Autophagy to survive is manipulating the host cell


Autophagyisolate cargo a into the membrane with   doublestructure commonly referred by autophagosome5. Induction of autophagy can bemonitored by MAP1LC3B (LC3) formation5. To survive inside macrophages,intracellular bacteria develope a variety of strategies to avoid or fight thehost defence system13. In this case, MTB has the ability to hold phagosomematuration20.

Autophagycan act as a tumor suppressor in normal cells based on the efficiency ofnon-apoptotic cell death from malignant cells and DNA damage by inhibiting ROSformation18. Antimicrobial activity and apoptosis of human macrophages can betriggered by cytosolic phospholipase activity through MTB which catalyze therelease of arachidonic acid. Arachidonic acid is product of a second messengerof TNF which induce apoptosis and oxygen radicals, which are produced duringarachidonic acid lipoxygenation, thus inducing the production of reactiveoxidative species and are involved in cell death4.Bacteriathat are resistant to drugs is a threat to human health. Resistant toantibiotics can be against two things: bacterial survival ability and theability to reproduce in the presence of macrophages. When bacteria enters themacrophages, they will experience environmental stress such as nutritionalrestriction induced by the host, acidification, toxic peptides, osmotic stress,and reactive oxygen species (ROS), which later became the biggest cause thedeath of the bacteria16.

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To survive inside macrophages, MTB developed a varietyof strategies to avoid or fight the host defence system13. One of themechanisms of MTB to survive is manipulating the host cell death pathways ininfected cells. One of the virulence factors are surface glycolipid PDIM(phthiocerol dimycocerosates)21. Lipid are not directly genetically encoded andtherfore are not amenable to traditional tagging methods, also cell wall lipidshave mutiple overlapping functions16.

Multiple role functions from PDIM onpathogenesis has been investigated before, including the invasion ofmacrophages, masking of pathogen-associated molecular pattern (PAMPS),resistance to death with nitric oxide, and the prevention of the recruitment ofactive macrophages to infected area19. PDIM supress recruitment of         microbicidal,   iNOS-positivemacrophagesby inhibiting TLR signaling (Figure 3)24. Interactions between host and bacterialcell wall are likely to be bidirectonal and change when infection24. PDIM invivo21abundance depend on expression of bisynthetic enzymes which decrease uponmacrophage infection, shift metabolic flux which occur during host lipidcatabolism10 and insertion of molecule into host membranes1. There maybevariable amount of PDIM on MTB surface at different time points afterinfection24.            MTB initiated human infections indistal lung, and reside in upper respiratory tract.

TLR signalling stimulatedby PAMPs from lung overrides PDIM and PGL-mediated immune evasion24. There issite named resistance-determining region (RRDR)22 that caused by mutations inMTB strains at 81-bp region of rpoB. This mutations result is high levels ofresistance to rifampicin. Accordingto Comas7 all laboratory-generated mutans of MTB withrifampicin-resistance  mutations in theRRDR reduced fitness compared to their respond for drug ancestors when withoutrifampicin8, MTB with RIF resistant caused by mutations in the rpoB gene, wherethe majority is on codon 531 and 52612. According to Kawamura mutation in codon526 related to oxidative stress sensitivity14. In addition, some reports saythat just one gene mutations in the rpoB encodes in sub-unit of RNA polymerase? can cause interaction between the RNA polymerase and some promoter alsotranscription regulation that trigger changes in phenotype16.Themechanism of the rpoB gene mutation caused by resistant rifampicin indicatesthat specific lead to mutations in the rpoB changes aspects of transcription.

These transcription factors causing changes in gene expression which encodesthe protein secretion, and proteomic changes produce some enzymes and lipidbiosynthetic of intermediate in the path of phthiocerol dymycocerosate (PDIM).To prove PDIM plays role in induction of autophagy and necrosis on MTB, Quigleyobserved conversion of cytosolic LC3I to autophagosome-bound LC3II, using theexpression of green fluorescent protein-LC3 (GFP) and flow cytometry21. As aresult, autophagy was decreased in cells infected by MTB. PDIM plays role ininduction of autophagy with decreasing autophagy on infected cells by MTB21.Resistanceto rifampicin caused by mutations in rpoB gene related with physiological  and metabolic changes in bacterial systems(Koch). These RIF resistance might be under dual selection in MTB, combinedbenefit and physiological advantage of rpoB gene can fix rpoB mutants to infectin MTB populations.

 

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