Mycobacterium tuberculosis Rv1096, facilitates mycobacterial survival by modulating the NF-κB/MAPK pathway as peptidoglycan N-deacetylase

Lü, Qian; Zhang, Wei; Fang, Juemin; Zheng, Jianjian; Dong, Chunsheng; Xiong, Sidong

doi:10.1016/j.molimm.2020.08.005

Cited by 17 publications

(12 citation statements)

References 37 publications

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“…Infected macrophages secrete proinflammatory cytokines, which play a crucial role in the inflammatory response and the outcome of mycobacterial infections (28,29). However, M. tuberculosis can suppress the expression of proinflammatory cytokines to avoid immune surveillance (30)(31)(32). Thus, the factors that suppress the expression of these proinflammatory cytokines are the ideal targets to control M. tuberculosis infection.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Rv0927c Inhibits NF-κB Pathway by Downregulating the Phosphorylation Level of IκBα and Enhances Mycobacterial Survival

Xia

Quan

et al. 2021

Front. Immunol.

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Through long-term coevolution with its host, Mycobacterium tuberculosis (M. tuberculosis) uses multiple strategies to escape host defenses. The M. tuberculosis Rv0927c protein is predicted to be a short-chain dehydrogenase/reductase related to bacterial metabolism. However, the role of Rv0927c during M. tuberculosis infection remains unclear. Here, we observed that Rv0927c inhibited the expression of IL-6, TNF-α, and IL-1β, an effect dependent on NF-κB and p38 pathways. Western blot analysis of macrophages infected with recombinant Mycobacterium smegmatis strains showed that Rv0927c attenuated NF-κB activation by downregulating the phosphorylation of IκBα. Additionally, Rv0927c enhanced intracellular survival of M. smegmatis and pathological effects in mice. In conclusion, our findings demonstrate that Rv0927c functions as a regulator of inflammatory genes and enhances the survival of M. smegmatis.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Rv0927c Inhibits NF-κB Pathway by Downregulating the Phosphorylation Level of IκBα and Enhances Mycobacterial Survival

Xia

Quan

et al. 2021

Front. Immunol.

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“…Finally, activation of the NF-κB and MAPK downstream signaling pathways leads to the host inflammatory response through the production of proinflammatory cytokines and chemokines such as IL6 , IL1B , TNF , IL18 , and IL8 , which in addition to inducing an innate immune response, regulate subsequent adaptive immune response ( Means et al, 2000 ; Mahla et al, 2013 ; Thakur et al, 2018 ). However, various reports suggest that M. tuberculosis and M. bovis modulates proinflammatory cytokine production via the NF-κB and MAPK signaling inhibition in favor of their survival and thus suppresses the innate immune response ( Pathak et al, 2007 ; Wang et al, 2015 ; Liu et al, 2016 ; Ha et al, 2020 ; Lu et al, 2020 ). On the other hand, activation of NF-κB and MAPK signaling pathways can also play an important role in TB immunopathology ( Bai et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

In-depth systems biological evaluation of bovine alveolar macrophages suggests novel insights into molecular mechanisms underlying Mycobacterium bovis infection

