Mycobacterium tuberculosis thesis

Contents:
  1. Innate Factors in Early Clearance of Mycobacterium tuberculosis
  2. Systems-level Modelling and Simulation of Mycobacterium tuberculosis
  3. In silico genome analysis and finding a target protein for mycobacterium tuberculosis (H37Rv)
  4. PhD defence of Willy Ssengooba
  5. Introduction

Only two of the encoded proteins have been biochemically characterized to date. Figure 4: Computer-based genome analysis supports the existence of mycobacterial glycan-binding proteins, which can be associated with known lectin and glycosaminoglycan-binding protein families, including agglutinin-like sequences ALS , mannose-sensitive hemagglutinin MSHA , C-type lectins, and R-type lectins, filamentous hemagglutinin FHA and heparin-binding hemagglutinin HBHA.

However, hitherto there is only limited information concerning expression, cell localization and function of mycobacterial lectins and glycosaminoglycan-binding proteins. Figure 4: Computer-based genome analysis supports the existence of mycobacterial glycan-binding proteins, whi This lectin is cell surface-localized and mediates adherence of the fungus to endothelial and epithelial cells [86,87].

Fucose-containing glycans were detected as potential carbohydrate ligands for the ALS1 protein [88]. Intriguingly, Rv is described as essential for in vitro growth of Mtb , as detected by transposon mutagenesis studies [89,90]. However, no further biochemical or genetic data are available for either Rv or Rv, and an associated ALS-like lectin function is only speculation. These genes encode for proteins involved in assembly of type IV pili T4P [91].

Innate Factors in Early Clearance of Mycobacterium tuberculosis

Since bacterial lectins are often located at the terminal ends of pili or fimbriae, this homology is of potential interest as it indicates that Mtb might express carbohydrate-binding pili on the cell surface discussed further below. These lectins bind carbohydrates in a calcium-dependent manner. The ligand specificity is highly diverse, including fucosides, mannosides, glucosides, N -acetylglucosamines, galactosides, and N -acetylgalactosamines.

While some of the C-type lectins are known to be secreted, others are membrane-associated proteins. They often oligomerize into homodimers, homotrimers, and higher-ordered oligomers, which increases their avidity for multivalent ligands. C-Type lectins play key roles in cell—cell interactions, such as host—pathogen interactions, and phagocytosis [92].


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TB in humans is primarily caused by Mtb , but can also be a consequence of infection with Mycobacterium africum, which is currently limited to West Africa [94]. Thus, the potential C-type lectin of Mtb might not be essential for a typical TB infection in humans. However, cell localization and function need to be investigated in further detail. Figure 5: Amino acid sequence and secondary structure alignments of Mtb proteins encoded by Rv and Rv to known proteins were determined using Phyre 2. Amino acids involved in heparin bind are colored in blue lysine and green alanine.

Figure 5: Amino acid sequence and secondary structure alignments of Mtb proteins encoded by Rv and Rv R-Type lectins are classified as lectins containing a carbohydrate-recognition domain similar to the CRD in ricin, a toxin of the poisonous plant Ricinus communis.

R-type lectins have been detected in plants, animals, and bacteria. Plant R-type lectins often contain a separate subunit functioning as a toxin. Furthermore, ricin-type lectin domains have been found in glycosyltransferases as well as in bacterial hydrolases [95]. This secreted protein was crystallized in by Patra et al.

Recently Nogueira et al. The results underline that mycobacterial lectins are expressed in vivo and might be important for Mtb infections. Furthermore, anti-sMTL antibodies could serve as a biomarker of disease treatment progression. The exact function of sMTL and its ligand specificity are, however, still unknown.

As described before some R-type lectins exhibit toxin activity. Until recently Mtb was regarded as a bacteria that does not express toxins []. In Danilchanka et al. Thus, it might be conceivable that certain Mtb lectins could also have toxin function. One of the most well-characterized FHAs is expressed by Bordetella pertussis. The FHA of this pathogen is both surface-exposed and secreted.

It functions as an adhesin, where it recognizes and binds to sulfated glycolipids on epithelial host—cell surfaces. The ability of the bacteria to attach to and infect the epithelium of the upper respiratory tract is essential in the pathogenesis of the pertussis organism, underlining the crucial role of this lectin in bacterial physiology [].

Systems-level Modelling and Simulation of Mycobacterium tuberculosis

FHA also promotes the formation of biofilms by mediating cell—substrate and interbacterial adhesions []. Singh et al. However, there is no reported biochemical evidence to date of similar lectin functions for any of these proteins. Furthermore, this transmembrane protein has been associated with mycobacterial aggregation [82,85].

It has also been shown that antibodies directed against HBHA can limit adhesion of mycobacteria to epithelial cells in vitro and in vivo [80,83]. Thus, a humoral immune response to HBHA might also be connected to a reduced dissemination of Mtb from human lungs. Apart from the potential lectins predicted by in silico genome analysis, a C-type lectin-like carbohydrate binding domain was recently identified to be present in the arabinofuranosyltransferase EmbC Rv , which is involved in the LAM biosynthesis of the Mtb cell wall [].

