Fig. 1.

Evasion of macrophage defense mechanisms by intracellular pathogens. Upon phagocytosis (1), the pathogens generally reside within phagosomal compartments where a plethora of microbicidal components cooperate in a multidirectional assault to the microbes (2). By transferring virulence factors, often via secretion systems (injectosomes), some pathogens can avoid the classical maturation steps of these compartments, creating a favorable niche for their intracellular growth (3, 4, 5). Fusion of the phagosome with endosomes and/or lysosomes can be blocked (6) and fusion with Golgi- and reticulum-like vesicles can be promoted (3), resulting in the formation of specialized replicative vacuoles (4, 5), in some cases also directed to non-lytic expulsion (7). Several intracellular pathogens are able to escape directly into the cytosol (8). Here, septin cages (9), galectin decoration (10), ubiquitylation (11) and specific routes of antimicrobial autophagy (12) are activated to capture the escapers and redirect them to lytic compartments. Additionally, ubiquitylation of microbial proteins (11) labels these for proteasomal degradation (13). Several intracellular pathogens can efficiently counteract this second line of intracellular defense and replicate freely within the cytosol (14), frequently also manipulating the cell cytoskeleton (15) to sustain their extrusion and dissemination to other host cells (16). Intracellular infections have profound influences also on a wide spectrum of host functions. Cell signaling pathways can be manipulated to modulate the host inflammatory response (17) and control gene expression (18). Some pathogens are also known to induce epigenetic modification of their host cells, leading to reprogramming (19). Some virulence factors directly impact the homeostatic mechanisms by interfering with normal mitochondrial functionality (20), membrane polarity and communication with the extracellular milieu (21). The ultimate possibility for the host to eradicate the infection is to initiate cell (pyroptotic, apoptotic or necroptotic) suicide programs (20, 22, 23, 24). However, the death mechanisms can also be modulated by pathogens, which can benefit from them by the induction of host damage, pathogen dissemination and the initiation of new replicative cycles.