et al. 2022

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ObjectiveBovine tuberculosis (bTB) is a chronic respiratory infectious disease of domestic livestock caused by intracellular Mycobacterium bovis infection, which causes ~$3 billion in annual losses to global agriculture. Providing novel tools for bTB managements requires a comprehensive understanding of the molecular regulatory mechanisms underlying the M. bovis infection. Nevertheless, a combination of different bioinformatics and systems biology methods was used in this study in order to clearly understand the molecular regulatory mechanisms of bTB, especially the immunomodulatory mechanisms of M. bovis infection.MethodsRNA-seq data were retrieved and processed from 78 (39 non-infected control vs. 39 M. bovis-infected samples) bovine alveolar macrophages (bAMs). Next, weighted gene co-expression network analysis (WGCNA) was performed to identify the co-expression modules in non-infected control bAMs as reference set. The WGCNA module preservation approach was then used to identify non-preserved modules between non-infected controls and M. bovis-infected samples (test set). Additionally, functional enrichment analysis was used to investigate the biological behavior of the non-preserved modules and to identify bTB-specific non-preserved modules. Co-expressed hub genes were identified based on module membership (MM) criteria of WGCNA in the non-preserved modules and then integrated with protein–protein interaction (PPI) networks to identify co-expressed hub genes/transcription factors (TFs) with the highest maximal clique centrality (MCC) score (hub-central genes).ResultsAs result, WGCNA analysis led to the identification of 21 modules in the non-infected control bAMs (reference set), among which the topological properties of 14 modules were altered in the M. bovis-infected bAMs (test set). Interestingly, 7 of the 14 non-preserved modules were directly related to the molecular mechanisms underlying the host immune response, immunosuppressive mechanisms of M. bovis, and bTB development. Moreover, among the co-expressed hub genes and TFs of the bTB-specific non-preserved modules, 260 genes/TFs had double centrality in both co-expression and PPI networks and played a crucial role in bAMs-M. bovis interactions. Some of these hub-central genes/TFs, including PSMC4, SRC, BCL2L1, VPS11, MDM2, IRF1, CDKN1A, NLRP3, TLR2, MMP9, ZAP70, LCK, TNF, CCL4, MMP1, CTLA4, ITK, IL6, IL1A, IL1B, CCL20, CD3E, NFKB1, EDN1, STAT1, TIMP1, PTGS2, TNFAIP3, BIRC3, MAPK8, VEGFA, VPS18, ICAM1, TBK1, CTSS, IL10, ACAA1, VPS33B, and HIF1A, had potential targets for inducing immunomodulatory mechanisms by M. bovis to evade the host defense response.ConclusionThe present study provides an in-depth insight into the molecular regulatory mechanisms behind M. bovis infection through biological investigation of the candidate non-preserved modules directly related to bTB development. Furthermore, several hub-central genes/TFs were identified that were significant in determining the fate of M. bovis infection and could be promising targets for developing novel anti-bTB therapies and diagnosis strategies.

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“…Numerous studies have reported significant NOD2 dependence of TNF production from various types of human and mouse cells in response to different mycobacteria [ 15 , 17 , 18 , 22 , 25 – 27 , 30 , 32 , 46 , 48 , 58 , 59 , 62 , 66 , 74 ]. TNF is critical for host resistance to mycobacterial infection: Animal studies of Mtb or BCG infection using knockouts or anti-TNF demonstrated that this pathway is essential for survival [ 161 – 164 ].…”

Section: Cell Signaling Effects Of Nod2 During Mycobacterial Infectionmentioning

confidence: 99%

A nod to the bond between NOD2 and mycobacteria

Dubé

Behr

2023

PLoS Pathog

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Mycobacteria are responsible for several human and animal diseases. NOD2 is a pattern recognition receptor that has an important role in mycobacterial recognition. However, the mechanisms by which mutations in NOD2 alter the course of mycobacterial infection remain unclear. Herein, we aimed to review the totality of studies directly addressing the relationship between NOD2 and mycobacteria as a foundation for moving the field forward. NOD2 was linked to mycobacterial infection at 3 levels: (1) genetic, through association with mycobacterial diseases of humans; (2) chemical, through the distinct NOD2 ligand in the mycobacterial cell wall; and (3) immunologic, through heightened NOD2 signaling caused by the unique modification of the NOD2 ligand. The immune response to mycobacteria is shaped by NOD2 signaling, responsible for NF-κB and MAPK activation, and the production of various immune effectors like cytokines and nitric oxide, with some evidence linking this to bacteriologic control. Absence of NOD2 during mycobacterial infection of mice can be detrimental, but the mechanism remains unknown. Conversely, the success of immunization with mycobacteria has been linked to NOD2 signaling and NOD2 has been targeted as an avenue of immunotherapy for diseases even beyond mycobacteria. The mycobacteria–NOD2 interaction remains an important area of study, which may shed light on immune mechanisms in disease.

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Mycobacterium tuberculosis Rv1096, facilitates mycobacterial survival by modulating the NF-κB/MAPK pathway as peptidoglycan N-deacetylase

Cited by 17 publications

References 37 publications

Mycobacterium tuberculosis Rv0927c Inhibits NF-κB Pathway by Downregulating the Phosphorylation Level of IκBα and Enhances Mycobacterial Survival

Mycobacterium tuberculosis Rv0927c Inhibits NF-κB Pathway by Downregulating the Phosphorylation Level of IκBα and Enhances Mycobacterial Survival

In-depth systems biological evaluation of bovine alveolar macrophages suggests novel insights into molecular mechanisms underlying Mycobacterium bovis infection

A nod to the bond between NOD2 and mycobacteria

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