In silico genome analysis and finding a target protein for mycobacterium tuberculosis (H37Rv)

As described above, only limited data exists concerning expression, subcellular localization and physiological functions of mycobacterial lectins and glycosaminoglycan-binding proteins to date. However, agglutination-inhibition and adhesion assays, genome analyses, and immunological studies have provided the first indications that glycan-binding proteins might be important mediators of TB infections and Mtb pathogenesis.

Detection of appendages on the mycobacterial surface, as extensively reviewed by Ramsugit et al. Mycobacteria have traditionally been regarded as a non-piliated genus; however, recently, studies using transmission electron microscopy TEM and atomic force microscopy AFP have identified long appendages on the surfaces of M. Interestingly, type IV pili are expressed by broth-grown Mtb , while curli-like pili are mainly produced by bacilli cultured on solid media [,].

Figure 6: Recently, pili were detected on the cell surface of Mtb , which were classified as curli and type IV pili T4P. While the expression of curli pili is associated with biofilm formation and adhesion to macrophages and epithelial cells, the function of T4P has not yet been examined. Pili often have carbohydrate-binding activity. Whether mycobacterial pili are associated with lectin functions is, however, not known to date. Figure 6: Recently, pili were detected on the cell surface of Mtb , which were classified as curli and type IV These cell surface structures are produced by several members of the Enterobacteriaceae family [].

PhD defence of Willy Ssengooba

The Mtb curli-like pili MTP encoded by RvA, although currently disputed [] , are 2—3 nm in diameter, have a similar ultrastructure to curli pili of E. The mtp gene is present in all strains of the Mtb complex MTBC , but absent in non-tuberculosis mycobacteria and other respiratory pathogens []. Ramsugit et al. It was shown that MTP is associated with Mtb aggregation and biofilm formation in vitro []. The importance of these interactions in patients, however, has yet to be confirmed, as the association of mycobacterial biofilms with bacterial pathogenesis has not yet been conclusively shown in vivo.

Besides mediating interactions among mycobacterial cells, MTP has been shown to play a role in Mtb adhesion and invasion of A pulmonary epithelial cells and THP-1 macrophages [,]. Furthermore, an impact of MTP on histopathology in a mouse model of infection has previously been described [].

Elsewhere, using purified proteins, Alteri et al. While the exact structure recognized by MTP has yet to be determined, laminin is a glycoprotein and so it is conceivable that MTP binds to mono- or oligosaccharide constituents of this protein. Type IV pili T4P are surface-exposed fibers that mediate many functions in both Gram-positive and Gram-negative bacteria, including motility, adhesion to host cells, biofilm formation, DNA uptake, and protein secretion [].

Mtb expresses T4P that appear by electron microscopy as rope-like bundles on the cell surface. Mature T4P are encoded by a seven gene operon, the expression of which is up-regulated during contact with A epithelial cells and within macrophages [,].


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However, their significance in Mtb pathogenicity has hitherto not been further investigated. Interestingly, one of the T4P-associated genes is Rv, previously identified by in silico genome analysis as coding for a potential mycobacterial lectin see above [78]. Although the related protein is most likely involved in pili assembly, it is not inconceivable that T4P have carbohydrate-binding characteristics and are involved in adhesion processes, although this has yet to be proven. The hypothesis is supported by the fact that T4P of other bacteria, for example bundle-forming pili from E.

Lectins are known to play a fundamental role in mediating and regulating numerous biological processes which are initiated by specific carbohydrate recognition. Much effort has been dedicated to the synthesis of specific lectin ligands in order to study and manipulate lectins. On the other hand, intensive work has been spent on the identification and characterization of lectins. Also in microbe—host cell interactions, specific carbohydrate—lectin interactions are the key to adhesion, microbial colonization as well as to infection.

For Mycobacterium tuberculosis it is known that the macrophage-associated lectins Dectin and Mincle, for example, specifically interact with Mtb cell surface glycans, which in many parts differ significantly from the carbohydrates found in eukaryotic cells. However, in spite of the fact that Mycobacterium tuberculosis has been the subject of intense research since its discovery in , many details of carbohydrate—protein interactions in Mtb infections are still to be discovered.

Introduction

This account has thus focused on reviewing the available knowledge on Mtb lectins, which are a promising field of research with a diagnostic and therapeutic perspective in the field of tuberculosis. Agglutination-inhibition and adhesion assays, as well as immunological studies have indeed provided the first indications that lectins might play an important and as yet underappreciated role in TB infections, underscoring the necessity of more research into these protein families.

Thisbe K. Matthew B. Calvert, Varsha R. Jumde and Alexander Titz. Sarah Wallrodt, Edward L. Simpson and Andreas Marx. Please note that the reuse, redistribution and reproduction in particular requires that the authors and source are credited. Twitter: BeilsteinInst.

Tuberculosis (TB) - Mycobacterium tuberculosis & How It Spreads

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