scholarly journals Cholesterol-dependent transcriptome remodeling reveals new insight into the contribution of cholesterol to Mycobacterium tuberculosis pathogenesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jakub Pawełczyk ◽  
Anna Brzostek ◽  
Alina Minias ◽  
Przemysław Płociński ◽  
Anna Rumijowska-Galewicz ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Sole Carbon Source ◽  
Transcriptome Profiling ◽  
Vitamin B ◽  
The Novel ◽  
Human Pathogen ◽  
Global Effect ◽  
Probable Role ◽  
Insight Into

AbstractMycobacterium tuberculosis (Mtb) is an obligate human pathogen that can adapt to the various nutrients available during its life cycle. However, in the nutritionally stringent environment of the macrophage phagolysosome, Mtb relies mainly on cholesterol. In previous studies, we demonstrated that Mtb can accumulate and utilize cholesterol as the sole carbon source. However, a growing body of evidence suggests that a lipid-rich environment may have a much broader impact on the pathogenesis of Mtb infection than previously thought. Therefore, we applied high-resolution transcriptome profiling and the construction of various mutants to explore in detail the global effect of cholesterol on the tubercle bacillus metabolism. The results allow re-establishing the complete list of genes potentially involved in cholesterol breakdown. Moreover, we identified the modulatory effect of vitamin B12 on Mtb transcriptome and the novel function of cobalamin in cholesterol metabolite dissipation which explains the probable role of B12 in Mtb virulence. Finally, we demonstrate that a key role of cholesterol in mycobacterial metabolism is not only providing carbon and energy but involves also a transcriptome remodeling program that helps in developing tolerance to the unfavorable host cell environment far before specific stress-inducing phagosomal signals occur.

scholarly journals Mycobacterium tuberculosis adhesins: potential biomarkers as anti-tuberculosis therapeutic and diagnostic targets

Microbiology ◽  
2014 ◽  
Vol 160 (9) ◽  
pp. 1821-1831 ◽  
Author(s):  
Viveshree S. Govender ◽  
Saiyur Ramsugit ◽  
Manormoney Pillay
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Control Strategies ◽  
Host Cells ◽  
Tuberculosis Control ◽  
Surface Molecules ◽  
Host Pathogen Interaction ◽  
Bacterial Aggregation ◽  
Insight Into

Adhesion to host cells is a precursor to host colonization and evasion of the host immune response. Conversely, it triggers the induction of the immune response, a process vital to the host’s defence against infection. Adhesins are microbial cell surface molecules or structures that mediate the attachment of the microbe to host cells and thus the host–pathogen interaction. They also play a crucial role in bacterial aggregation and biofilm formation. In this review, we discuss the role of adhesins in the pathogenesis of the aetiological agent of tuberculosis, Mycobacterium tuberculosis. We also provide insight into the structure and characteristics of some of the characterized and putative M. tuberculosis adhesins. Finally, we examine the potential of adhesins as targets for the development of tuberculosis control strategies.

scholarly journals Investigation of the genetic variation in ACE2 on the structural recognition by the novel coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Xingyi Guo ◽  
Zhishan Chen ◽  
Yumin Xia ◽  
Weiqiang Lin ◽  
Hongzhi Li
Keyword(s):  
Genetic Variation ◽  
The Novel ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Missense Variants ◽  
Catalytic Metal ◽  
Using Data ◽  
Novel Coronavirus ◽  
Insight Into

Abstract Background: The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2. Methods: We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program.Results: Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian.Conclusions: We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment.

scholarly journals Role of Short-wavelength Blue Light in the Formation of Cataract and Expression of Caspase-1, -11 and Gasdermin D in rat Lens Epithelium Cells: Insight into the Novel Pathogenesis of Cataract.

2019 ◽  
Author(s):  
Yamin Wang ◽  
Min Zhang ◽  
Ying Sun ◽  
Xiaohui Wang ◽  
Zhaowei Song ◽  
...  
Keyword(s):  
Blue Light ◽  
Short Wavelength ◽  
Light Exposure ◽  
The Novel ◽  
Blue Led ◽  
Caspase 1 ◽  
Epithelium Cells ◽  
Experimental Group ◽  
Insight Into

