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Pathogenesis of Tuberculosis
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Divya B. Reddy, Jerrold J. Ellner
MTB virulence factors have been the subject of intense research. Previously, three major virulence factors from the outer layer of the complex mycobacterial cell wall have been characterized molecularly: mycobacterial glycolipids (cord factor), mycobacterial sulfolipids (SL), and mycosides. Cord factor(s) are trehalose-6,6′-dimycolates,13 that exist in either a non-toxic and protective micellar conformation or a toxic and immunogenic monolayer conformation. The latter is capable of killing macrophages in minutes, exacerbates acute and chronic TB in mice, and interferes with the ability of isoniazid to kill MTB.14 The toxic effects of cord factor have been attributed to an interaction with mitochondrial membranes resulting in reduction of the activity of nicotinamide adenine dinucleotide-dependent microsomal enzymes in various tissues (lung, liver, and spleen).15,16 As the most abundant lipid produced by virulent MTB, it is directly responsible for MTB multiplication in lung cavities with consequent expulsion into the environment and person-to-person spread.17
Multidrug-Resistant Tuberculosis (MDR-TB)
Published in Meera Chand, John Holton, Case Studies in Infection Control, 2018
Helen McAuslane, Dominik Zenner
M. tuberculosis bacilli are facultative intracellular parasites and slow growing organisms with a generation time of around 12 to 18 hours. The cell wall of M. tuberculosis bacilli is composed of over 60% lipid, containing mycolic acid, cord factor, and wax. Mycolic acid is hydrophobic, forming a lipid shell and affecting permeability, and it is this feature that is thought to be a significant factor in the virulence of M. tuberculosis. This lipid cell wall contributes to the survival of the organism inside macrophages, and impermeability makes it difficult to target with drugs, and contributes to the development of drug resistance. Mycobacteria are also often found in organs or body parts where the delivery of antibiotics may be more difficult, including pulmonary cavities and solid caseous material.
Lipids of Histoplasma Capsulatum
Published in Rajendra Prasad, Mahmoud A. Ghannoum, Lipids of Pathogenic Fungi, 2017
Histoplasmosis is initiated by the inhalation of a sufficient quantity of spores or conidia. The primary site of infection is lungs.2 In its pathology, histoplasmosis resembles tuberculosis, which is caused by Mycobacterium tuberculosis. Studies in the 1950’s on the pathology of tuberculosis focused on a lipid-like component which was isolated from the organism and was toxic to certain strains of mice.8 This factor was called “cord factor” and was found to be trehalose-6,6’-dimycolate.9 This suggested that lipid associated with the bacilli could be involved in the pathogenicity of the organism. Due to its similarity to tuberculosis, an analysis of the lipids of both phases of H. capsulatum was undertaken in an effort to determine what role such compounds could play in the pathogenicity or in the dimorphism of the organism. This chapter will present our current knowledge of the lipids of H. capsulatum, with emphasis on novel phosphoinositol SPH isolated from the yeast phase which reacted with sera from patients with histoplasmosis.
Scavenger receptor A in immunity and autoimmune diseases: Compelling evidence for targeted therapy
Published in Expert Opinion on Therapeutic Targets, 2022
Yang Xie, Yuan Jia, Zhanguo Li, Fanlei Hu
However, interestingly, it has also been demonstrated that in the context of fungal pathogen Pneumocystis Carinii infection, SR-A controls inflammatory cytokine production and dampens the inflammatory responses [57]. Moreover, after stimulated with mycobacterial cord factor, SR-A is capable of down-regulating the production of TNF-α and MIP-1α by hepatic and alveolar macrophages [58]. In another separate study of sterile peritonitis, SR-A was found to limit specific CXC chemokine production and then attenuate the infiltration of granulocytes in the early phase [59]. In addition, in the mouse model of sepsis, the absence of SR-A+ macrophage resulted in elevated levels of TNF-α and IL-6 [60]. Therefore, studies in different inflammatory responses suggest the inhibitory role of SR-A in cytokine production, unveiling its distinct characteristics in innate immunity.
Mycobacterial biofilms as players in human infections: a review
Published in Biofouling, 2021
Esmeralda Ivonne Niño-Padilla, Carlos Velazquez, Adriana Garibay-Escobar
The finest and strongest machineries of mycobacteria rely on their high variety of lipids that, in addition to the numerous strategies to circumvent immune mechanisms, provide them with the possibility of creating strong physico-chemical barriers and heterogeneous networks resistant to high drug doses (Figure 1). Since its description in the 1950s, it has been traditionally recognized that the so-called “cord factor” trehalose 6,6-dimycolate (TDM), is directly involved in the pathogenicity of MTBC members and granuloma formation, although not necessarily associated with the formation of cord structures (Bloch and Noll 1954; Baba et al. 1997; Hamasaki et al. 2000; Yamagami et al. 2001). However, this glycolipid is associated with the development of fast-growing in vitro pellicles from M. tuberculosis sputum isolates probably derived from cavities and granulomas, compared with mid-pellicle forming extrapulmonary isolates, suggesting that its overproduction promotes in vivo lung spreading and a possible contribution to in vivo biofilm formation (Arora et al. 2016).
Targeting strategies of liposomal subunit vaccine delivery systems to improve vaccine efficacy
Published in Journal of Drug Targeting, 2019
Rui Yu, Yaping Mai, Yue Zhao, Yanhui Hou, Yanhua Liu, Jianhong Yang
Additionally, mycobacterial cord factor and its synthetic analogue trehalose 6,6′-dimycolate and trehalose 6,6′-dibehenate (TDB) activate the CLR Mincle on macrophages. To investigate the available Mincle ligands for use as adjuvants, researchers have tested an array of synthetic TDB analogues of different structures for their potential in binding to murine Mincle in vitro and activating macrophages. In vitro and in vivo experiments suggest that Mincle expression on macrophages is an absolute requirement for binding and activation by all analogues; moreover, the trehalose diester structure is superior to monoesters for efficient activation of macrophages via interaction with Mincle [20]. Therefore, in designing the next generation of vaccines, these new vaccine adjuvant candidates could be fully utilised by co-administration with liposomes.