Cyclic di-GMP mediates Mycobacterium tuberculosis dormancy and pathogenecity.
Dormancy of Mycobacterium tuberculosis is likely to be a major cause of extended chemotherapeutic regimens and wide prevalence of tuberculosis. The molecular mechanisms underlying M. tuberculosis dormancy are not well understood. In this study, single-copy genes responsible for synthesis (dgc) and degradation (pde) of the ubiquitous bacterial second messenger, cyclic di-GMP (c-di-GMP), were deleted in the virulent M. tuberculosis strain H37Rv to generate dgc(mut) and Δpde, respectively. Under aerobic growth conditions, the two mutants and wild-type cells showed similar phenotypes. However, dgc(mut) and Δpde exhibited increased and reduced dormancy, respectively, in both anaerobiosis-triggered and vitamin C-triggered in vitro dormancy models, as determined by survival and growth recovery from dormancy. The transcriptomes of aerobic cultures of dgc(mut) and wild-type H37Rv exhibited no difference, whereas those of anaerobic cultures showed a significant difference with 61 genes that are not a part of the dosR regulon. Furthermore, Δpde but not dgc(mut) showed decreased infectivity with human THP-1 cells. Δpde also showed attenuated pathogenicity in a C57BL/6 mouse infection model. These findings are explained by c-di-GMP-mediated signaling negatively regulating M. tuberculosis dormancy and pathogenicity.
School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
Yuzhi
Y
Hong
Xiaodan
X
Zhou
Haihong
H
Fang
Dan
D
Yu
Chuanyou
C
Li
Baolin
B
Sun
D000693:Anaerobiosis / Q000502:physiology; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000502:physiology; D004195:Disease Models, Animal; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity / Q000502:physiology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D014397:Tuberculosis, Pulmonary / Q000382:microbiology* / Q000473:pathology; D014774:Virulence / Q000502:physiology
C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP
Cyclic di-GMP; Dormancy; Mycobacterium tuberculosis; Pathogenicity; Signaling