Abstract Background Cataracts have been verified to be associated with a number of risk factors. The sun and artificial light sources, including light-emitting diode (LED) and fluorescent light tubes, are the primary sources of short-wavelength blue light. With the increasing popularity of blue-rich LED-backlit display devices, our eyes are now exposed to more short-wavelength blue light than they were in the past. The goal of this study was to evaluate the role of short-wavelength blue light in the formation of cataract. Additionally, the pathogenesis of cataracts after short-wavelength light exposure was investigated.Methods SD rats were randomly divided into 2 main groups: a control group (10 rats each for the 4-, 8-, and 12-week groups) and an experimental group (10 rats each for the 4-, 8-, and 12-week groups). The rats in the experimental group were exposed to a short-wavelength blue LED lamp for 12 hours per day. After exposure to the blue LED lamp, the rats were maintained in total darkness for 12 hours, after which a 12-hour light/dark cycle was resumed. The intensity of the lamp was 3000 lux. At the end of the short-wavelength blue LED lamp exposure (for 4, 8, and 12 weeks), the expression levels of caspase-1, caspase-11 and gasdermin D (GSDMD) in rat epithelium cells (LECs) were examined in rat epithelial cells (LECs) using qRT-PCR and Western blotting analyses. Results After 6 weeks, cataracts had developed in the experimental rats (4/20 eyes). The clarity of the lens then gradually worsened with the duration of exposure. Twelve weeks later, all of the rat eyes had developed cataracts. Then the expression levels of caspase-1, caspase-11 and GSDMD at 4, 8, and 12 weeks were significantly higher in samples from rats exposed to a short-wavelength blue LED lamp than samples from control rat (p˂0.05). Conclusion The data indicate that pyroptosis play a key role of in cataracts induced by short-wavelength blue light exposure, highlighting caspase-1, caspase-11 and GSDMD as possible therapeutic targets for cataract treatment. This study might provide new insight into the novel pathogenesis of cataracts.

scholarly journals The Role of the Novel Exopolyphosphatase MT0516 in Mycobacterium tuberculosis Drug Tolerance and Persistence

PLoS ONE ◽  
2011 ◽  
Vol 6 (11) ◽  
pp. e28076 ◽  
Author(s):  
Seema M. Thayil ◽  
Norman Morrison ◽  
Norman Schechter ◽  
Harvey Rubin ◽  
Petros C. Karakousis
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Tolerance ◽  
The Novel

scholarly journals Evaluation the Expression of Efflux Pump Genes “Tap & P55 in Mycobacterium Tuberculosis Clinical Isolates in Fars, Iran

2020 ◽  
Author(s):  
Fardis Khoob ◽  
Milad Shahini Shams Abadi ◽  
Nahal Hadi ◽  
Farzaneh Avazzadeh ◽  
Zahra Zarei
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Target Genes ◽  
Efflux Pump ◽  
Expression Level ◽  
Genetic Mutations ◽  
Antimicrobial Sensitivity ◽  
Probable Role ◽  
Tuberculosis Therapy

Abstract BackgroundThe increasing drug resistance in Mycobacterium tuberculosis isolates has become a global problem for tuberculosis therapy programs. Genetic mutations in rifampin (RIF), one of the key drugs in the treatment of tuberculosis are main mechanism of resistant to this drug in M. tuberculosis. Absence of mutation in target genes, other mechanisms such as efflux pump suggests possible role of drug resistant.The objective of this study was to find out mutations in rpoB genes in rifampin resistant isolates and to compare the expression level of tap and p55 efflux pump genes in non mutated isolates, mutated isolates in rpoB genes and susceptible isolates.MethodsIn this study, antimicrobial sensitivity test on first line drugs was performed on 200 M. tuberculosis isolates, obtained from TB center in Shiraz (IRAN) and genetic mutations were evaluated in rpoB gene in RIF resistant isolates by multiplex PCR, followed expression level evaluated by Real-time PCR.Resultsout of the 200 isolates tested, 23 (34.33%) showed resistant to RIF. 12 of 23 RIF resistant isolates have mutation in rpoB gene, and frequency of mutations in codons 516, 526 and 531 were 3 (25%), 4 (33.33%) and 5 (41.67%) respectively. The expression level of tap and p55 genes was considerably higher in resistant isolates which had no mutation compared to the expression level of genes in the isolates which had mutation in target genes.ConclusionThe accumulating data suggest the probable role of efflux pump in M. tuberculosis drug resistance, the validation of data needs further phenotypic assays of these pumps.

scholarly journals miR-539 activates the SAPK/JNK signaling pathway to promote ferropotosis in colorectal cancer by directly targeting TIPE

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yan Yang ◽  
Zeyang Lin ◽  
Zhaopu Han ◽  
Zhengxin Wu ◽  
Jianyu Hua ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
High Recurrence Rate ◽  
The Novel ◽  
Potential Therapeutic Target ◽  
Tnf Α ◽  
Jnk Signaling Pathway ◽  
The Relationship ◽  
Insight Into ◽  
Necrosis Factor

