Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis
Plague caused by Yersinia pestis remains a public health threat worldwide. Because multidrug-resistant Y. pestis strains have been found in both humans and animals, phage therapy has attracted increasing attention as an alternative strategy against plague. However, phage resistance is a potential dr...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2023.1174510/full |
| _version_ | 1797819793699504128 |
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| author | Lisheng Xiao Lisheng Xiao Lisheng Xiao Zhizhen Qi Zhizhen Qi Kai Song Ruichen Lv Rong Chen Haihong Zhao Haihong Zhao Hailian Wu Hailian Wu Cunxiang Li Cunxiang Li Youquan Xin Youquan Xin Yong Jin Yong Jin Xiang Li Xiang Li Xiaoqing Xu Xiaoqing Xu Yafang Tan Zongmin Du Yujun Cui Xuefei Zhang Xuefei Zhang Ruifu Yang Ruifu Yang Xilin Zhao Yajun Song Yajun Song Yajun Song |
| author_facet | Lisheng Xiao Lisheng Xiao Lisheng Xiao Zhizhen Qi Zhizhen Qi Kai Song Ruichen Lv Rong Chen Haihong Zhao Haihong Zhao Hailian Wu Hailian Wu Cunxiang Li Cunxiang Li Youquan Xin Youquan Xin Yong Jin Yong Jin Xiang Li Xiang Li Xiaoqing Xu Xiaoqing Xu Yafang Tan Zongmin Du Yujun Cui Xuefei Zhang Xuefei Zhang Ruifu Yang Ruifu Yang Xilin Zhao Yajun Song Yajun Song Yajun Song |
| author_sort | Lisheng Xiao |
| collection | DOAJ |
| description | Plague caused by Yersinia pestis remains a public health threat worldwide. Because multidrug-resistant Y. pestis strains have been found in both humans and animals, phage therapy has attracted increasing attention as an alternative strategy against plague. However, phage resistance is a potential drawback of phage therapies, and the mechanism of phage resistance in Y. pestis is yet to be investigated. In this study, we obtained a bacteriophage-resistant strain of Y. pestis (S56) by continuously challenging Y. pestis 614F with the bacteriophage Yep-phi. Genome analysis identified three mutations in strain S56: waaA* (9-bp in-frame deletion 249GTCATCGTG257), cmk* (10-bp frameshift deletion 15CCGGTGATAA24), and ail* (1-bp frameshift deletion A538). WaaA (3-deoxy-D-manno-octulosonic acid transferase) is a key enzyme in lipopolysaccharide biosynthesis. The waaA* mutation leads to decreased phage adsorption because of the failure to synthesize the lipopolysaccharide core. The mutation in cmk (encoding cytidine monophosphate kinase) increased phage resistance, independent of phage adsorption, and caused in vitro growth defects in Y. pestis. The mutation in ail inhibited phage adsorption while restoring the growth of the waaA null mutant and accelerating the growth of the cmk null mutant. Our results confirmed that mutations in the WaaA–Cmk–Ail cascade in Y. pestis contribute to resistance against bacteriophage. Our findings help in understanding the interactions between Y. pestis and its phages. |
| first_indexed | 2024-03-13T09:27:50Z |
| format | Article |
| id | doaj.art-0e1143d034104ebc92ddfee5c9f480c7 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-03-13T09:27:50Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-0e1143d034104ebc92ddfee5c9f480c72023-05-26T04:41:35ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882023-05-011310.3389/fcimb.2023.11745101174510Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestisLisheng Xiao0Lisheng Xiao1Lisheng Xiao2Zhizhen Qi3Zhizhen Qi4Kai Song5Ruichen Lv6Rong Chen7Haihong Zhao8Haihong Zhao9Hailian Wu10Hailian Wu11Cunxiang Li12Cunxiang Li13Youquan Xin14Youquan Xin15Yong Jin16Yong Jin17Xiang Li18Xiang Li19Xiaoqing Xu20Xiaoqing Xu21Yafang Tan22Zongmin Du23Yujun Cui24Xuefei Zhang25Xuefei Zhang26Ruifu Yang27Ruifu Yang28Xilin Zhao29Yajun Song30Yajun Song31Yajun Song32Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, ChinaSchool of Basic Medicine, Anhui Medical University, Hefei, ChinaState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, ChinaQinghai Institute for Endemic Disease Prevention and Control, Xining, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, ChinaHua Dong Research Institute for Medicine and Biotechniques, Nanjing, ChinaDepartment of Laboratory Medicine, First Medical Center of Chinese People’s Liberation Army (PLA) General Hospital, Beijing, ChinaQinghai Institute for Endemic Disease Prevention