An immunomodulatory role for the <i>Mycobacterium tuberculosis</i> Acr protein in the formation of the tuberculous granuloma

Healy, Eamonn F.; Goering, Lisa M.; Hauser, Charles R.; King, Peter

doi:10.1002/1873-3468.13998

Cited by 4 publications

(6 citation statements)

References 41 publications

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“…Similar sequences (shown in bold) are to be found in both ADAM10 ( 651 D GPL AR_KK 659 ) and ADAM17 ( 621 N LFL RK_K 628 ) proximate to the cationic sequence identified as responsible for PS-activation. By facilitating a protein-protein interaction (PPI) between the ADAM10 and the pathogenic sHsp Mtb Acr we have previously shown how these residues provide a mechanism for the heat shock activation of ADAM10, providing an immunomodulatory role for the mycobacterium in the formation of the tubercular granuloma [ 19 ]. The ΔΔG binding , i.e.…”

Section: Resultsmentioning

confidence: 99%

“…In the case of tubulin and F-actin this interaction serves to stabilize the cytoskeleton by affecting the spatio-temporal organization of the components and preventing reorganization [ 18 ]. We have previously demonstrated how the M. tuberculosis Hsp Acr can exploit the host innate response by dysregulating shedding of the inflammatory cytokine CXCL16 by ADAM10 [ 19 ]. Among the over 80 cell-bound substrates of ADAM17 at least 9 are cytokines or cytokine receptors that have been reported as triggering inflammation when dysregulated [ [20] , [21] , [22] ].…”

Section: Introductionmentioning

confidence: 99%

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A model for COVID-19-induced dysregulation of ACE2 shedding by ADAM17

Healy

Lilic

2021

Biochemical and Biophysical Research Communications

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The angiotensin Converting Enzyme 2 (ACE2) receptor is a key component of the renin-angiotensin-aldesterone system (RAAS) that mediates numerous effects in the cardiovascular system. It is also the cellular point of contact for the coronavirus spike protein. Cleavage of the receptor is both important to its physiological function as well as being necessary for cell entry by the virus. Shedding of ACE2 by the metalloprotease ADAM17 releases a catalytically active soluble form of ACE2, but cleavage by the serine protease TMPRSS2 is necessary for virion internalization. Complicating the issue is the observation that circulating ACE2 can also bind to the virus effectively blocking attachment to the membrane-bound receptor. This work investigates the possibility that the inflammatory response to coronavirus infection can abrogate shedding by ADAM17, thereby favoring cleavage by TMPRSS2 and thus cell entry by the virion.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A model for COVID-19-induced dysregulation of ACE2 shedding by ADAM17

Healy

Lilic

2021

Biochemical and Biophysical Research Communications

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“…After surviving the immune response of lung alveolar macrophages, neutrophils, and dendritic cells, M. tb establishes a primary infection in the lung parenchyma with typical granulomatous inflammation [ 12 ]. Depending on the patient’s immune status and the virulence of the bacillus, the M. tb infection may be halted by the formation of granulomas, in which macrophages, epithelioid cells, and lymphocytes gather to establish a latent infection, or it may disseminate from local invasion to the blood and lymphatic systems, which is common in both miliary and extrapulmonary TB [ 4 , 13 , 14 ]. Various mechanisms underlie the hematogenous translocation of M. tb from the respiratory epithelium to the meninges.…”

Section: Pathogenesis Of Tbmmentioning

confidence: 99%

Potential of Neuroinflammation-Modulating Strategies in Tuberculous Meningitis: Targeting Microglia

