Establishment of mouse model of chronic mucocutaneous candidiasis disease and use them to find therapeutic target

• Project/Area Number: 25670477
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Hiroshima University
• Principal Investigator: OKADA Satoshi 広島大学, 大学病院, 病院助教 (80457241)
• Co-Investigator(Kenkyū-buntansha): TSUMURA Miyuki 広島大学, 医師薬保健学研究院, 研究員 (80646274)
• Co-Investigator(Renkei-kenkyūsha): OHARA Osamu 公益財団法人かずさDNA研究所, ヒトゲノム研究部, 研究室長 (20370926)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: STAT1 / CMCD / IL-17 / マウス / ノックインマウス / 治療

Outline of Final Research Achievements

We clarified the impact of STAT1 GOF mutations on the development of IL-17 producing T cells. We first investigated the effect of IFN-a/b, IFN-g and IL-27, cytokines that predominantly activate STAT1, in the differentiation of naive T cells into IL-17A-producing cells. We observed a much stronger reduction of the proportion of IL-17A T cells in the patients than in healthy controls. These data suggested that the poor development of IL-17 T cells in patients heterozygous for STAT1 alleles could result from enhanced IFNs and IL-27 responses via STAT1. We then treated cells with neutralizing antibodies (Abs) against IFN-a/b, IFN-g and IL-27. The combination of these Abs rescued the development of IL-17 T cells in CMCD patients carrying STAT1 mutations. These experiments established a key mechanism underlying impaired development of IL-17 T cells in the patients. This discovery also give us a new potential therapeutic target to cure host susceptibility to Candida in those patients.

Research Products

• [Journal Article] DOCK2 and a Recessive Immunodeficiency with Early-Onset Invasive Infections. (2015)
  • Author(s): Dobbs K, Conde CD, Zhang SY, Parolini S, Audry M, Chou J, Haapaniemi E, Keles S, Bilic I, Okada S, et al.
  • Journal Title: N Engl J Med Volume: in press
  • Peer Reviewed
• [Journal Article] Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. (2015)
  • Author(s): Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer SD, Yuan C, Volpi S, Li Z, Sanal O, Mansouri D, Tezcan I, Rice GI, Chen C, Mansouri N, Mahdaviani SA, Itan Y, Boisson B, Okada S, et al.
  • Journal Title: Nature Volume: 517 Issue: 7532 Pages: 667-76
  • DOI: 10.1038/nature13801
  • Peer Reviewed
• [Journal Article] Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency (2014)
  • Author(s): Ciancanelli MJ, Huang SX, Luthra, Garner H, Itan Y, Volpi S, Lafaille FG, Trouillet C, Schmolke M, Albrecht RA, Israelsson E, Lim HK, Casadio M, Hermesh T, Lorenzo L, Leung LW, Pedergnana V, Boisson B, Okada S, et al.
  • Journal Title: Science Volume: Epub Issue: 6233 Pages: 448-53
  • DOI: 10.1126/science.aaa1578
  • Peer Reviewed
• [Journal Article] Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. (2014)
  • Author(s): Mizoguchi Y, Tsumura M, Okada S, Hirata O, Minegishi S, Imai K, Hyakuna N, Muramatsu H, Kojima S, Ozaki Y, Imai T, Takeda S, Okazaki T, Ito T, Yasunaga S, Takihara Y, Bryant VL, Kong XF, Cypowyj S, Boisson-Dupuis S, Puel A, Casanova JL, Morio T, Kobayashi M.
  • Journal Title: J Leukoc Biol. Volume: 95 Issue: 4 Pages: 667-76
  • DOI: 10.1038/jid.2013.480
  • Peer Reviewed
• [Journal Article] New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe. (2013)
  • Author(s): Soltesz B, Toth B, Shabashova N, Bondarenko A, Okada S, Cypowyj S, Abhyankar A, Csorba G, Tasko S, Sarkadi AK, Mehes L, Rozsival P, Neumann D, Chernyshova L, Tulassay Z, Puel A, Casanova JL, Sediva A, Litzman J, Marodi L.
  • Journal Title: J Med Genet. Volume: 50 Issue: 9 Pages: 567-78
  • DOI: 10.1136/jmedgenet-2013-101570
  • Peer Reviewed
• [Journal Article] Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis (2013)
  • Author(s): Hirata, O.
  • Journal Title: Haematologica Volume: 98 Issue: 10 Pages: 1641-1649
  • DOI: 10.3324/haematol.2013.083741
  • Peer Reviewed
• [Journal Article] Partial IFN-γR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation. (2013)
  • Author(s): Moncada-Velez M, Martinez-Barricarte R, Bogunovic D, Kong XF, Blancas-Galicia L, Tirpan C, Aksu G, Vincent QB, Boisson B, Itan Y, Ramirez-Alejo N, Okada S, et. al.
  • Journal Title: Blood Volume: 122 Issue: 14 Pages: 2390-401
  • DOI: 10.1182/blood-2013-01-480814
  • Peer Reviewed
• [Journal Article] A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease. (2013)
  • Author(s): Kong XF, Bousfiha A, Rouissi A, Itan Y, Abhyankar A, Bryant V, Okada S, Ailal F, Bustamante J, Casanova JL, Hirst J, Boisson-Dupuis S.
  • Journal Title: PLoS One Volume: 8 Issue: 3 Pages: e58286-e58286
  • DOI: 10.1371/journal.pone.0058286
  • Peer Reviewed
• [Journal Article] Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region. (2013)
  • Author(s): Grant AV, El Baghdadi J, Sabri A, El Azbaoui S, Alaoui-Tahiri K, Abderrahmani Rhorfi I, Gharbaoui Y, Abid A, Benkirane M, Raharimanga V, Richard V, Orlova M, Boland A, Migaud M, Okada S, et al.
  • Journal Title: Am J Hum Genet. Volume: 92 Issue: 3 Pages: 407-14
  • DOI: 10.1016/j.ajhg.2013.01.013
  • Peer Reviewed
• [Presentation] Chronic Mucocutaneous Candidiasis (2015)
  • Author(s): Okada S
  • Organizer: Pediatric Academic Society annual meeting 2015
  • Place of Presentation: San Diego, USA
  • Year and Date: 2015-04-25 – 2015-04-28
• [Presentation] 新生児期の好中球減少症 (2014)
  • Author(s): 岡田 賢, 中村和洋, 小林正夫
  • Organizer: 第24回 日本産婦人科・新生児血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-06-13 – 2014-06-14
  • Invited
• [Presentation] 新生児期の好中球減少症 (2014)
  • Author(s): 岡田 賢
  • Organizer: 日本産婦人科・新生児血液学会学術集会
  • Place of Presentation: 横浜
• [Presentation] STAT1異常による原発性免疫不全症 (2013)
  • Author(s): 岡田 賢
  • Organizer: 日本小児科学会
  • Place of Presentation: 広島