Journal of Microbiology

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Glucose affects capsular polysaccharides synthesis via CcpA and HPr in Streptococcus pneumoniae: Rui Yang, Yapeng Zhang, Hong Wang, Hanyi Wang, Jiangming Xiao, Lian Li, Yuan Yuan, Yibing Yin, Xuemei Zhang; J. Microbiol. 2025;63(5):e2411024. Published online May 27, 2025; DOI: https://doi.org/10.71150/jm.2411024

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Abstract PDF Supplementary Material: Streptococcus pneumoniae is a conditionally pathogenic bacteria that colonizes the nasopharynx of 27% to 65% of children and 10% of adults. Capsular polysaccharides are the most critical virulence factor of S. pneumoniae, and nonencapsulated strains are usually non-pathogenic. Previous studies have shown that glucose regulates capsule synthesis. To investigate the mechanism of carbon metabolism regulatory factors CcpA and HPr regulating capsule synthesis in the presence of glucose as the sole carbon source, we constructed deletion mutants (D39ΔccpA and ΔptsH) and complemented strains (D39ΔccpA::ccpA and ΔptsH::ptsH). In this study, we found that the promoting effect of capsule synthesis by glucose disappeared after the deletion of ccpA and ptsH, and demonstrated that the protein CcpA regulates capsule synthesis by binding to the cps promoter and altering the transcription level of the cps gene cluster. Increased glucose concentration up-regulated the level of HPr-Ser46~P, which enhanced the binding ability of CcpA to the DNA sequence of the cps promoter, thus promoting capsule synthesis. HPr also has a regulatory effect on capsule synthesis. These insights reveal a new synthesis mechanism of capsular polysaccharide and provide a new strategy of antibacterial drugs for S. pneumoniae.

Journal Articles

Streptococcus pneumoniae aminopeptidase N contributes to bacterial virulence and elicits a strong innate immune response through MAPK and PI3K/AKT signaling: Ling Wang , Xuemei Zhang , Guangying Wu , Yuhong Qi , Jinghui Zhang , Jing Yang , Hong Wang , Wenchun Xu; J. Microbiol. 2020;58(4):330-339. Published online February 27, 2020; DOI: https://doi.org/10.1007/s12275-020-9538-0

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Streptococcus pneumoniae is a Gram-positive pathogen with high morbidity and mortality globally but some of its pathogenesis remains unknown. Previous research has provided evidence that aminopeptidase N (PepN) is most likely a virulence factor of S. pneumoniae. However, its role in S. pneumoniae virulence and its interaction with the host remains to be confirmed. We generated a pepN gene deficient mutant strain and found that its virulence for mice was significantly attenuated as were in vitro adhesion and invasion of host cells. The PepN protein could induce a strong innate immune response in vivo and in vitro and induced secretion of IL-6 and TNF-α by primary peritoneal macrophages via the rapid phosphorylation of MAPK and PI3K/AKT signaling pathways and this was confirmed using specific pathway inhibitors. In conclusion, PepN is a novel virulence factor that is essential for the virulence of S. pneumoniae and induces host innate immunity via MAPK and PI3K/AKT signaling.

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Heterologous prime-boost immunization with live SPY1 and DnaJ protein of Streptococcus pneumoniae induces strong Th1 and Th17 cellular immune responses in mice: Yulan Qiu , Xuemei Zhang , Xinyuan Zhang , Yunjun Mo , Xiaoyu Sun , Jichao Wang , Yibing Yin , Wenchun Xu; J. Microbiol. 2017;55(10):823-829. Published online September 28, 2017; DOI: https://doi.org/10.1007/s12275-017-7262-1

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Abstract

diseases in children under 5-year-old. Vaccine has been used as an indispensable strategy to prevent S. pneumoniae infection for more than 30 years. Our previous studies confirmed that mucosal immunization with live attenuated strain SPY1 can protect mice against nasopharyngeal colonization of S. pneumoniae and lethal pneumococcal infection, and the protective effects are comparable with those induced by commercially available 23-valent polysaccharide vaccine. However, live attenuated vaccine SPY1 needs four inoculations to get satisfactory protective effect, which may increase the risk of virulence recovery. It is reported that heterologous primeboost approach is more effective than homologous primeboost approach. In the present study, to decrease the doses of live SPY1 and improve the safety of SPY1 vaccine, we immunized mice with SPY1 and DnaJ protein alternately. Our
results
showed that heterologous prime-boost immunization with SPY1 and DnaJ protein could significantly reduce the colonization of S. pneumoniae in the respiratory tract of mice, and induce stronger Th1 and Th17 cellular immune responses than SPY1 alone. These results indicate heterologous prime-boost immunization method not only elicits better protective effect than SPY1 alone, but also reduces the doses of live SPY1 and decreases the risk of SPY1 vaccine. This work is the first time to study the protective efficiency with two different forms of S. pneumoniae candidate vaccine, and provides a new strategy for the development of S. pneumoniae vaccine.

