PMID- 30232332
OWN - NLM
STAT- MEDLINE
DCOM- 20190122
LR  - 20190226
IS  - 2222-1751 (Electronic)
IS  - 2222-1751 (Linking)
VI  - 7
IP  - 1
DP  - 2018 Sep 19
TI  - Rv2346c enhances mycobacterial survival within macrophages by inhibiting TNF-alpha 
      and IL-6 production via the p38/miRNA/NF-kappaB pathway.
PG  - 158
LID - 10.1038/s41426-018-0162-6 [doi]
LID - 158
AB  - The intracellular survival of Mycobacterium tuberculosis (Mtb) has a central role 
      in the pathogenesis of tuberculosis. Mtb Rv2346c is a member of 6-kDa early 
      secreted antigenic target family of proteins, which are known to inhibit the host 
      immune responses to promote bacillary persistence in macrophages. However, the 
      mechanism through which Rv2346c participates in Mtb pathogenesis is unclear. In 
      the present study, recombinant Rv2346c protein was synthesized and used to treat 
      Bacillus Calmette-Guerin (BCG)-infected macrophages. The results showed that 
      Rv2346c inhibited the proliferation of BCG-infected macrophages and enhanced the 
      survival of BCG in macrophages. Tumor necrosis factor-alpha (TNF-alpha) and interleukin 
      (IL)-6 were upregulated during BCG infection but downregulated by Rv2346c. 
      Additional experiments showed that nuclear transcription factor-kappaB (NF-kappaB) in 
      BCG-infected macrophages induced the production of TNF-alpha and IL-6. In addition, 
      miR-155 and miR-99b had a suppressive effect on NF-kappaB, and the expression of 
      these miRNAs was promoted by p38. Furthermore, Rv2346c was shown to decrease the 
      activation of NF-kappaB, whereas it enhanced the phosphorylation of p38 and the 
      expression of miR-155 and miR-99b. The function of Rv2346c was also verified in 
      Mtb-infected mice. The results showed that Rv2346c increased the observed 
      bacterial load and lung injury and downregulated TNF-alpha and IL-6 in vivo. Overall, 
      our results reveal that Rv2346c enhances mycobacterial survival in macrophages 
      via inhibiting the production of TNF-alpha and IL-6 in a p38/miRNA/NF-kappaB 
      pathway-dependent manner, suggesting that Rv2346c acts as a crucial virulence 
      factor in Mtb infection and has potential use as a target for anti-tuberculosis 
      therapy.
FAU - Yao, Jing
AU  - Yao J
AD  - Department of Respiratory Medicine, the Second Affiliated Hospital of Nanjing 
      Medical University, Nanjing, Jiangsu, 210011, China.
FAU - Du, Xingran
AU  - Du X
AD  - Department of Infectious Diseases, the Second Affiliated Hospital of Nanjing 
      Medical University, Nanjing, Jiangsu, 210011, China.
FAU - Chen, Sixia
AU  - Chen S
AD  - Department of Respiratory Medicine, the Second Affiliated Hospital of Nanjing 
      Medical University, Nanjing, Jiangsu, 210011, China.
FAU - Shao, Yan
AU  - Shao Y
AD  - Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, Jiangsu, 
      210009, China.
FAU - Deng, Kaili
AU  - Deng K
AD  - Department of Respiratory Medicine, the Second Affiliated Hospital of Nanjing 
      Medical University, Nanjing, Jiangsu, 210011, China.
FAU - Jiang, Mingzi
AU  - Jiang M
AD  - Department of Respiratory Medicine, the First People's Hospital of Kunshan, 
      Kunshan, Jiangsu, 215300, China.
FAU - Liu, Jingning
AU  - Liu J
AD  - Department of Respiratory Medicine, the Second Affiliated Hospital of Nanjing 
      Medical University, Nanjing, Jiangsu, 210011, China.
FAU - Shen, Ziyan
AU  - Shen Z
AD  - Department of Respiratory Medicine, the Second Affiliated Hospital of Nanjing 
      Medical University, Nanjing, Jiangsu, 210011, China.
FAU - Chen, Xiaolin
AU  - Chen X
AD  - Department of Respiratory Medicine, Sir Run Run Hospital, Nanjing, Jiangsu, 
      211100, China.
FAU - Feng, Ganzhu
AU  - Feng G
AD  - Department of Respiratory Medicine, the Second Affiliated Hospital of Nanjing 
      Medical University, Nanjing, Jiangsu, 210011, China. zhu1635253@163.com.
LA  - eng
GR  - 81470209/National Natural Science Foundation of China (National Science 
      Foundation of China)/
PT  - Journal Article
DEP - 20180919
PL  - United States
TA  - Emerg Microbes Infect
JT  - Emerging microbes & infections
JID - 101594885
RN  - 0 (Bacterial Proteins)
RN  - 0 (Interleukin-6)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn155 microRNA, mouse)
RN  - 0 (Mirn99 microRNA, mouse)
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Bacterial Proteins/genetics/*immunology
MH  - Female
MH  - Host-Pathogen Interactions
MH  - Humans
MH  - Interleukin-6/genetics/*metabolism
MH  - Macrophages/metabolism/*microbiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - MicroRNAs/genetics/metabolism
MH  - Microbial Viability
MH  - Mycobacterium tuberculosis/genetics/*immunology
MH  - NF-kappa B/genetics/*metabolism
MH  - Tuberculosis/genetics/metabolism/*microbiology
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/genetics/*metabolism
PMC - PMC6145905
COIS- The authors declare no conflicts of interest.
EDAT- 2018/09/21 06:00
MHDA- 2019/01/23 06:00
PMCR- 2018/09/19
CRDT- 2018/09/21 06:00
PHST- 2018/04/16 00:00 [received]
PHST- 2018/08/20 00:00 [accepted]
PHST- 2018/08/15 00:00 [revised]
PHST- 2018/09/21 06:00 [entrez]
PHST- 2018/09/21 06:00 [pubmed]
PHST- 2019/01/23 06:00 [medline]
PHST- 2018/09/19 00:00 [pmc-release]
AID - 10.1038/s41426-018-0162-6 [pii]
AID - 162 [pii]
AID - 10.1038/s41426-018-0162-6 [doi]
PST - epublish
SO  - Emerg Microbes Infect. 2018 Sep 19;7(1):158. doi: 10.1038/s41426-018-0162-6.