64. Rutsch, F., M. MacDougall, C. Lu, I. Buers, O. Mamaeva, Y. Nitschke, G.I. Rice, H. Erlandsen, H.G. Kehl, H. Thiele, et al. 2015. A specific IFIH1 gain-offunction mutation causes Singleton-Merten syndrome. Am. J. Hum. Genet. 96:275-282. http ://dx. doi. org /10. 1016 /j. ajhg. 2014. 12. 014
65. Salomon-Ferrer, R., A.W. Goetz, D. Poole, S. Le Grand, and R.C. Walker. 2013. Routine microsecond molecular dynamics simulations with AMB ER-Part II: Particle Mesh Ewald. J. Chem. Theory Comput. 9:3878-3888. http ://dx. doi. org /10. 1021 /ct400314y
66. Shingai, M., T. Ebihara, N.A. Begum, A. Kato, T. Honma, K. Matsumoto, H. Saito, H. Ogura, M. Matsumoto, and T. Seya. 2007. Differential type I IFN-inducing abilities of wild-type versus vaccine strains of measles virus. J. Immunol. 179:6123-6133. http ://dx. doi. org /10. 4049 /jimmunol.179. 9. 6123
67. Sirén, J., T. Imaizumi, D. Sarkar, T. Pietilä, D.L. Noah, R. Lin, J. Hiscott, R.M. Krug, P.B. Fisher, I. Julkunen, and S. Matikainen. 2006. Retinoic acid inducible gene-I and mda-5 are involved in influenza A virus-induced expression of antiviral cytokines. Microbes Infect. 8:2013-2020. http ://dx.doi. org /10. 1016 /j. micinf. 2006. 02. 028
68. Slater, L., N.W. Bartlett, J.J. Haas, J. Zhu, S.D. Message, R.P. Walton, A. Sykes, S. Dahdaleh, D.L. Clarke, M.G. Belvisi, et al. 2010. Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium. PLoS Pathog. 6:e1001178. http ://dx. doi. org /10.1371 /journal. ppat. 1001178
69. Smyth, D.J., J.D. Cooper, R. Bailey, S. Field, O. Burren, L.J. Smink, C. Guja, C. Ionescu-Tirgoviste, B. Widmer, D.B. Dunger, et al. 2006. A genomewide association study of nonsynonymous SNPs identifies a type 1. diabetes locus in the interferon-induced helicase (IFIH1) region. Nat. Genet. 38:617-619. http ://dx. doi. org /10. 1038 /ng1800
70. Stewart, S.A., D.M. Dykxhoorn, D. Palliser, H. Mizuno, E.Y. Yu, D.S. An, D.M. Sabatini, I.S. Chen, W.C. Hahn, P.A. Sharp, et al. 2003. Lentivirusdelivered stable gene silencing by RNAi in primary cells. RNA. 9:493-501. http ://dx. doi. org /10. 1261 /rna. 2192803
71. Sulem, P., H. Helgason, A. Oddson, H. Stefansson, S.A. Gudjonsson, F. Zink, E. Hjartarson, G.T. Sigurdsson, A. Jonasdottir, A. Jonasdottir, et al. 2015. Identification of a large set of rare complete human knockouts. Nat. Genet. 47:448-452. http ://dx. doi. org /10. 1038 /ng. 3243
72. Suprynowicz, F.A., G. Upadhyay, E. Krawczyk, S.C. Kramer, J.D. Hebert, X. Liu, H. Yuan, C. Cheluvaraju, P.W. Clapp, R.C. Boucher Jr., et al. 2012. Conditionally reprogrammed cells represent a stem-like state of adult epithelial cells. Proc. Natl. Acad. Sci. USA. 109:20035-20040. http ://dx.doi. org /10. 1073 /pnas. 1213241109
73. Triantafilou, K., E. Vakakis, E.A. Richer, G.L. Evans, J.P. Villiers, and M. Triantafilou. 2011. Human rhinovirus recognition in non-immune cells is mediated by Toll-like receptors and MDA-5, which trigger a synergetic pro-inflammatory immune response. Virulence. 2:22-29. http ://dx. doi. org /10. 4161 /viru. 2. 1. 13807
74. Van Eyck, L., L. De Somer, D. Pombal, S. Bornschein, G. Frans, S. Humblet-Baron, L. Moens, F. de Zegher, X. Bossuyt, C. Wouters, and A. Liston. 2015. IFIH1 mutation causes systemic lupus erythematosus with selective IgA-deficiency. Arthritis Rheumatol. 67:1592-1597. http ://dx.doi. org /10. 1002 /art. 39110
75. Wang, J.P., A. Cerny, D.R. Asher, E.A. Kurt-Jones, R.T. Bronson, and R.W. Finberg. 2010. MDA5 and MAVS mediate type I interferon responses to coxsackie B virus. J. Virol. 84:254-260. http ://dx. doi. org /10. 1128 / JVI. 00631-09
76. Wang, Q., D.R. Nagarkar, E.R. Bowman, D. Schneider, B. Gosangi, J. Lei, Y. Zhao, C.L. McHenry, R.V. Burgens, D.J. Miller, et al. 2009. Role of double-stranded RNA pattern recognition receptors in rhinovirusinduced airway epithelial cell responses. J. Immunol. 183:6989-6997. http ://dx. doi. org /10. 4049 /jimmunol. 0901386
77. Wang, Q., D.J. Miller, E.R. Bowman, D.R. Nagarkar, D. Schneider, Y. Zhao, M.J. Linn, A.M. Goldsmith, J.K. Bentley, U.S. Sajjan, and M.B. Hershenson. 2011. MDA5 and TLR3 initiate pro-inflammatory signaling pathways leading to rhinovirus-induced airways inflammation and hyperresponsiveness. PLoS Pathog. 7:e1002070. http ://dx. doi. org /10. 1371 /journal. ppat. 1002070
78. Wiszniewski, W., J.V. Hunter, N.A. Hanchard, J.R. Willer, C. Shaw, Q. Tian, A. Illner, X. Wang, S.W. Cheung, A. Patel, et al. 2013. TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities. Am. J. Hum. Genet. 93:197-210. http ://dx. doi. org /10. 1016 /j. ajhg. 2013. 05. 027
79. Wu, B., A. Peisley, C. Richards, H. Yao, X. Zeng, C. Lin, F. Chu, T. Walz, and S. Hur. 2013. Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell. 152:276-289. http ://dx.doi. org /10. 1016 /j. cell. 2012. 11. 048
80. Yang, Y., D.M. Muzny, J.G. Reid, M.N. Bainbridge, A. Willis, P.A. Ward, A. Braxton, J. Beuten, F. Xia, Z. Niu, et al. 2013. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 369:1502-1511. http ://dx. doi. org /10. 1056 /NEJMoa1306555
81. Yang, Y., D.M. Muzny, F. Xia, Z. Niu, R. Person, Y. Ding, P. Ward, A. Braxton, M. Wang, C. Buhay, et al. 2014. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 312:1870-1879. http ://dx. doi. org /10. 1001 /jama. 2014. 14601
82. Züst, R., L. Cervantes-Barragan, M. Habjan, R. Maier, B.W. Neuman, J. Ziebuhr, K.J. Szretter, S.C. Baker, W. Barchet, M.S. Diamond, et al. 2011. Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat. Immunol. 12:137-143. http ://dx. doi. org /10. 1038 /ni. 1979