and Control, Xining, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaQinghai Institute for Endemic Disease Prevention and Control, Xining, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaQinghai Institute for Endemic Disease Prevention and Control, Xining, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaQinghai Institute for Endemic Disease Prevention and Control, Xining, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaQinghai Institute for Endemic Disease Prevention and Control, Xining, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaQinghai Institute for Endemic Disease Prevention and Control, Xining, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaQinghai Institute for Endemic Disease Prevention and Control, Xining, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, ChinaState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, ChinaState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, ChinaQinghai Institute for Endemic Disease Prevention and Control, Xining, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaLaboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, ChinaSchool of Basic Medicine, Anhui Medical University, Hefei, ChinaState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, ChinaNational Health Commission - Qinghai Co-construction Key Laboratory for Plague Control, Xining, ChinaPlague caused by Yersinia pestis remains a public health threat worldwide. Because multidrug-resistant Y. pestis strains have been found in both humans and animals, phage therapy has attracted increasing attention as an alternative strategy against plague. However, phage resistance is a potential drawback of phage therapies, and the mechanism of phage resistance in Y. pestis is yet to be investigated. In this study, we obtained a bacteriophage-resistant strain of Y. pestis (S56) by continuously challenging Y. pestis 614F with the bacteriophage Yep-phi. Genome analysis identified three mutations in strain S56: waaA* (9-bp in-frame deletion 249GTCATCGTG257), cmk* (10-bp frameshift deletion 15CCGGTGATAA24), and ail* (1-bp frameshift deletion A538). WaaA (3-deoxy-D-manno-octulosonic acid transferase) is a key enzyme in lipopolysaccharide biosynthesis. The waaA* mutation leads to decreased phage adsorption because of the failure to synthesize the lipopolysaccharide core. The mutation in cmk (encoding cytidine monophosphate kinase) increased phage resistance, independent of phage adsorption, and caused in vitro growth defects in Y. pestis. The mutation in ail inhibited phage adsorption while restoring the growth of the waaA null mutant and accelerating the growth of the cmk null mutant. Our results confirmed that mutations in the WaaA–Cmk–Ail cascade in Y. pestis contribute to resistance against bacteriophage. Our findings help in understanding the interactions between Y. pestis and its phages.https://www.frontiersin.org/articles/10.3389/fcimb.2023.1174510/fullYersinia pestisphagephage resistancefitness costwaaAcmk |
| spellingShingle | Lisheng Xiao Lisheng Xiao Lisheng Xiao Zhizhen Qi Zhizhen Qi Kai Song Ruichen Lv Rong Chen Haihong Zhao Haihong Zhao Hailian Wu Hailian Wu Cunxiang Li Cunxiang Li Youquan Xin Youquan Xin Yong Jin Yong Jin Xiang Li Xiang Li Xiaoqing Xu Xiaoqing Xu Yafang Tan Zongmin Du Yujun Cui Xuefei Zhang Xuefei Zhang Ruifu Yang Ruifu Yang Xilin Zhao Yajun Song Yajun Song Yajun Song Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis Frontiers in Cellular and Infection Microbiology Yersinia pestis phage phage resistance fitness cost waaA cmk |
| title | Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis |
| title_full | Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis |
| title_fullStr | Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis |
| title_full_unstemmed | Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis |
| title_short | Interplays of mutations in waaA, cmk, and ail contribute to phage resistance in Yersinia pestis |
| title_sort | interplays of mutations in waaa cmk and ail contribute to phage resistance in yersinia pestis |
| topic | Yersinia pestis phage phage resistance fitness cost waaA cmk |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2023.1174510/full |
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