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Microorganisms
Volume 14
Issue 6
10.3390/microorganisms14061323
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Disruption of Histidine Biosynthesis Impairs Outer Membrane Stability and Intracellular Survival of Brucella melitensis, Resulting in Attenuated Virulence

by
Yang Li
1,2,
Qiumei Shi
2,
Guangyu Yang
1,
Simin Chen
1,
Jinyue Liu
1,2,
Na Li
1,2,
Li Chen
2,
Zhenhua Wang
3,
Run Li
4,
Jiao Wang
5,
Shaohui Wang
1,
Yanqing Bao
1,
Jingjing Qi
1,
Tonglei Wu
2,* and
Mingxing Tian
1,*
1
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China
2
Hebei Key Laboratory of Preventive Veterinary Medicine, College of Animal Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao 066600, China
3
Shijiazhuang Shengbo Biological Technology Co., Ltd., Shijiazhuang 050031, China
4
Tangshan Yian Biological Engineering Co., Ltd., Tangshan 063000, China
5
Beijing Nabai Biotechnology Co., Ltd., Beijing, China
*
Authors to whom correspondence should be addressed.
Microorganisms 2026, 14(6), 1323; https://doi.org/10.3390/microorganisms14061323 (registering DOI)
Submission received: 21 May 2026 / Revised: 10 June 2026 / Accepted: 11 June 2026 / Published: 12 June 2026
(This article belongs to the Section Veterinary Microbiology)
Versions Notes

Abstract

Background: Brucellosis is a global zoonosis caused by Brucella. Histidine biosynthesis is essential for bacterial growth, but its role in Brucella melitensis virulence remains unclear. HisD catalyzes the final two steps of histidine synthesis and is absent in mammals, making it a potential drug target. Results: We constructed a hisD deletion mutant (ΔhisD) and complemented strain (ChisD) via homologous recombination. ΔhisD failed to grow in medium without histidine supplementation. It showed reduced survival under polymyxin B and SDS stress, and impaired outer membrane integrity under polymyxin B challenge, though no defect was observed under non-stressed conditions. Intracellularly, ΔhisD replicated poorly in HeLa and RAW264.7 cells, and this defect was rescued by exogenous histidine. In a mouse model, ΔhisD exhibited lower bacterial loads in liver and spleen, reduced splenomegaly, and attenuated hepatic granuloma formation. Conclusions: Histidine biosynthesis deficiency attenuates Brucella virulence by restricting nutritional acquisition and conditionally compromising outer membrane stability. HisD is a promising target for anti-brucellosis drug development, and ΔhisD holds potential as a live attenuated vaccine candidate.
Keywords: Brucella melitensis; hisD; histidine biosynthesis; virulence; outer membrane stability; intracellular survival Brucella melitensis; hisD; histidine biosynthesis; virulence; outer membrane stability; intracellular survival

Share and Cite

MDPI and ACS Style

Li, Y.; Shi, Q.; Yang, G.; Chen, S.; Liu, J.; Li, N.; Chen, L.; Wang, Z.; Li, R.; Wang, J.; et al. Disruption of Histidine Biosynthesis Impairs Outer Membrane Stability and Intracellular Survival of Brucella melitensis, Resulting in Attenuated Virulence. Microorganisms 2026, 14, 1323. https://doi.org/10.3390/microorganisms14061323

AMA Style

Li Y, Shi Q, Yang G, Chen S, Liu J, Li N, Chen L, Wang Z, Li R, Wang J, et al. Disruption of Histidine Biosynthesis Impairs Outer Membrane Stability and Intracellular Survival of Brucella melitensis, Resulting in Attenuated Virulence. Microorganisms. 2026; 14(6):1323. https://doi.org/10.3390/microorganisms14061323

Chicago/Turabian Style

Li, Yang, Qiumei Shi, Guangyu Yang, Simin Chen, Jinyue Liu, Na Li, Li Chen, Zhenhua Wang, Run Li, Jiao Wang, and et al. 2026. "Disruption of Histidine Biosynthesis Impairs Outer Membrane Stability and Intracellular Survival of Brucella melitensis, Resulting in Attenuated Virulence" Microorganisms 14, no. 6: 1323. https://doi.org/10.3390/microorganisms14061323

APA Style

Li, Y., Shi, Q., Yang, G., Chen, S., Liu, J., Li, N., Chen, L., Wang, Z., Li, R., Wang, J., Wang, S., Bao, Y., Qi, J., Wu, T., & Tian, M. (2026). Disruption of Histidine Biosynthesis Impairs Outer Membrane Stability and Intracellular Survival of Brucella melitensis, Resulting in Attenuated Virulence. Microorganisms, 14(6), 1323. https://doi.org/10.3390/microorganisms14061323

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