a number of pathogenic Gram-negative bacteria use a complex, needle-like protein assembly—a type iii or iV secretion system, or injectisome—to inject virulence proteins into target cells to compromise host defenses and establish infection. these ‘nanoinjectors’ are assembled from more than 20 proteins, and are composed of a base that spans the two bacterial membranes, a needle that is anchored in the base and is formed by the polymerization of repeating α-helical subunits, and a tip complex that serves as a docking structure for the translocon, which penetrates the host-cell membrane to allow bacterial effector proteins to pass into the host cell.
Fig. 13.20 T-cell and macrophage responses to Mycobacterium leprae are sharply different in the two polar forms of leprosy. infection with M. leprae, whose cells stain as small dark red dots in the photographs, can lead to two very different forms of disease (top panels). in tuberculoid leprosy (left), growth of the organism is well controlled by tH1-like cells that activate infected macrophages. the tuberculoid lesion contains granulomas and is inflamed, but the inflammation is local and causes only local effects, such as peripheral nerve damage. in lepromatous leprosy (right), infection is widely disseminated and the bacilli grow uncontrolled in macrophages; in the late stages of disease there is major damage to connective tissues and to the peripheral nervous system. there are several intermediate stages between these two polar forms (not shown). the lower panel shows northern blots demonstrating that the cytokine patterns in the two polar forms of the disease are sharply different, as shown by the analysis of Rna isolated from lesions of four patients with lepromatous leprosy and four patients with tuberculoid leprosy. Cytokines typically produced by tH2 cells (il-4, il-5, and il-10) dominate in the lepromatous form, whereas cytokines produced by tH1 cells (il-2, iFn-γ, and tnF-β) dominate in the tuberculoid form. it therefore seems that tH1-like cells predominate in tuberculoid leprosy, and tH2-like cells in lepromatous leprosy. iFn-γ would be expected to activate macrophages, enhancing the killing of M. leprae, whereas il-4 can actually inhibit the induction of bactericidal activity in macrophages. Photographs courtesy of G. Kaplan; cytokine patterns courtesy of R.l. Modlin.
As a tradeoff for their intracellular lifestyle, intracellular bacteria risk activation of immune effectors that target these pathogens: NK cells and T cells. As discussed in Section 115, a major function of the type 1 immune response is activation of NK cells and TH1 cells that activate phagocytes for enhanced intracellular killing by secretion of IFNγ or expression of CD40L. Additionally, those intracellular pathogens that have evolved mechanisms for escape of the phagosome, such as Listeria, generate cytosolic peptides that feed the MHC class I antigen presentation pathway and thus induce cytotoxic Tcell responses that target their host cell for destruction. In leprosy, a disease caused by skin and peripheral nerve infection with Mycobacterium leprae, effective host defense requires macrophage activation by NK and TH1 cells (Fig. 13.20).