Lu¹,

Guo²,

Wei³

2023

Aging and disease

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Tuberculous meningitis (TBM) is the most severe complication of tuberculosis (TB) and is associated with high rates of disability and mortality. Mycobacterium tuberculosis (M. tb), the infectious agent of TB, disseminates from the respiratory epithelium, breaks through the blood-brain barrier, and establishes a primary infection in the meninges. Microglia are the core of the immune network in the central nervous system (CNS) and interact with glial cells and neurons to fight against harmful pathogens and maintain homeostasis in the brain through pleiotropic functions. However, M. tb directly infects microglia and resides in them as the primary host for bacillus infections. Largely, microglial activation slows disease progression. The non-productive inflammatory response that initiates the secretion of pro-inflammatory cytokines and chemokines may be neurotoxic and aggravate tissue injuries based on damages caused by M. tb. Host-directed therapy (HDT) is an emerging strategy for modulating host immune responses against diverse diseases. Recent studies have shown that HDT can control neuroinflammation in TBM and act as an adjunct therapy to antibiotic treatment. In this review, we discuss the diverse roles of microglia in TBM and potential host-directed TB therapies that target microglia to treat TBM. We also discuss the limitations of applying each HDT and suggest a course of action for the near future.

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“…To facilitate the eradication of active tuberculosis (ATB), host cells have evolved several clearance processes, which include apoptosis, autophagy, inflammation, and macrophage polarization. Concurrently, Mtb has developed an array of near-perfect immune evasion mechanisms to help it evade the host immune system ( Boro et al, 2016 ; Healy et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Long non-coding RNA expression in PBMCs of patients with active pulmonary tuberculosis

Li,

Feng,

Song

et al. 2023

Front. Microbiol.

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PurposeMycobacterium tuberculosis (Mtb) infection is the primary cause of the chronic infectious illness tuberculosis (TB). Long non-coding RNAs (lncRNAs) are functional RNA molecules that cannot be translated into proteins and play a crucial role in regulating the immune system’s innate and adaptive responses. It has been demonstrated that the dysregulation of lncRNA expression is associated with various human diseases. However, the mechanism underlying the involvement of so many lncRNAs in the immune response to TB infection remains unclear. The objective of our current study was to identify a number of significantly differentially expressed lncRNAs in peripheral blood mononuclear cells (PBMCs) from TB patients and to select the most indicative lncRNAs as potential biomarkers for active pulmonary tuberculosis.MethodsMicroarray analysis was performed to determine the lncRNA and mRNA expression profiles in TB patients using a case-control model. The differentially expressed lncRNAs were subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to investigate potential roles and pathways associated with the pathogenesis of TB infection, and to screen lncRNAs specifically linked to TB infection. Using real-time fluorescence quantitative PCR (QRT-PCR), specific lncRNAs were identified in TB patients and latent infections.ResultsOur findings revealed that various signaling pathways were differentially expressed in TB-infected individuals, suggesting a potential role for lncRNAs in the immunological responses driven by TB infection. This study provides crucial guidelines for future functional research. Upregulated lncRNAs were mainly enriched in Neutrophil extracellular trap formation and Chemokine signaling pathways, while downregulated lncRNAs were enriched in Neuroactive ligand-receptor interaction and Cushing syndrome in TB PBMCs. Furthermore, we found that lnc-XPNPEP1-5, lnc-CASKIN2-2, lnc-HSPA13-6, lnc-CLIC5-1, and LINC02502 were significantly downregulated in TB-infected patients, while LINC00528, lnc-SLC45A4-3, and LINC00926 were significantly upregulated in TB patients and latent infections. These eight lncRNAs, identified as novel biological marker candidates for diagnosing TB infection, were validated by real-time fluorescence quantitative PCR (QRT-PCR).ConclusionThe abnormally expressed lncRNAs identified in this research may provide crucial information for understanding the pathophysiological characteristics of TB patients and the dysfunction of PBMCs. Our findings reveal potential targets for early TB diagnosis and therapy, as well as offer new insights into the mechanisms underlying TB infection.

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An immunomodulatory role for the Mycobacterium tuberculosis Acr protein in the formation of the tuberculous granuloma

Cited by 4 publications

References 41 publications

A model for COVID-19-induced dysregulation of ACE2 shedding by ADAM17

A model for COVID-19-induced dysregulation of ACE2 shedding by ADAM17

Potential of Neuroinflammation-Modulating Strategies in Tuberculous Meningitis: Targeting Microglia

Long non-coding RNA expression in PBMCs of patients with active pulmonary tuberculosis

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