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The Metabolism of Nucleic Acids, Cell Division, Cholesterol Degradation, Cell Wall Biosynthesis and Host–Pathogen Interactions in Tuberculosis

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 19346

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Special Issue Editors

Prof. Dr. Jarosław Dziadek

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Guest Editor

Institute of Medical Biology, Polish Academy of Sciences, 93-232 LODZ, Poland
Interests: DNA replication and repair; signal transduction; cholesterol metabolism and cell wall biosynthesis in respect to the virulence of tubercle bacilli and as potential targets for the development of new antituberculosis drugs

Prof. Dr. Jolanta Zakrzewska-Czerwińska

E-Mail Website
Guest Editor

Faculty of Biotechnology, University of Wrocław, 50-383 Wrocław, Poland
Interests: chromosome replication and segregation; chromosome structure (nucleoid-associated proteins and SMC); regulation of gene expression; mycobacterial cell cycle

Special Issue Information

Dear Colleagues,

There could hardly be a better time to realise the importance of infectious diseases for public health. The World Health Organization’s statistics show that communicable diseases such as lower respiratory tract infections, diarrhoeal diseases, and tuberculosis still place within the top ten causes of death worldwide. Meanwhile, the ones that reach public eye are most often newly emerged pathogens or ones that have gained the ability to infect humans, such as the unfortunate protagonist of the recent months, SARS-CoV-2. However, it is imperative we do not forget about microorganisms that have existed alongside humanity for millennia which still constitute a danger to public health, especially in the age of increasingly common drug resistance. Mycobacterium tuberculosis is without doubt deserving of attention, being the etiological factor of tuberculosis. This microbe, identified by Robert Koch in 1882, is responsible for 10 million new cases of tuberculosis and 1.5 million deaths every year. Researching the primary processes within mycobacteria cells seems to be key to understanding the virulence of Mycobacterium tuberculosis, and would form a basis in the search for new targets and drugs effective in treating it. These primary processes include those connected to the metabolism of nucleic acids (i.e., DNA replication and repair, RNA decay and maturation), cell division, cell wall component biosynthesis, the ability to degrade cholesterol, and interactions with cellular and soluble host molecules.

As such, within a single thematic Issue, we would like to gather research dedicated to the study and explanation of the molecular basis of metabolic processes in mycobacteria and host–pathogen interactions. These are an essential element on the route to understanding the pathogenetic processes of such dangerous microbes, and constitute a possible avenue for finding new targets for a new generation of effective anti-mycobacteria drugs. We look forward to your contributions.

Prof. Dr. Jarosław Dziadek
Prof. Dr. Jolanta Zakrzewska-Czerwińska
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Mycobacterium
tuberculosis
drug targets
host–pathogen interactions
DNA replication and repair

Published Papers (6 papers)

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Research

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17 pages, 4384 KiB

Open AccessArticle

Direct Interaction of Polar Scaffolding Protein Wag31 with Nucleoid-Associated Protein Rv3852 Regulates Its Polar Localization

by Rajni Garg, Chinmay Anand, Sohini Ganguly, Sandhya Rao, Rinkee Verma and Valakunja Nagaraja

Cells 2021, 10(6), 1558; https://doi.org/10.3390/cells10061558 - 20 Jun 2021

Cited by 1 | Viewed by 2822

Abstract

Rv3852 is a unique nucleoid-associated protein (NAP) found exclusively in Mycobacterium tuberculosis (Mtb) and closely related species. Although annotated as H-NS, we showed previously that it is very different from H-NS in its properties and is distinct from other NAPs, anchoring to cell membrane by virtue of possessing a C-terminal transmembrane helix. Here, we investigated the role of Rv3852 in Mtb in organizing architecture or synthesis machinery of cell wall by protein–protein interaction approach. We demonstrated a direct physical interaction of Rv3852 with Wag31, an important cell shape and cell wall integrity determinant essential in Mtb. Wag31 localizes to the cell poles and possibly acts as a scaffold for cell wall synthesis proteins, resulting in polar cell growth in Mtb. Ectopic expression of Rv3852 in M. smegmatis resulted in its interaction with Wag31 orthologue DivIVA_Msm. Binding of the NAP to Wag31 appears to be necessary for fine-tuning Wag31 localization to the cell poles, enabling complex cell wall synthesis in Mtb. In Rv3852 knockout background, Wag31 is mislocalized resulting in disturbed nascent peptidoglycan synthesis, suggesting that the NAP acts as a driver for localization of Wag31 to the cell poles. While this novel association between these two proteins presents one of the mechanisms to structure the elaborate multi-layered cell envelope of Mtb, it also exemplifies a new function for a NAP in mycobacteria. Full article

(This article belongs to the Special Issue The Metabolism of Nucleic Acids, Cell Division, Cholesterol Degradation, Cell Wall Biosynthesis and Host–Pathogen Interactions in Tuberculosis)

