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Role of sphingomyelinases in mycobacterial infection
Mycobacterial infection-induced diseases, particularly tuberculosis (TB), cause more than 1 million deaths annually. Mycobacteria initially infect lungs, invade alveolar macrophages and can develop a systemic infection with high lethality. However, currently available drugs are only partially effective due to the development of drug-resistant mycobacteria. The sphingomyelinase/ceramide system has been implicated to play many roles in mycobacterial infections. Thus, this study aims to identify the mechanisms of sphingomyelinase/ceramide-regulated mycobacterial infection and provide potential therapeutic strategies. The present work investigated roles of neutral sphingomyelinase (Nsm) and acid sphingomyelinase (Asm)/ceramide system in the systemic infection of murine macrophages and mice with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). Nsm has been shown to allow mycobacterial persistence in mice by suppressing autophagy. The present study focused on the role of Nsm in the generation of granuloma, the hallmark of mycobacterial infections. The results in this thesis reveal a novel mechanism of Nsm-dependent granuloma formation upon mycobacterial infection. The results indicate that the infection of bone marrow-derived macrophages (BMDMs) with BCG leads to rapid activation of Nsm and activation of surface β1-integrin via phosphorylation of p38 mitogen-activated protein kinases (p38K) and c-Jun N-terminal kinase (JNK). Nsm-dependent β1-integrin activation results in the activation of small GTPase Rac1 and reorganization of the cytoskeleton. This leads to macrophage migration and granuloma-like clusters in vitro. Mice heterozygous for Nsm or mice treated with neutralizing antibodies against β1-integrin contain fewer macrophage clusters in vitro, fewer granulomas in vivo and, most importantly, fewer bacteria in vivo. These findings indicate that the Nsm/ceramide system plays an important role in mycobacteria-induced granuloma formation by regulating a signaling cascade via p38, JNK, β1-integrin and Rac1. ...
Role of sphingomyelinases in mycobacterial infection
Mycobacterial infection-induced diseases, particularly tuberculosis (TB), cause more than 1 million deaths annually. Mycobacteria initially infect lungs, invade alveolar macrophages and can develop a systemic infection with high lethality. However, currently available drugs are only partially effective due to the development of drug-resistant mycobacteria. The sphingomyelinase/ceramide system has been implicated to play many roles in mycobacterial infections. Thus, this study aims to identify the mechanisms of sphingomyelinase/ceramide-regulated mycobacterial infection and provide potential therapeutic strategies. The present work investigated roles of neutral sphingomyelinase (Nsm) and acid sphingomyelinase (Asm)/ceramide system in the systemic infection of murine macrophages and mice with Mycobacterium bovis Bacillus Calmette-Guerin (BCG). Nsm has been shown to allow mycobacterial persistence in mice by suppressing autophagy. The present study focused on the role of Nsm in the generation of granuloma, the hallmark of mycobacterial infections. The results in this thesis reveal a novel mechanism of Nsm-dependent granuloma formation upon mycobacterial infection. The results indicate that the infection of bone marrow-derived macrophages (BMDMs) with BCG leads to rapid activation of Nsm and activation of surface β1-integrin via phosphorylation of p38 mitogen-activated protein kinases (p38K) and c-Jun N-terminal kinase (JNK). Nsm-dependent β1-integrin activation results in the activation of small GTPase Rac1 and reorganization of the cytoskeleton. This leads to macrophage migration and granuloma-like clusters in vitro. Mice heterozygous for Nsm or mice treated with neutralizing antibodies against β1-integrin contain fewer macrophage clusters in vitro, fewer granulomas in vivo and, most importantly, fewer bacteria in vivo. These findings indicate that the Nsm/ceramide system plays an important role in mycobacteria-induced granuloma formation by regulating a signaling cascade via p38, JNK, β1-integrin and Rac1. ...
Role of sphingomyelinases in mycobacterial infection
Wu, Yuqing (Autor:in) / Gulbins, Erich
12.06.2019
Hochschulschrift
Elektronische Ressource
Englisch
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