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Combined prime-boost immunization with systemic and mucosal pneumococcal vaccines based on Pneumococcal surface protein A to enhance protection against lethal pneumococcal infections
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Research Support, Non-U.S. Gov'ts

Pneumococcal wall teichoic acid is required for the pathogenesis of Streptococcus pneumoniae in murine models: Hongmei Xu , Libin Wang , Jian Huang , Yanqing Zhang , Feng Ma , Jianmin Wang , Wenchun Xu , Xuemei Zhang , Yibing Yin , Kaifeng Wu; J. Microbiol. 2015;53(2):147-154. Published online January 28, 2015; DOI: https://doi.org/10.1007/s12275-015-4616-4

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Abstract

Pneumococcal asymptomatic colonization of the respiratory tracts is a major risk for invasive pneumococcal disease. We have previously shown that pneumococcal wall teichoic acid (WTA) was involved in pneumococcal infection of sepsis and adherence to epithelial and endothelial cells. In this study, we investigated the contribution of pneumococcal WTA to bacterial colonization and dissemination in murine models. The result showed that nasopharynx colonizing D39 bacterial cells have a distinct phenotype showing an increased exposure of teichoic acids relative to medium-grown bacteria. The WTA-deficient mutants were impaired in their colonization to the nasopharynx and lungs, and led to a mild inflammation in the lungs at 36 h post-inoculation. Pretreatment of the murine nares with WTA reduced the ability of wild type D39 bacteria to colonize the nasopharynx. In addition, the WTA-deficient strain was impaired in its ability to invade the blood and brain following intranasal administration. WTA-deficient D39 strain was reduced in C3 deposition but was more susceptible to the killing by the neutrophils as compared with its parent strain. Our results also demonstrated that the WTA enhanced pneumococcal colonization and dissemination independently of the host strains. These results indicate that WTA plays an important role in pneumococcal pathogenesis, both in colonization and dissemination processes.

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Insight into the structure, biosynthesis, isolation method and biological function of teichoic acid in different gram-positive microorganisms: A review
Jiarun Han, Xin Zhao, Xilian Zhao, Ping Li, Qing Gu
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spd1672, a novel in vivo-induced gene, affects inflammatory response in a murine model of Streptococcus pneumoniae infection
Lingling Gan, Xuemei Zhang, Xiuyu Xu, Wenchun Xu, Chang Lu, Jin Cui, Hong Wang
Canadian Journal of Microbiology.2018; 64(6): 401. CrossRef
Lipoteichoic acid deficiency permits normal growth but impairs virulence of Streptococcus pneumoniae
Nathalie Heß, Franziska Waldow, Thomas P. Kohler, Manfred Rohde, Bernd Kreikemeyer, Alejandro Gómez-Mejia, Torsten Hain, Dominik Schwudke, Waldemar Vollmer, Sven Hammerschmidt, Nicolas Gisch
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Serotype-Independent Protection against Pneumococcal Infections Elicited by Intranasal Immunization with Ethanol-Killed Pneumococcal Strain, SPY1: Xiuyu Xu , Jiangping Meng , Yiping Wang , Jie Zheng , Kaifeng Wu , Xuemei Zhang , Yibing Yin , Qun Zhang; J. Microbiol. 2014;52(4):315-323. Published online March 29, 2014; DOI: https://doi.org/10.1007/s12275-014-3583-5

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Abstract

The 23-valent polysaccharide vaccine and the 7-valent pneumococcal conjugate vaccine are licensed vaccines that protect against pneumococcal infections worldwide. However, the incidence of pneumococcal diseases remains high in lowincome countries. Whole-cell vaccines with high safety and strong immunogenicity may be a favorable choice. We previously obtained a capsule-deficient Streptococcus pneumoniae mutant named SPY1 derived from strain D39. As an attenuated live pneumococcal vaccine, intranasal immunization with SPY1 elicits broad serotype-independent protection against pneumococcal infection. In this study, for safety consideration, we inactivated SPY1 with 70% ethanol and intranasally immunized BALB/c mice with killed SPY1 plus cholera toxin adjuvant for four times. Results showed that intranasal immunization with inactivated SPY1 induced strong humoral and cellular immune responses. Intranasal immunization with inactivated SPY1 plus cholera toxin adjuvant elicited effective serotype-independent protection against the colonization of pneumococcal strains 19F and 4 as well as lethal infection of pneumococcal serotypes 2, 3, 14, and 6B. The protection rates provided by inactivated SPY1 against lethal pneumococcal infection were comparable to those of currently used polysaccharide vaccines. In addition, vaccinespecific B-cell and T-cell immune responses mediated the protection elicited by SPY1. In conclusion, the 70% ethanolinactivated pneumococcal whole-cell vaccine SPY1 is a potentially safe and less complex vaccine strategy that offers broad protection against S. pneumoniae.