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26 pages, 5274 KiB

Open AccessArticle

Mycobacterium tuberculosis Binds Human Serum Amyloid A, and the Interaction Modulates the Colonization of Human Macrophages and the Transcriptional Response of the Pathogen

by Malwina Kawka, Anna Brzostek, Katarzyna Dzitko, Jakub Kryczka, Radosław Bednarek, Renata Płocińska, Przemysław Płociński, Dominik Strapagiel, Justyna Gatkowska, Jarosław Dziadek and Bożena Dziadek

Cells 2021, 10(5), 1264; https://doi.org/10.3390/cells10051264 - 20 May 2021

Cited by 8 | Viewed by 2762

Abstract

As a very successful pathogen with outstanding adaptive properties, Mycobacterium tuberculosis (Mtb) has developed a plethora of sophisticated mechanisms to subvert host defenses and effectively enter and replicate in the harmful environment inside professional phagocytes, namely, macrophages. Here, we demonstrated the binding interaction of Mtb with a major human acute phase protein, namely, serum amyloid A (SAA1), and identified AtpA (Rv1308), ABC (Rv2477c), EspB (Rv3881c), TB 18.6 (Rv2140c), and ThiC (Rv0423c) membrane proteins as mycobacterial effectors responsible for the pathogen-host protein interplay. SAA1-opsonization of Mtb prior to the infection of human macrophages favored bacterial entry into target phagocytes accompanied by a substantial increase in the load of intracellularly multiplying and surviving bacteria. Furthermore, binding of human SAA1 by Mtb resulted in the up- or downregulation of the transcriptional response of tubercle bacilli. The most substantial changes were related to the increased expression level of the genes of two operons encoding mycobacterial transporter systems, namely, mmpL5/mmpS5 (rv0676c), and rv1217c, rv1218c. Therefore, we postulate that during infection, Mtb-SAA1 binding promotes the infection of host macrophages by tubercle bacilli and modulates the functional response of the pathogen. Full article

(This article belongs to the Special Issue The Metabolism of Nucleic Acids, Cell Division, Cholesterol Degradation, Cell Wall Biosynthesis and Host–Pathogen Interactions in Tuberculosis)

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20 pages, 3931 KiB

Open AccessFeature PaperArticle

Dissecting the RecA-(In)dependent Response to Mitomycin C in Mycobacterium tuberculosis Using Transcriptional Profiling and Proteomics Analyses

by Anna Brzostek, Przemysław Płociński, Alina Minias, Aneta Ciszewska, Filip Gąsior, Jakub Pawełczyk, Bożena Dziadek, Marcin Słomka and Jarosław Dziadek

Cells 2021, 10(5), 1168; https://doi.org/10.3390/cells10051168 - 11 May 2021

Cited by 10 | Viewed by 3385

Abstract

Mycobacteria exploit at least two independent global systems in response to DNA damage: the LexA/RecA-dependent SOS response and the PafBC-regulated pathway. Intracellular pathogens, such as Mycobacterium tuberculosis, are exposed to oxidative and nitrosative stress during the course of infection while residing inside host macrophages. The current understanding of RecA-independent responses to DNA damage is based on the saprophytic model of Mycobacterium smegmatis, a free-living and nonpathogenic mycobacterium. The aim of the present study was to identify elements of RecA-independent responses to DNA damage in pathogenic intracellular mycobacteria. With the help of global transcriptional profiling, we were able to dissect RecA-dependent and RecA-independent pathways. We profiled the DNA damage responses of an M. tuberculosis strain lacking the recA gene, a strain with an undetectable level of the PafBC regulatory system, and a strain with both systems tuned down simultaneously. RNA-Seq profiling was correlated with the evaluation of cell survival in response to DNA damage to estimate the relevance of each system to the overall sensitivity to genotoxic agents. We also carried out whole-cell proteomics analysis of the M. tuberculosis strains in response to mitomycin C. This approach highlighted that LexA, a well-defined key element of the SOS system, is proteolytically inactivated during RecA-dependent DNA repair, which we found to be transcriptionally repressed in response to DNA-damaging agents in the absence of RecA. Proteomics profiling revealed that AlkB was significantly overproduced in the ΔrecA pafBC^{CRISPRi/dCas9} strain and that Holliday junction resolvase RuvX was a DNA damage response factor that was significantly upregulated regardless of the presence of functional RecA and PafBC systems, thus falling into a third category of DNA damage factors: RecA- and PafBC-independent. While invisible to the mass spectrometer, the genes encoding alkA, dnaB, and dnaE2 were significantly overexpressed in the ΔrecA pafBC^{CRISPRi/dCas9} strain at the transcript level. Full article

(This article belongs to the Special Issue The Metabolism of Nucleic Acids, Cell Division, Cholesterol Degradation, Cell Wall Biosynthesis and Host–Pathogen Interactions in Tuberculosis)

