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文件 2:自傳 CURRICULUM VITAE 顧 正 崙 Cheng-Lung KU, Ph. D Assistant professor, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan Adjunct assistant professor, Graduate Institute of Clinical Medical Science, China Medical University, Taiwan, Contact: 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, Taiwan, 333, R.O.C. Tel: (886) (03)211-880 ext 3896 Mobile: 0933650723 Email: [email protected] EDUCATION 2007 Ph. D. 2000 Master Degree PROFESSIONAL EXPERIENCE 2010 Assistant professor Graduate Institute of Clinical Medical Science, Chang-Gung University, Taoyuan, Taiwan Adjunct assistant professor Graduate Institute of Clinical Medical Science, China 2011 2008-2010 Université Paris V René Descartes, Doctoral. INSERM U550 Paris, France. Institute of Microbiology and Immunology, Faculty of life science, National Yang-Ming University, Taipei, Taiwan Assistant professor Medical University, Taichung, Taiwan Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan FIELD OF INTERESTS Human Immunology Human genetic infectious disease Primary immunodeficiency Autoimmune and infection disease Ku, C.L. 1 文件 2:自傳 HONORS Keystone Symposia Global Health Travel Award, funding by Bill & Melinda Gates Foundation (2013). Ph.D. fellowship from the French ministry of foreign affairs (2001). CURRENT RESEARCH TOPICS 1. Autoantibodies against Interferon- in adults with severe mycobacterial infection Severe infections caused by less virulent nontuberculous mycobacterium (NTM) are always found acquired immunodeficiency syndrome patients and in primary immunodeficiency children with genetic defect in IFN--IL-12/23 circuit. In adult, the prevalence of mycobacterial infections is increasing with ages; however, the molecular basis of the susceptibility is largely unknown. Acquired functional impairment or genetic variants in these pathways might diminish host immune system and cause the predispose to mycobacterial infection in adult, and they couldn’t be diagnosed by clinical routine examination. We have found around 50 patients with disseminated mycobacterial infections who have high affinity, naturally occurred autoantibodies against IFN-. Patients with autoantibodies to different cytokines have been found recently and were predispose to infectious diseases. In literature, autoantibodies to IFN- had found in some patients with disseminated NTM and TB infection world-wide. Compared with previous reports, our patients have a specific and very narrow clinical manifestation: 1: high coincident with reactivation of varicella-zoster virus (VZV) and salmonella species infections. 2: no clinical autoimmune phenotype and no other autoantibodies observed. 3: high prevalence of presence of anti-IFN- autoantibodies in our mycobacterial infection patients recruited. Therefore, we plan to address the role of anti-cytokines autoantibodies in adult mycobacterial infection, and using this particular cohort to study the role of IFN- in immune system and infectious diseases in natural. We listed some ongoing studying: “Anti-IFN-γ Autoantibody-Mediated Mycobacterial Disease is Strongly Associated with HLADR*15:02/16:02 and -DQ*05:01/05:02 in Patients from South East Asia.” We conducted an international survey with other laboratories. We confirmed the association of DRB1*16:02 and DQB1*05:02 in patients from other regions and we also identified a new risk allele DRB1*15:02- DQB1*05:01 in Thai population. “ Clinical