Alveolar Macrophages(AMs) are the leading defence mechanism for modulating pulmonary infections. Mycobacterium Tuberculosis(Mtb) by manipulating the unique regulatory roles of AMs, distorts their innate activities, promoting the formation of granuloma. Upon Mtb internalisation, formation of phagolysosome is detrimental for the eradication of the pathogen. Efficient operation of Mtb hijacking mechanisms against phagolysosome fusion, permits pathogen survival within the phagosome.
In the alveoli, inflammation must be down-regulated to prevent lung-structure destruction. AMs are alternative activated macrophages(AAM) induced by Th2-responses, leading to the production of anti-inflammatory cytokines and peroxisome proliferator-activated…show more content… Granuloma is thought to be a control measure for pathogen dissemination, characterised by immune cell accumulation (Guirado E.,et al, 2013).
Following phagocytosis, the transportation, uncoating and fusion of the phagosome vesicle are achieved by the recruitment of GTPase Rab proteins. Mtb blocks the conversion of Rab5 to Rab7, a fundamental process for phagosome maturation. Rab5 is found in early phagosomes, stimulating receptor-mediated endocytosis and clathrin-vesicle formation while Rab7 is associated with endosomal membrane trafficking of the late phagosome. Rab5 recruits the early endosomal autoantigen 1(EEA1) and hepatocyte growth factor-regulated tyrosine kinase(Hrs) which can bind to phosphatidylinositol-3-phosphate(PI3P) to promote phagosome maturation. PI3P is a lipid intermediate produced by Type III phosphatidylinositol-3-kinase(PI3K) on early endosomal and phagosomal membranes, significant for the recruitment of the vacuole GTPases. Mtb produces the lipid LAM and a PI3P phosphatase known as SapM, both targeting PI3P (Mario C.R., 2010). LAM was suggested that inhibits generation of PI3P by affecting the calcium/calmodulin pathway, important for recruitment of PI3K, while SapM degrades any remaining PI3P. As a result, EEA1 and Hrs cannot bind to PI3P, prohibiting phagosome maturation, hence Mtb resides in a phagosome with an abnormally high pH and limited fusion (Vojo D.,et al, 2006).