Phagocyte sabotage: disruption of macrophage signalling by bacterial pathogens

A key strategy for pathogens to survive in a hostile host environment is to interfere with normal cell signalling to defuse the defences that are aimed at controlling and eliminating foreign invaders. Macrophages are the immune system's journeymen that are well situated to recognize rapidly, internalize and degrade bacterial pathogens, and to contain an infection for long enough to initiate adaptive immunity. Macrophages function as both sentinels and the first line of defence against infection, and they are therefore an essential barrier that pathogens must overcome to be successful. Many successful bacterial pathogens are able to alter their recognition, either by modifying their surface, interrupting the signalling that is triggered by receptor–ligand binding, or by engaging alternative receptors, ultimately escaping macrophage surveillance. Different bacterial pathogens avoid uptake by, or trafficking within, macrophages to minimize damage from the cell's antimicrobial arsenal. Microbial recognition initiates robust signalling by the extracellular signal-regulated kinase/mitogen-activated protein kinase, nuclear factor κB, and interferon-γ pathways, which are crucial for many responses to infection. They present a strategic target for bacterial subversion, which involves producing bacterial proteins that mimic, inhibit, or perturb the localization of eukaryotic signalling molecules. Some pathogens capitalize on the destructive consequences of an over-exuberant inflammatory response on the host. Other pathogens persist by avoiding or attenuating the inflammatory response that is orchestrated by macrophages. By altering macrophage signalling, pathogens can alter the production of, or response to, cytokines, which impairs the communication between cells that is necessary for clearance of the infection. Disease can result from dysregulated macrophage signalling that is driven by the host or pathogen and does not necessarily benefit either player. It is therefore important to consider the net balance of signalling within a macrophage when determining if response to infection favours host or pathogen survival.