Manifestations, Courses, and Outcomes in 45 Patients with Anti-Interferon-γ Autoantibodies and Disseminated Non-Tuberculous Mycobacterial Infections. “Role of Anti-IFN-γ Autoantibody in TB infection” 2. Molecular Mechanism of Anti-IFN- Autoantibodies Disease We are interested in studying the molecular basis of development of anti-IFN- autoantibodies among patients with severe NTM infections and keen to develop a novel therapeutic strategy based on the molecular mechanisms of these autoantibodies. In this project, we aim to clarify if the development of anti-IFN- autoantibody is induced by “mimicry molecule” mechanism and to Ku, C.L. 2 文件 2:自傳 establish a proof of principle alternative therapeutic strategy to anti-IFN- autoantibodies and other Anticytokine autoantibodies diseases. In our preliminary data, we identified a shared and critical B cell epitope of anti-IFN-γ autoantibodies in patients and raised a molecular mimicry model that the production of anti-IFN-γ autoantibodies was triggered by a microbe protein. 3. Role of Innate Immunity Against Enterovirus infection in human. The enteroviruses are a genus of (+) single-strained RNA viruses associated with several human and mammalian diseases. EV71 infection is endemic in Taiwan and caused threat to the health of children. Toll-like receptors (TLRs) is a proto-type PRRs and there are 10 TLRs found in human which could recognize various molecules associated with most pathogens. They acted as the sensor for the microbial infection and the activated TLRs played critical role in host immune system in face of virus. The function of TLRs against viral infection is confirmed by the discovered of human TLR3 deficient patients who suffered from severe HSV encephalitis. Moreover, TRAF3, TRIF, TBK1 and UNC-93B are molecules associated with TLR3signaling, the defects of these two genes in human were also found to associate with severe HSV encephalitis. This is also a proof-of-principle studying that severe viral infection might be caused by the genetic mutation in innate immunity. Clinically, the severe EV71 would manifest the encephalitis or even progress to cardiopulmonary collapse. We hypothesize that patients with the genetic defect or variant in TLR3 or other PRRs pathways which might cause the lack of appropriated immune response might have more severe clinical manifestation in compared with normal patients infected by EV71. In preliminary data, we had found three patients with TLR3 deficiency in children with CNS-involved EV71 infection and we are currently studying the impact of these mutation. However, we had applied the whole exomic sequencing to search new morbid genes in 7 children with CNS-involved EV71 infection. LIST OF PUBLISHCATIONs H-Index: 1726,27,24,25,18-23,14-17,10-13,8,9,6,7,5,1-4 *: first, co-first or corresponding author. 1. Chi CY, Chu CC, Liu JP, Lin CH, Ho MW, Lo WJ, Lin PC, Chen HJ, Chou CH, Feng JY, Fung CP, Sher YP, Li CY, Wang JH & *Ku CL. Anti-IFN-gamma autoantibodies in adults with disseminated nontuberculous mycobacterial infections are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster 2. 3. virus infection. Blood. 2013, 121: 1357-1366. Lee WI, Huang JL, Wu TS, Lee MH, Chen IJ, Yu KH, Liu CY, Yang CH, Hsieh MY, Lin YL, Shih YF, Jaing TH, Huang SC, Kuo TT & Ku CL. Patients with inhibitory and neutralizing auto-antibodies to interferon-gamma resemble the sporadic adult-onset phenotype of Mendelian Susceptibility to Mycobacterial Disease (MSMD) lacking Bacille Calmette-Guerin (BCG)-induced diseases. Immunobiology. 