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28 pages, 3057 KiB

Open AccessArticle

Mycobacterial Populations Partly Change the Proportions of the Cells Undergoing Asymmetric/Symmetric Divisions in Response to Glycerol Levels in Growth Medium

by Atul Pradhan, Nagaraja Mukkayyan, Kishor Jakkala and Parthasarathi Ajitkumar

Cells 2021, 10(5), 1160; https://doi.org/10.3390/cells10051160 - 11 May 2021

Cited by 1 | Viewed by 2658

Abstract

Twenty to thirty percent of the septating mycobacterial cells of the mid-log phase population showed highly deviated asymmetric constriction during division (ACD), while the remaining underwent symmetric constriction during division (SCD). The ACD produced short-sized cells (SCs) and normal/long-sized cells (NCs) as the sister–daughter cells, but with significant differential susceptibility to antibiotic/oxidative/nitrite stress. Here we report that, at 0.2% glycerol, formulated in the Middlebrook 7H9 medium, a significantly high proportion of the cells were divided by SCD. When the glycerol concentration decreased to 0.1% due to cell-growth/division, the ACD proportion gradually increased until the ACD:SCD ratio reached ~50:50. With further decrease in the glycerol levels, the SCD proportion increased with concomitant decrease in the ACD proportion. Maintenance of glycerol at 0.1%, through replenishment, held the ACD:SCD proportion at ~50:50. Transfer of the cells from one culture with a specific glycerol level to the supernatant from another culture, with a different glycerol level, made the cells change the ACD:SCD proportion to that of the culture from which the supernatant was taken. RT-qPCR data showed the possibility of diadenosine tetraphosphate phosphorylase (MSMEG_2932), phosphatidylinositol synthase (MSMEG_2933), and a Nudix family hydrolase (MSMEG_2936) involved in the ACD:SCD proportion-change in response to glycerol levels. We also discussed its physiological significance. Full article

(This article belongs to the Special Issue The Metabolism of Nucleic Acids, Cell Division, Cholesterol Degradation, Cell Wall Biosynthesis and Host–Pathogen Interactions in Tuberculosis)

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25 pages, 8607 KiB

Open AccessArticle

Functional Characterization of the N-Acetylmuramyl-l-Alanine Amidase, Ami1, from Mycobacterium abscessus

by Tanja Küssau, Niël Van Wyk, Matt D. Johansen, Husam M. A. B. Alsarraf, Aymeric Neyret, Claire Hamela, Kasper K. Sørensen, Mikkel B. Thygesen, Claire Beauvineau, Laurent Kremer and Mickaël Blaise

Cells 2020, 9(11), 2410; https://doi.org/10.3390/cells9112410 - 04 Nov 2020

Cited by 5 | Viewed by 3354

Abstract

Peptidoglycan (PG) is made of a polymer of disaccharides organized as a three-dimensional mesh-like network connected together by peptidic cross-links. PG is a dynamic structure that is essential for resistance to environmental stressors. Remodeling of PG occurs throughout the bacterial life cycle, particularly during bacterial division and separation into daughter cells. Numerous autolysins with various substrate specificities participate in PG remodeling. Expression of these enzymes must be tightly regulated, as an excess of hydrolytic activity can be detrimental for the bacteria. In non-tuberculous mycobacteria such as Mycobacterium abscessus, the function of PG-modifying enzymes has been poorly investigated. In this study, we characterized the function of the PG amidase, Ami1 from M. abscessus. An ami1 deletion mutant was generated and the phenotypes of the mutant were evaluated with respect to susceptibility to antibiotics and virulence in human macrophages and zebrafish. The capacity of purified Ami1 to hydrolyze muramyl-dipeptide was demonstrated in vitro. In addition, the screening of a 9200 compounds library led to the selection of three compounds inhibiting Ami1 in vitro. We also report the structural characterization of Ami1 which, combined with in silico docking studies, allows us to propose a mode of action for these inhibitors. Full article

(This article belongs to the Special Issue The Metabolism of Nucleic Acids, Cell Division, Cholesterol Degradation, Cell Wall Biosynthesis and Host–Pathogen Interactions in Tuberculosis)

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Review

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19 pages, 1127 KiB

Open AccessReview

A Small Protein but with Diverse Roles: A Review of EsxA in Mycobacterium–Host Interaction

by Yanqing Bao, Lin Wang and Jianjun Sun

Cells 2021, 10(7), 1645; https://doi.org/10.3390/cells10071645 - 30 Jun 2021

Cited by 8 | Viewed by 3280

Abstract

As a major effector of the ESX-1 secretion system, EsxA is essential for the virulence of pathogenic mycobacteria, such as Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm). EsxA possesses an acidic pH-dependent membrane permeabilizing activity and plays an essential role by mediating mycobacterial escape from the phagosome and translocation to the cytosol for intracellular replication. Moreover, EsxA regulates host immune responses as a potent T-cell antigen and a strong immunoregulator. EsxA interacts with multiple cellular proteins and stimulates several signal pathways, such as necrosis, apoptosis, autophagy, and antigen presentation. Interestingly, there is a co-dependency in the expression and secretion of EsxA and other mycobacterial factors, which greatly increases the complexity of dissecting the precise roles of EsxA and other factors in mycobacterium–host interaction. In this review, we summarize the current understandings of the roles and functions of EsxA in mycobacterial infection and discuss the challenges and future directions. Full article

(This article belongs to the Special Issue The Metabolism of Nucleic Acids, Cell Division, Cholesterol Degradation, Cell Wall Biosynthesis and Host–Pathogen Interactions in Tuberculosis)

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