The growth-down of Mycobacterium tuberculosis by macrophages-derived extracellular vesicles

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08836
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Bacteriology (including mycology)
• Research Institution: Kyoto Prefectural University
• Principal Investigator: Oka Mayuko 京都府立大学, 生命環境科学研究科, 准教授 (40347498)
• Co-Investigator(Kenkyū-buntansha): 堀口 安彦 大阪大学, 微生物病研究所, 教授 (00183939)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 結核菌 / マクロファージ / HIF-1alpha / 細胞外小胞

Outline of Final Research Achievements

Macrophages are major components of tuberculosis granulomas and are responsible for host defenses against the intracellular pathogen, Mycobacterium tuberculosis (Mtb). We herein showed the strong expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in tuberculosis granulomas and in Mtb-infected mouse bone marrow-derived macrophages (BMDM). Moreover, HIF-1alpha has a role in a fundamental host-protective mechanism against Mtb. Macrophages are known to produced and secrete exosomes, extracellular vesicles, which are a key factor of inflammation. When both growth phase and latent bacilli were infected in mouse BMDM, both macrophage-derived exosomes enhanced the increase in the pro-inflammatory cytokines. However, the exosomes that were derived from HIF-1 alpha deficient macrophages, did not increase in the level of cytokines. Thus, these result suggest that HIF-1 has a role in the function of exosomes.

Free Research Field

細菌学

Academic Significance and Societal Importance of the Research Achievements

結核は、単一病原体による最大級の感染症である。ワクチンや治療薬が開発されているにもかかわらず、年間1000万人が発症するのには、休眠期結核菌が持続潜伏感染する無症候状態の患者（潜在性結核）の存在が大きい。そのため、結核菌の増殖と休眠の調節機構の解明は重要である。申請者は、肺結核肉芽腫のマクロファージに発現するHIF-1alphaが増殖期と休眠期の結核菌感染により、さらにこのHIF-1alphaが結核菌の増殖調節や細胞外小胞による炎症性サイトカイン産生に寄与することを明らかにした。HIF-1alphaがマクロファージ内での結核菌に大きな影響を与える新たな因子の1つであることを示す。