What is the bodys first line of defense against disease

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Overview of pathogen-induced phagocytosis and xenophagy mechanisms in epithelial cells. Non-professional phagocytes like epithelial cells can internalise pathogens (dark green) via “trigger” or “zipper” mechanisms. Pathogens using the “trigger” mechanism secrete effector proteins in the host cell. These factors modulate the actin cytoskeleton leading to the generation of membrane ruffles and internalisation. The “zipper” mechanism based on the interaction of host receptors on the plasma membrane with invasion proteins expressed on the pathogen surface. These interactions lead to localised cytoskeleton rearrangement and pathogen uptake. The internalised pathogen-containing vesicles may follow as classical phagosome (P) the lysosomal degradation route (blue arrows). Pathogen-mediated activation of PRRs (surface TLRs, Dectin-1) can lead to LC3-associated phagocytosis (LAP, magenta arrows) and the formation of a LAPosome (L) which is characterised by LC3 (orange spot) on the outer leaflet of the vesicle membrane and a more rapid fusion with the lysosome. In addition, xenophagy (black, solid arrows) may be activated by PRR pathways. TLR signalling activates the E3 ubiquitin ligase TRAF6 that ubiquitinates (Ub) Beclin 1 necessary for xenophagy initiation (a). Activated NODs interact with ATG16L1 which is relevant for phagophore elongation (b). If the pathogen escapes into the cytosol, rupture of the vesicles is sensed via xenophagy receptors (SLRs) that bind galectins. These in turn recognise the cytosolic presence of glycans being normally hidden inside the vesicles. Pathogens entering the cytosol are ubiquitinated (Ub) by different host factors. Some SLRs can bind that ubiquitin coat surrounding the pathogen. Subsequently, SLRs bind LC3 on the elongating phagophore and thereby tag the pathogens and/or cellular regions harbouring the bugs for xenophagic degradation. PRR signalling (orange arrows) often leads to high cellular levels of nitric oxide (NO+) and reactive oxygen species (ROS). ROS upregulate ATG4 expression concurrently mediating oxidation of ATG4 at cysteine (S−). Both events facilitate LC3 enrichment on the phagophore membranes promoting its elongation as well as substrate targeting. NO+ formed by the activity of inducible nitric oxide synthases (iNOS) can nitrify cGMP to 8-nitro-cGMP that modifies cysteines on the bacterial surface (S-guanylation). This leads to enhanced ubiquitination, thereby tagging the pathogen for recognition by SLRs. Members of the TRIM family of auto-/xenophagy receptors are involved in precision xenophagy. TRIMs recognise pathogenic targets (like viral capsids, dark green hexagon) and form a platform for core xenophagy factors (ULK1, Beclin 1, and ATG16L1). Thereby, they bundle initiation, elongation, and substrate targeting to one specific cellular area. After enclosure, the xenophagic vesicle undergoes a maturation process marked by the dissociation of LC3 from the outer membrane (d) and eventually fuses with the lysosome (e) leading to the degradation of the pathogens