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Lingling Gan, Xuemei Zhang, Xiuyu Xu, Wenchun Xu, Chang Lu, Jin Cui, Hong Wang
Canadian Journal of Microbiology.2018; 64(6): 401. CrossRef
Heterologous prime-boost immunization with live SPY1 and DnaJ protein of Streptococcus pneumoniae induces strong Th1 and Th17 cellular immune responses in mice
Yulan Qiu, Xuemei Zhang, Hong Wang, Xinyuan Zhang, Yunjun Mo, Xiaoyu Sun, Jichao Wang, Yibing Yin, Wenchun Xu
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Screening and Identification of ClpE Interaction Proteins in Streptococcus pneumoniae by a Bacterial Two-Hybrid System and Co-immunoprecipitation: WenJuan Yan , YingYing Cai , Qun Zhang , YuSi Liu , WenChun Xu , YiBing Yin , YuJuan He , Hong Wang , XueMei Zhang; J. Microbiol. 2013;51(4):453-460. Published online August 30, 2013; DOI: https://doi.org/10.1007/s12275-013-3001-4

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Abstract: Hsp100/Clp proteins have crucial functions in the protein quality control, stress tolerance, and virulence of many pathogenic bacteria. ClpE is an important virulence factor involved in adherence and invasion in Streptococcus pneumoniae. To explore the underlying mechanism, we screened ClpE interaction proteins using a bacterial two-hybrid system and co-immunoprecipitation. We used ClpE as bait and constructed the pBT-ClpE bait plasmid for two-hybrid screening. Then, we constructed ClpE::GFP fusion for co-immunoprecipitation screening using anti-GFP monoclonal antibody. We obtained eight potential ClpE interaction proteins, including carbamoyl-phosphate synthase, pyruvate oxidase (SpxB), phosphoenolpyruvate-protein phosphotransferase, aminopeptidase N (pepN), L-lactate dehydrogenase, ribosomal protein S4, sensor histidine kinase (SPD_2019), and FtsW (a cell division protein). FtsW, SpxB, pepN, and SPD_2019 were confirmed to interact with ClpE using Bacterial Two-hybrid or Co-immunoprecipitation. Morphologic observations found that ΔclpE strain existed in abnormal division. β-Galactosidase activity assay suggested that ClpE contributed to the degradation of FtsW. Furthermore, FtsW could be induced by heat shock. The results suggested that ClpE might affect cell division by regulating the level of FtsW. These data may provide new insights in studying the role of ClpE in S. pneumoniae.

SP0454, A Putative Threonine Dehydratase, Is Required For Pneumococcal Virulence In Mice: WenJuan Yan , Hong Wang , WenChun Xu , KaiFeng Wu , Run Yao , XiuYu Xu , Jie Dong , YanQing Zhang , Wen Zhong , XueMei Zhang; J. Microbiol. 2012;50(3):511-517. Published online June 30, 2012; DOI: https://doi.org/10.1007/s12275-012-2014-8

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Abstract: Increasing pressure in antibiotic resistance and the requirement for the design of new vaccines are the objectives of clarifying the putative virulence factors in pneumococcal infection. In this study, the putative threonine dehydratase sp0454 was inactivated by erythromycin-resistance cassette replacement in Streptococcus pneumoniae CMCC 31203 strain. The sp0454 mutant was tested for cell growth, adherence, colonization, and virulence in a murine model. The Δsp0454 mutant showed decreased ability for colonization and impaired ability to adhere to A549 cells. However, the SP0454 polypeptide or its antiserum did not affect pneumococcal CMCC 31203 adhesion to A549 cells. The sp0454 deletion mutant was less virulent in a murine intranasal infection model. Real-time RT-PCR analysis revealed significant decrease of the pneumococcal surface antigen A expression in the sp0454 mutant. These results suggest that SP0454 contributes to virulence and colonization, which could be explained in part by modulating the expression of other virulence factors, such as psaA in pneumococcal infection.

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