An unusual feature of Gramnegative pathogens, including both extracellular and intracellular bacteria, is their capacity to inject immune modulatory bacterial proteins directly into host cells via specialized structures: the type III and type IV secretion systems (T3SS and T4SS, respectively) (Fig. 13.19). These needlelike structures, or injectisomes, assemble on the bacterial surface and provide a conduit through which bacterial proteins are secreted directly into the cytosol of target cells. A range of bacterial virulence factors that aid in subverting the host immune response are delivered via this mechanism, including bacterial factors that block signaling cascades central to the inflammatory response: NFκB and MAP kinases. Among the most remarkable of these are the Yersinia outer proteins (Yops) produced by Yersinia pestis, the causative agent of bubonic plague. Secretion of several of these factors (for example, YopH, YopE, YopO, and YopT) into phagocytes disrupts the actin cytoskeleton, which is essential for phagocytosis. The essential roles played by T3SS or T4SS in immune subversion by a number of Gramnegative pathogens are demonstrated by the loss of pathogenicity of mutant bacteria lacking components of these structures.
13-20 Intracellular bacterial pathogens can evade the immune system by seeking shelter within phagocytes.
To avoid the major effectors directed against extracellular bacteria—complement and antibodies—some bacterial pathogens have evolved specialized mechanisms for surviving within macrophages, using these phagocytes as their primary host cell, as well as a vehicle for dissemination within the host. This ‘Trojan horse’ strategy is achieved by three general strategies: blockade of phagosome–lysosome fusion; escape from the phagosome into the cytosol; and resistance to killing mechanisms within the phagolysosome. Mycobacterium tuberculosis, for example, is taken up by macrophages but prevents the fusion of the phagosome with the lysosome, protecting itself from the bactericidal actions of the lysosomal contents. Other microorganisms, such as the bacterium Listeria monocytogenes, escape from the phagosome into the cytoplasm of the macrophage, where they multiply. They then spread to adjacent cells in the tissue without emerging into the extracellular environment. They do this by hijacking the cytoskeletal protein actin, which assembles into filaments at the rear of the bacterium. The actin filaments drive the bacteria forward into vacuolar projections to adjacent cells; the vacuoles are then lysed by the listeria, releasing the bacteria into the cytoplasm of the adjacent cell. Moreover, Listeria has been shown to induce the formation of bacteriacontaining blebs on the surface of infected cells. These blebs which express phosphatidyl serine on the outer membrane leaflet. This membrane phospholipid is normally restricted to the inner membrane leaflet, and when exposed on the outer membrane leaflet is normally recognized by phagocytes as a signal for the uptake of apoptotic cell debris. In this way, Listeria is delivered directly to phagocytic cells, thereby avoiding attack by antibodies.
Following uptake, Salmonella species use a type III secretion system (see Fig. 13.19) to secrete effectors such as SifA into the host cytosol and membranes in order to alter the composition of the Salmonellacontaining vacuole so as to avoid destruction. Remarkably, Salmonella can also inject factors that delay the apoptotic death of host macrophages, prolonging the phagocytes’ lifespans until their bacterial cargo can be delivered to new cellular hosts. Other actions of intracellular bacteria counter reactive oxygen species or microbicidal peptides delivered into the phagolysosome by the ingesting phagocyte.
Fig. 13.19 Pathogenic bacteria use specialized secretion systems to inject effector molecules into host cells.