Roles of neutrophil extracellular trap degradation products in Group A Streptococcus pharyngitis

• Project/Area Number: 17K14974
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Laboratory animal science
• Research Institution: Niigata University (2021); The University of Tokyo (2017-2020)
• Principal Investigator: TANAKA MOTOTSUGU 新潟大学, 医歯学総合病院, 准教授 (40755740)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 化膿レンサ球菌 / 好中球細胞外トラップ / Group A streptococcus / Streptococcus pyogenes / NETs / DNase / 自然免疫 / 上皮細胞障害 / 細胞毒性

Outline of Final Research Achievements

Group A Streptococcus (GAS) secretes deoxyribonucleases (DNase) and evades host defence by degrading neutrophil extracellular traps (NETs). However, limited information is available on the roles of NET degradation products in GAS pharyngitis. In this study, we modified a mouse model of GAS pharyngitis and revealed an essential role for DNase in this model. A significant apoptosis of the nasal mucosa was induced by intranasal infection, however, in neutrophil-depleted mice, GAS colonization and damage to the nasal mucosa were significantly decreased. Furthermore, mice infected with DNase-knockout GAS mutants (spd(-), endA(-), and sdaD2(-)) survived significantly better than those infected with wild-type GAS. In addition, the supernatants of digested NETs enhanced GAS-induced cell death in vitro. These results indicate that NET degradation products may contribute to the establishment of pharyngeal infection caused by GAS.

Academic Significance and Societal Importance of the Research Achievements

化膿レンサ球菌（GAS）は、ヒトに感染して様々な疾患を引き起こす病原性細菌である。特に急性扁桃炎が多く、腎疾患の発症や増悪にも関与することが知られている。GASは、好中球の強力な殺菌機序である好中球細胞外トラップ（NETs）を分解する能力を有しているが、GAS扁桃炎におけるNET分解産物の役割については解明されていなかった。申請者は、GASをマウスに経鼻感染させた扁桃炎モデルとヒトの白血球を用いた実験を行い、NET分解産物がGAS扁桃感染に重要であることを見出した。本研究によって、GAS感染で発動する好中球の感染防御機構を適切に制御することがGAS扁桃炎の治療ターゲットになる可能性が示された。

Research Products

• [Journal Article] A bacterial small RNA regulates the adaptation of Helicobacter pylori to the host environment (2021)
  • Author(s): Kinoshita-Daitoku, R., Kiga, K., Miyakoshi, M. et al.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 2085-2085
  • DOI: 10.1038/s41467-021-22317-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutational diversity in mutY deficient Helicobacter pylori and its effect on adaptation to the gastric environment. (2020)
  • Author(s): Kinoshita-Daitoku R, Kiga K, Sanada T, Ogura Y, Bo Z, Iida T, Yokomori R, Kuroda E, Tanaka M, Sood A, Suzuki T, Nakai K, Hayashi T, Mimuro H.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 525 Issue: 3 Pages: 806-811
  • DOI: 10.1016/j.bbrc.2020.02.087
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Group A Streptococcus establishes pharynx infection by degrading the deoxyribonucleic acid of neutrophil extracellular traps. (2020)
  • Author(s): Tanaka M, Kinoshita-Daitoku R, Kiga K, Sanada T, Zhu B, Okano T, Aikawa C, Iida T, Ogura Y, Hayashi T, Okubo K, Kurosawa M, Hirahashi J, Suzuki T, Nakagawa I, Nangaku M, Mimuro H.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 3251-3251
  • DOI: 10.1038/s41598-020-60306-w
  • Peer Reviewed / Open Access / Int'l Joint Research