AbstractColorectal cancer (CRC) is a common tumor that harms human health with a high recurrence rate. It has been reported that the expression of microRNA-539 (miR-539) is low in several types of cancer, including CRC. Tumor necrosis factor (TNF)-α-induced protein 8 (TNFAIP8/TIPE) is highly expressed in CRC and promotes the proliferation, migration and angiogenesis of CRC. However, the relationship between miR-539 and TIPE and the mechanisms by which they regulate the proliferation of CRC remain to be explored. We aimed to investigate the functions and mechanisms of miR-539 in CRC proliferation. Functionally, miR-539 can bind to and regulate the expression of TIPE, and miR-539 activates SAPK/JNK to downregulate the expression of glutathione peroxidase 4 (GPX4) and promote ferroptosis. Our data reveal the novel role of miR-539 in regulating ferroptosis in CRC via activation of the SAPK/JNK axis, providing new insight into the mechanism of abnormal proliferation in CRC and a novel potential therapeutic target for advanced CRC.

The role of BCG in prevention of tuberculosis and the strategies to improve its immunogenicity

2018 ◽  
Vol 2 (1) ◽  
pp. 21-26
Author(s):  
Jolanta Mazurek
Keyword(s):  
Public Health ◽  
Antibiotic Resistance ◽  
Mycobacterium Tuberculosis ◽  
Health Problem ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Human Pathogen ◽  
Deadly Disease ◽  
A Current

Tuberculosis (TB) remains a major public health problem and the main cause of death from the infectious diseases worldwide. Mycobacterium tuberculosis (Mtb), a causative agent of tuberculosis, is the oldest known human pathogen. The only available TB vaccine, BCG, was first administered in 1921 and since then remains the only protecting tool against TB. Yet, its efficacy is limited and there is an urgent need to design and produce a novel vaccine that will protect against this deadly disease in the era of emerging problems with antibiotic resistance. In this review a current, global TB situation is outlined and the characteristics of BCG are presented. Finally, the strategies leading to generation of BCG variants providing improved protecting efficacy are shortly described.

scholarly journals MmpL Proteins in Physiology and Pathogenesis of M. tuberculosis

2019 ◽  
Vol 7 (3) ◽  
pp. 70 ◽  
Author(s):  
Geoff Melly ◽  
Georgiana Purdy
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Membrane Protein ◽  
Molecular Mechanisms ◽  
Cell Envelope ◽  
Human Pathogen ◽  
Unique Structure ◽  
Bacterial Structure ◽  
Insight Into

Mycobacterium tuberculosis (Mtb) remains an important human pathogen. The Mtb cell envelope is a critical bacterial structure that contributes to virulence and pathogenicity. Mycobacterial membrane protein large (MmpL) proteins export bulky, hydrophobic substrates that are essential for the unique structure of the cell envelope and directly support the ability of Mtb to infect and persist in the host. This review summarizes recent investigations that have enabled insight into the molecular mechanisms underlying MmpL substrate export and the role that these substrates play during Mtb infection.

scholarly journals Massive Gene Duplication Event among Clinical Isolates of the Mycobacterium tuberculosis W/Beijing Family

2010 ◽  
Vol 192 (18) ◽  
pp. 4562-4570 ◽  
Author(s):  
Pilar Domenech ◽  
Gaëlle S. Kolly ◽  
Lizbel Leon-Solis ◽  
Ashley Fallow ◽  
Michael B. Reed
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Duplication Event ◽  
The Novel ◽  
Beijing Family ◽  
Antitubercular Drugs ◽  
Sister Chromatids ◽  
Sequences Analysis ◽  
Overexpression Phenotype

ABSTRACT As part of our effort to uncover the molecular basis for the phenotypic variation among clinical Mycobacterium tuberculosis isolates, we have previously reported that isolates belonging to the W/Beijing lineage constitutively overexpress the DosR-regulated transcriptional program. While generating dosR knockouts in two independent W/Beijing sublineages, we were surprised to discover that they possess two copies of dosR. This dosR amplification is part of a massive genomic duplication spanning 350 kb and encompassing >300 genes. In total, this equates to 8% of the genome being present as two copies. The presence of IS6110 elements at both ends of the region of duplication, and in the novel junction region, suggests that it arose through unequal homologous recombination of sister chromatids at the IS6110 sequences. Analysis of isolates representing the major M. tuberculosis lineages has revealed that the 350-kb duplication is restricted to the most recently evolved sublineages of the W/Beijing family. Within these isolates, the duplication is partly responsible for the constitutive dosR overexpression phenotype. Although the nature of the selection event giving rise to the duplication remains unresolved, its evolution is almost certainly the result of specific selective pressure(s) encountered inside the host. A preliminary in vitro screen has failed to reveal a role of the duplication in conferring resistance to common antitubercular drugs, a trait frequently associated with W/Beijing isolates. Nevertheless, this first description of a genetic remodeling event of this nature for M. tuberculosis further highlights the potential for the evolution of diversity in this important global pathogen.

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