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TbD1 缺失作为现代流行结核分枝杆菌谱系进化成功的驱动因素。

TbD1 deletion as a driver of the evolutionary success of modern epidemic Mycobacterium tuberculosis lineages.

机构信息

Department of Biology, University of Pisa, Pisa, Italy.

Institut Pasteur, Unit for Integrated Mycobacterial Pathogenomics, CNRS UMR 3525, Paris, 75015, France.

出版信息

Nat Commun. 2020 Feb 4;11(1):684. doi: 10.1038/s41467-020-14508-5.

DOI:10.1038/s41467-020-14508-5
PMID:32019932
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7000671/
Abstract

Mycobacterium tuberculosis (Mtb) strains are classified into different phylogenetic lineages (L), three of which (L2/L3/L4) emerged from a common progenitor after the loss of the MmpS6/MmpL6-encoding Mtb-specific deletion 1 region (TbD1). These TbD1-deleted "modern" lineages are responsible for globally-spread tuberculosis epidemics, whereas TbD1-intact "ancestral" lineages tend to be restricted to specific geographical areas, such as South India and South East Asia (L1) or East Africa (L7). By constructing and characterizing a panel of recombinant TbD1-knock-in and knock-out strains and comparison with clinical isolates, here we show that deletion of TbD1 confers to Mtb a significant increase in resistance to oxidative stress and hypoxia, which correlates with enhanced virulence in selected cellular, guinea pig and C3HeB/FeJ mouse infection models, the latter two mirroring in part the development of hypoxic granulomas in human disease progression. Our results suggest that loss of TbD1 at the origin of the L2/L3/L4 Mtb lineages was a key driver for their global epidemic spread and outstanding evolutionary success.

摘要

结核分枝杆菌（Mtb）菌株分为不同的系统发育谱系（L），其中三个谱系（L2/L3/L4）在失去 MmpS6/MmpL6 编码的 Mtb 特异性缺失 1 区（TbD1）后，从一个共同的祖先中出现。这些 TbD1 缺失的“现代”谱系负责全球传播的结核病流行，而 TbD1 完整的“祖先”谱系往往局限于特定的地理区域，如印度南部和东南亚（L1）或东非（L7）。通过构建和表征一组重组 TbD1 敲入和敲除菌株，并与临床分离株进行比较，我们在这里表明，TbD1 的缺失赋予 Mtb 对氧化应激和缺氧的显著抗性增加，这与在选定的细胞、豚鼠和 C3HeB/FeJ 小鼠感染模型中增强的毒力相关，后两者部分反映了人类疾病进展中缺氧性肉芽肿的发展。我们的结果表明，L2/L3/L4 Mtb 谱系起源时 TbD1 的缺失是其全球流行传播和卓越进化成功的关键驱动因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/fc270e5d442d/41467_2020_14508_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/c3cec151fff5/41467_2020_14508_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/82aa556af51c/41467_2020_14508_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/04ce5580ccb9/41467_2020_14508_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/f6b7d73abcd6/41467_2020_14508_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/fc270e5d442d/41467_2020_14508_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/c3cec151fff5/41467_2020_14508_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/f264f9147c49/41467_2020_14508_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/d9cf3de46798/41467_2020_14508_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/82aa556af51c/41467_2020_14508_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/04ce5580ccb9/41467_2020_14508_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/f6b7d73abcd6/41467_2020_14508_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2ed0/7000671/fc270e5d442d/41467_2020_14508_Fig7_HTML.jpg

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