2013, 218: 762-771. Lin CJ, Wang SC, Ku CL, Kao JK, Chen M & Liu CS. Successful Unrelated Cord Blood Stem Cell Transplantation in an X-linked Chronic Granulomatous Disease Patient with Disseminated BCG-induced Infection. Pediatrics and neonatology. 2013, (In press) Ku, C.L. 3 文件 2:自傳 4. Savolainen L, Kantele A, Sandboge B, Siren M, Valleala H, Tuompo R, Pusa L, Erkinjuntti-Pekkanen R, Knuuttila A, Ku CL, Chi CY, Vasankari T & Tuuminen T. Modification of Clearview Tuberculosis (TB) Enzyme-Linked Immunosorbent Assay for TB 5. 6. Patients Not Infected with HIV. Clin. Vaccine Immunol. 2013, 20: 1479-1482. Mahlaoui N, Minard-Colin V, Picard C, Bolze A, Ku CL, Tournilhac O, Gilbert-Dussardier B, Pautard B, Durand P, Devictor D, Lachassinne E, Guillois B, Morin M, Gouraud F, Valensi F, Fischer A, Puel A, Abel L, Bonnet D & Casanova JL. Isolated congenital asplenia: a French nationwide retrospective survey of 20 cases. The Journal of pediatrics. 2011, 158: 142-148, 148 e141. Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, McDonald D, Geha RS, Takada H, Krause JC, Creech CB, Ku CL, Ehl S, Marodi L, Al-Muhsen S, Al-Hajjar S, Al-Ghonaium A, Day-Good NK, Holland SM, Gallin JI, Chapel H, Speert DP, Rodriguez-Gallego C, Colino E, Garty BZ, Roifman C, Hara T, Yoshikawa H, Nonoyama S, Domachowske J, Issekutz AC, Tang M, Smart J, Zitnik SE, Hoarau C, Kumararatne DS, Thrasher AJ, Davies EG, Bethune C, Sirvent N, de Ricaud D, Camcioglu Y, Vasconcelos J, Guedes M, Vitor AB, Rodrigo C, Almazan F, Mendez M, Arostegui JI, Alsina L, Fortuny C, Reichenbach J, Verbsky JW, Bossuyt X, Doffinger R, Abel L, Puel A & Casanova JL. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore). 7. 2010, 89: 403-425. Wu WP, Chang CH, Chiu YT, Ku CL, Wen MC, Shu KH & Wu MJ. A reduction of unilateral ureteral obstruction-induced renal fibrosis by a therapy combining valsartan with aliskiren. 8. Am. J. Physiol. Renal Physiol. 2010, 299: F929-941. Comeau JL, Lin TJ, Macken MB, Li B, Ku CL, von Bernuth H, Casanova JL & Issekutz AC. Staphylococcal pericarditis, and liver and paratracheal abscesses as presentations in two new 9. cases of interleukin-1 receptor associated kinase 4 deficiency. Pediatr. Infect. Dis. J. 2008, 27: 170-174. von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, Chrabieh M, Mustapha IB, Ghandil P, Camcioglu Y, Vasconcelos J, Sirvent N, Guedes M, Vitor AB, Herrero-Mata MJ, Arostegui JI, Rodrigo C, Alsina L, Ruiz-Ortiz E, Juan M, Fortuny C, Yague J, Anton J, Pascal M, Chang HH, Janniere L, Rose Y, Garty BZ, Chapel H, Issekutz A, Marodi L, Rodriguez-Gallego C, Banchereau J, Abel L, Li X, Chaussabel D, Puel A & Casanova JL. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008, 321: 691-696. 10. 11. Ku, C.L. Ku CL, Picard C, Erdos M, Jeurissen A, Bustamante J, Puel A, von Bernuth H, Filipe-Santos O, Chang HH, Lawrence T, Raes M, Marodi L, Bossuyt X & Casanova JL. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J. Med. Genet. 2007, 44: 16-23. Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J, Holland SM, Roifman C, Ehl S, Smart J, Tang M, Barrat FJ, Levy O, McDonald D, Day-Good NK, Miller R, Takada H, Hara T, Al-Hajjar S, Al-Ghonaium A, Speert D, Sanlaville D, Li X, Geissmann F, Vivier E, Marodi L, Garty BZ, Chapel H, 4 文件 2:自傳 Rodriguez-Gallego C, Bossuyt X, Abel L, Puel A & Casanova JL. Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise 12. 