Macrophage apoptosis in mycobacterial infections

Abstract

Mycobacterial diseases are a major public health concern. In the case of tuberculosis, the problem has been acerbated due to the emergence of drug-resistant strains of Mycobacterium tuberculosis, and Mycobacterium avium is the major opportunistic pathogen in HIV-1 infection in the United States. M. tuberculosis and M. avium replicate in human macrophages and induce apoptosis. Incubation of freshly added uninfected autologous macrophages with apoptotic M. avium-infected macrophages results in 90% inhibition of bacterial growth. Apoptosis also prevents the release of intracellular components and the spread of mycobacterial infection by sequestering the pathogens within apoptotic bodies. Consistent with the model that host cell apoptosis is a defense mechanism against mycobacteria is the finding that the virulent M. tuberculosis strain H37Rv induces substantially less macrophage apoptosis than the attenuated strain H37Ra. Evasion of apoptosis by this pathogen is achieved by enhanced release of sTNFR2 by H37Rv-infected macrophages and subsequent formation of inactive TNF-␣-TNFR2 complexes. These observations contribute to the hypothesis that apoptosis of the host macrophage is an important defense mechanism in mycobacterial infections, which prevents the spread of the infection.

Activation of the Mitogen-Activated Protein Kinase Signaling Pathway Is Instrumental in Determining the Ability ofMycobacterium aviumto Grow in Murine Macrophages

“…Interestingly, we were not able to detect any decrease in cell viability as determined by trypan blue exclusion or MTT-formazan assay (data not shown) following M. avium infection either in the presence or absence of SB203580. It is likely that the low MOI and the strain of M. avium used greatly reduced the tendency of the bacteria to induce apoptosis in the model reported in this study (43)(44)(45)). …”

Multiple Roles of CLAN (Caspase-Associated Recruitment Domain, Leucine-Rich Repeat, and NAIP CIIA HET-E, and TP1-Containing Protein) in the Mammalian Innate Immune Response

“…Bacteria such as Salmonella produce several virulence proteins associated with type III secretion systems that enable these microorganisms to subvert host antibacterial processes in the cytosol of phagocytes (40,41). Another hypothesized benefit of residing within the macrophage is that these host cells carry organisms through the lymph and blood to other tissues, thus facilitating their in vivo dissemination (42,43). Our observation that the overexpression of CLAN predisposes macrophages to cell death upon exposure to large bacterial loads suggests that this protein may serve to counter the "hitch-hiking" effect exploited by intracellular pathogens, similar to the hypersensitive response of plants (9).…”

Pathogen-induced apoptosis of macrophages: a common end for different pathogenic strategies. Microreview

“…Also, by undergoing apoptosis, macrophages may be able to expose the invaders to more potent bactericidal cells, such as neutrophils, and to the humoral arm of the immune system. This hypothesis has been advanced previously to explain the ability of macrophage apoptosis to help control infections with Mycobacterium tuberculosis (Fratazzi et al, 1999). In this manner, we imagine that, through suicide, macrophages attempt to both prevent the spread of intracellular pathogens and, in some cases, elicit a potent antibacterial immune response via the release of inflammatory cytokines.…”