Phage infection and sub-lethal antibiotic exposure mediate Enterococcus faecalis type VII secretion system dependent inhibition of bystander bacteria.
Phage infection and sub-lethal antibiotic exposure mediate Enterococcus faecalis type VII secretion system dependent inhibition of bystander bacteria.
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DOI：
10.1371/journal.pgen.1009204
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发表时间：
2021-01
期刊：
影响因子：
4.5
通讯作者：
Duerkop BA
中科院分区：
文献类型：
--
作者：
Chatterjee A;Willett JLE;Dunny GM;Duerkop BA
噬菌体（phages）被视为治疗多重耐药细菌感染的替代疗法。考虑到噬菌体具有较窄的宿主范围，人们普遍认为治疗性噬菌体对非靶标细菌影响较小。我们发现裂解性噬菌体感染会诱导致病性粪肠球菌中VIIb型分泌系统（T7SS）基因的转录。噬菌体感染过程中的膜损伤会诱导T7SS基因表达，从而导致对不同革兰氏阳性旁观细菌的细胞接触依赖性拮抗作用。essB（T7SS的一个结构成分）的缺失会消除噬菌体介导的对旁观者的杀伤作用。一个预测的免疫基因可提供针对T7SS介导的抑制的保护作用，其上游LXG毒素基因的破坏可挽救粪肠球菌和金黄色葡萄球菌旁观者的生长。噬菌体诱导T7SS基因表达和旁观者抑制需要丝氨酸/苏氨酸激酶IreK以及预测的GntR家族转录因子OG1RF_11099。此外，亚致死剂量的靶向膜和损伤DNA的抗生素可独立于噬菌体感染激活T7SS表达，引发针对旁观者细菌的T7SS抗菌活性。我们的研究结果强调了噬菌体感染和靶标细菌的抗生素暴露如何影响非靶标旁观者细菌，并意味着除抗生素之外的疗法，如噬菌体疗法，可能会对微生物群落造成附带损害。
人们对噬菌体作为治疗多重耐药细菌感染的替代疗法重新产生兴趣，这凸显了在微生物群落背景下理解噬菌体 - 细菌相互作用后果的重要性。尽管已经明确噬菌体对其宿主细菌具有高度特异性，但对于噬菌体感染（以及因此噬菌体疗法）是否会对微生物群落中的非靶标细菌造成附带损害，尚未达成明确共识。在此我们提供了直接证据，表明临床相关病原体的噬菌体感染如何触发一种内在的VII型分泌系统（T7SS）抗菌反应，从而限制了对噬菌体感染不敏感的邻近细菌细胞的生长。噬菌体诱导T7SS活性是一种应激反应，除噬菌体外，使用促进膜或DNA损伤的亚抑制浓度的抗生素也可诱导T7SS拮抗作用。这些数据共同表明，一种细菌病原体对多种应激源作出反应以诱导T7SS活性，这种活性通过对邻近非亲缘旁观者细菌细胞的拮抗作用表现出来。
Bacteriophages (phages) are being considered as alternative therapeutics for the treatment of multidrug resistant bacterial infections. Considering phages have narrow host-ranges, it is generally accepted that therapeutic phages will have a marginal impact on non-target bacteria. We have discovered that lytic phage infection induces transcription of type VIIb secretion system (T7SS) genes in the pathobiont Enterococcus faecalis. Membrane damage during phage infection induces T7SS gene expression resulting in cell contact dependent antagonism of different Gram positive bystander bacteria. Deletion of essB, a T7SS structural component, abrogates phage-mediated killing of bystanders. A predicted immunity gene confers protection against T7SS mediated inhibition, and disruption of its upstream LXG toxin gene rescues growth of E. faecalis and Staphylococcus aureus bystanders. Phage induction of T7SS gene expression and bystander inhibition requires IreK, a serine/threonine kinase, and OG1RF_11099, a predicted GntR-family transcription factor. Additionally, sub-lethal doses of membrane targeting and DNA damaging antibiotics activated T7SS expression independent of phage infection, triggering T7SS antibacterial activity against bystander bacteria. Our findings highlight how phage infection and antibiotic exposure of a target bacterium can affect non-target bystander bacteria and implies that therapies beyond antibiotics, such as phage therapy, could impose collateral damage to polymicrobial communities. Renewed interest in phages as alternative therapeutics to combat multi-drug resistant bacterial infections, highlights the importance of understanding the consequences of phage-bacteria interactions in the context of microbial communities. Although it is well established that phages are highly specific for their host bacterium, there is no clear consensus on whether or not phage infection (and thus phage therapy) would impose collateral damage to non-target bacteria in polymicrobial communities. Here we provide direct evidence of how phage infection of a clinically relevant pathogen triggers an intrinsic type VII secretion system (T7SS) antibacterial response that consequently restricts the growth of neighboring bacterial cells that are not susceptible to phage infection. Phage induction of T7SS activity is a stress response and in addition to phages, T7SS antagonism can be induced using sub-inhibitory concentrations of antibiotics that facilitate membrane or DNA damage. Together these data show that a bacterial pathogen responds to diverse stressors to induce T7SS activity which manifests through the antagonism of neighboring non-kin bystander bacterial cells.
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影响因子：
12.3
作者：
Bourgogne, Agathe;Garsin, Danielle A.;Qin, Xiang;Singh, Kavindra V.;Sillanpaa, Jouko;Yerrapragada, Shailaja;Ding, Yan;Dugan-Rocha, Shannon;Buhay, Christian;Shen, Hua;Chen, Guan;Williams, Gabrielle;Muzny, Donna;Maadani, Arash;Fox, Kristina A.;Gioia, Jason;Chen, Lei;Shang, Yue;Arias, Cesar A.;Nallapareddy, Sreedhar R.;Zhao, Meng;Prakash, Vittal P.;Chowdhury, Shahreen;Jiang, Huaiyang;Gibbs, Richard A.;Murray, Barbara E.;Highlander, Sarah K.;Weinstock, George M.
通讯作者：
Weinstock, George M.
影响因子：
6.4
作者：
Dale JL;Beckman KB;Willett JLE;Nilson JL;Palani NP;Baller JA;Hauge A;Gohl DM;Erickson R;Manias DA;Sadowsky MJ;Dunny GM
通讯作者：
Dunny GM
DOI：
10.1038/nrmicro3432
发表时间：
2015-05
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
Flores-Mireles AL;Walker JN;Caparon M;Hultgren SJ
通讯作者：
Hultgren SJ
影响因子：
6.4
作者：
Chatterjee, Anushila;Willett, Julia L. E.;Duerkop, Breck A.
通讯作者：
Duerkop, Breck A.
影响因子：
3.6
作者：
Aoki, Stephanie K.;Malinverni, Juliana C.;Jacoby, Kyle;Thomas, Benjamin;Pamma, Rupinderjit;Trinh, Brooke N.;Remers, Susan;Webb, Julia;Braaten, Bruce A.;Silhavy, Thomas J.;Low, David A.
通讯作者：
Low, David A.