13. 14. 15. 16. redundant in protective immunity. J. Exp. Med. 2007, 204: 2407-2422. Picard C, von Bernuth H, Ku CL, Yang K, Puel A & Casanova JL. Inherited human IRAK-4 deficiency: an update. Immunol. Res. 2007, 38: 347-352. Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, Segal D, Sancho-Shimizu V, Lorenzo L, Puel A, Picard C, Chapgier A, Plancoulaine S, Titeux M, Cognet C, von Bernuth H, Ku CL, Casrouge A, Zhang XX, Barreiro L, Leonard J, Hamilton C, Lebon P, Heron B, Vallee L, Quintana-Murci L, Hovnanian A, Rozenberg F, Vivier E, Geissmann F, Tardieu M, Abel L & Casanova JL. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007, 317: 1522-1527. Cardenes M, von Bernuth H, Garcia-Saavedra A, Santiago E, Puel A, Ku CL, Emile JF, Picard C, Casanova JL, Colino E, Bordes A, Garfia A & Rodriguez-Gallego C. Autosomal recessive interleukin-1 receptor-associated kinase 4 deficiency in fourth-degree relatives. J. Pediatr. 2006, 148: 549-551. Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, Frucht DM, Christel K, von Bernuth H, Jouanguy E, Feinberg J, Durandy A, Senechal B, Chapgier A, Vogt G, de Beaucoudrey L, Fieschi C, Picard C, Garfa M, Chemli J, Bejaoui M, Tsolia MN, Kutukculer N, Plebani A, Notarangelo L, Bodemer C, Geissmann F, Israel A, Veron M, Knackstedt M, Barbouche R, Abel L, Magdorf K, Gendrel D, Agou F, Holland SM & Casanova JL. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J. Exp. Med. 2006, 203: 1745-1759. Puel A, Reichenbach J, Bustamante J, Ku CL, Feinberg J, Doffinger R, Bonnet M, Filipe-Santos O, de Beaucoudrey L, Durandy A, Horneff G, Novelli F, Wahn V, Smahi A, Israel A, Niehues T & Casanova JL. The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation. Am. J. Hum. 17. Genet. 2006, 78: 691-701. von Bernuth H, Ku CL, Rodriguez-Gallego C, Zhang S, Garty BZ, Marodi L, Chapel H, Chrabieh M, Miller RL, Picard C, Puel A & Casanova JL. A fast procedure for the detection 18. of defects in Toll-like receptor signaling. Pediatrics. 2006, 118: 2498-2503. Ku CL, Dupuis-Girod S, Dittrich AM, Bustamante J, Santos OF, Schulze I, Bertrand Y, Couly G, Bodemer C, Bossuyt X, Picard C & Casanova JL. NEMO mutations in 2 unrelated 19. boys with severe infections and conical teeth. Pediatrics. 2005, 115: e615-619. Ku CL, Yang K, Bustamante J, Puel A, von Bernuth H, Santos OF, Lawrence T, Chang HH, Al-Mousa H, Picard C & Casanova JL. Inherited disorders of human Toll-like receptor 20. signaling: immunological implications. Immunol. Rev. 2005, 203: 10-20. Lawrence T, Puel A, Reichenbach J, Ku CL, Chapgier A, Renner E, Minard-Colin V, Ouachee M & Casanova JL. Autosomal-dominant primary immunodeficiencies. Curr. Opin. 21. Hematol. 2005, 12: 22-30. Puel A, Yang K, Ku CL, von Bernuth H, Bustamante J, Santos OF, Lawrence T, Chang HH, Al-Mousa H, Picard C & Casanova JL. Heritable defects of the human TLR signalling Ku, C.L. 5 文件 2:自傳 pathways. J Endotoxin Res. 2005, 11: 220-224. 22. von Bernuth H, Puel A, Ku CL, Yang K, Bustamante J, Chang HH, Picard C & Casanova JL. Septicemia without sepsis: inherited disorders of nuclear factor-kappa B-mediated inflammation. Clin. Infect. Dis. 2005, 41 Suppl 7: S436-439. Yang K, Puel A, Zhang S, Eidenschenk C, Ku CL, Casrouge A, Picard C, von Bernuth H, Senechal B, Plancoulaine S, Al-Hajjar S, Al-Ghonaium A, Marodi L, Davidson D, Speert D, Roifman C, Garty BZ, Ozinsky A, Barrat FJ, Coffman RL, Miller RL, Li X, Lebon P, Rodriguez-Gallego C, Chapel H, Geissmann F, Jouanguy E & Casanova JL. Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and 23. redundant for protective immunity to viruses. Immunity. 2005, 23: 465-478. Feinberg J, Fieschi C, Doffinger R, Feinberg M, Leclerc T, Boisson-Dupuis S, Picard C, 24. Bustamante J, Chapgier A, Filipe-Santos O, Ku CL, de Beaucoudrey L, Reichenbach J, Antoni G, Balde R, Alcais A & Casanova JL. Bacillus Calmette Guerin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes. Eur. J. Immunol. 2004, 34: 3276-3284. Puel A, Picard C, Ku CL, Smahi A & Casanova JL. Inherited disorders of 25. NF-kappaB-mediated immunity in man. Curr. Opin. Immunol. 2004, 16: 34-41. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al-Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A & 26. Casanova JL. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003, 299: 2076-2079. Picard C, Puel A, Bustamante J, Ku CL & Casanova JL. Primary immunodeficiencies 27. associated with pneumococcal disease. Curr. Opin. Allergy Clin. Immunol. 2003, 3: 451-459. Impact Factor and Journal Ranking is according to the JCR of the year of publication or of 2012. CONFERENCE 9,8,7,6,5,4,3,1,2 1. 2. 3. The 16th Biennial Meeting of the European Society for Immunodeficiencies; Prague, Czech Republic. 2014/10/29-11/02. "Anti-Interferon-Gamma Autoantibodies in Adults with Disseminated Nontuberculous Mycobacterial Infections Are Associated with HLA-DRB1*16:02 and DQB1*05:02", Poster. Supported by NHRI. The 16th Biennial Meeting of the European Society for Immunodeficiencies; Prague, Czech Republic. 2014/10/29-11/02. "Severe Enterovirus 71 Infection in Children with Toll-Like Receptor 3 Deficiency", Poster Talk. Supported by CMRP. [Best Poster Award] Joint Symposium Between Taiwan-Austria Research Commmunites: Host-Pathogen Interaction: Regulation of Innate Immuntiy Signaling; Taipei Medical University, Taipei, Taiwan. 2014/05/06-07. "Anti-Interferon-γ Autoantibodies in Adults with Disseminated Nontuberculous Mycobacterial Infections: From clinical to mechanism. ", Oral. Supported by Ku, C.L. 6 文件 2:自傳 4. 15th International Congress of Immunology; Milan, Italy. 2013/08/22-27. "Presence of 5. 6. 7. 8. 9. Ku, C.L. Anti-Interferon Gamma Autoantibodies in Mycobacterial Infected Patients Associated with the HLA-DRB1*16:02 and DQB1*05:02", Poster. Supported by NHRI. The Innate Immune Response in the Pathogenesis of Infectious Disease; Ouro preto, Brazil. 2013/05/09-15. "Presence of Anti-Interferon Gamma Autoantibodies in Mycobacterial Infected Patients Associated with the HLA-DRB1*16:02 and DQB1*05:02", Poster. Supported by Bill & Melinda Gates Foundation. Taiwan-UK Conference on Life Sciences; Oxford, UK. 2012/09/01-02. "Anti-Cytokine Autoantibodies (ACADs): A Crossroad of Autoimmune and Infectious Disease", Invited speaker. Supported by Human Immunity; Lisbon, Portugal. 2012/08/19-21. "Presence of Anti-Interferon Gamma Autoantibodies in Mycobacterial Infected Patients Associated with the HLA-DRB1*16:02 and DQB1*05:02", Poster. Supported by NHRI. 8th International Congress on Autoimmunity; Granada, Spain. 2012/05/09-13. "Presence of Anti-Interferon Gamma Autoantibodies in Mycobacterial Infected Patients Associated with the HLA-DRB1*16:02 and DQB1*05:02", Oral Presentation. Supported by NSC. CHSA Immunity & Infection; Suzhou, China. 2011/09/08-12. "Disseminated Nontuberculous Mycobacterial Infections in Patients with Anti-Interferon-gamma Autoantibodies", Oral presentation. Supported by NHRI. 7