How macrophages kill tubercle bacilli

Abstract

Despite over 30 years of intermittent investigations, there is no definitive evidence that macrophages kill Mycobacterium tuberculosis. This is largely because all attempts to demonstrate such killing by macrophages in vitro have produced only rather unconvincing results. How then can I discuss how macrophages kill tubercle bacilli when it is not proven that they do? The answer is that just as there is a large and growing body of indirect evidence that makes it highly likely that macrophages can kill tubercle bacilli, there is also a body of evidence that makes it likely that they do so by producing hydrogen peroxide.I will spend most of this lecture summarising the more recent body of evidence that macrophages kill tubercle bacilli by producing hydrogen peroxide but I will also refer briefly to the question whether macrophage lysosomes have any direct activity against tubercle bacilli, for it is unlikely that macrophages are dependent solely on one antimycobacterial product. Different macrophage products may be of crucial importance under different circumstances.The peroxide story, in relation to host defence against M . tuberculosis, begins around 1953. After the chemotherapeutic drug isoniazid had been in use for a few years, reports began to appear of the isolation of isoniazid-resistant mutants of M . tuberculosis that had low virulence in the guinea-pig, were catalase-negative and were susceptible to killing by hydrogen peroxide (Barnett, Bushby and Mitchison, 1953;Cohn et al., 1954;Mitchison, 1954;Morse et al., 1954;Peizer and Widelock, 1955). At that time hydrogen peroxide production by mammalian tissues had not even been demonstrated but the implication that peroxide might reach tuberculocidal concentrations inside leucocytes was not missed by Coleman and Middlebrook (1956). This idea was strengthened considerably in the early 1960s by reports that a substantial proportion of isolates of M . tuberculosis from patients in the Indian subcontinent were of low virulence in the guinea-pig and peroxide-susceptible even though they had a normal catalase content and isoniazid susceptibility (Subbaiah, Mitchison and Selkon,

Growth of group IV mycobacteria on medium containing various saturated and unsaturated fatty acids

“…This may indicate a certain role for highly unsaturated C20 fatty acids in the killing mechanisms for rapidly growing mycobacteria other than M. fortuitum and M. chelonei by phagocytes. Our findings that M. fortuitum and M. chelonei were highly resistant to most of the fatty acids and our previous observations (25) that M. chelonei was effectively killed by activated macrophages indicate that fatty acids play only a minor role in the killing of these two mycobacteria by activated macrophages and that the antimycobacterial ability of the phagocytic cells can be attributed to their function in the generation of active oxygen (12,20,25) and to bactericidal proteins (19,23,24). Here, we examined the growth-inhibitory activity of fatty acids at pH 7.5, because phagosomal pH in phagocytic cells is known to increase temporarily to 7.5 and this is associated with enhanced production of active oxygen (8,26).…”

Novel structure of the recA locus of Mycobacterium tuberculosis implies processing of the gene product

“…tuberculosis bacilli reside in macrophages where they would be exposed to hydrogen peroxide as part of the macrophage defense mechanism (36). In E. coli, resistance to hydrogen peroxide correlates with the recA genotype of the cells, rather than with levels of the protecting enzymes catalase, peroxidase, or superoxide dismutase (9), although this appears not to be the case with Neisseria gonorrhoeae (22).…”

Identification of aMycobacterium tuberculosisGene That Enhances Mycobacterial Survival in Macrophages

“…M. tuberculosis is resistant to macrophage killing, and its survival during phagocytosis and its subsequent multiplication within these professional phagocytes are critical to its pathogenesis. A variety of mechanisms have been suggested to contribute to the survival of M. tuberculosis within macrophages (15,39), including inhibition of phagosome-lysosome fusion (2), inhibition of the acidification of phagosomes (41), resistance to killing by reactive oxygen intermediates (26) and reactive nitrogen intermediates (12,27), and modification of the lipid composition of the mycobacterial cell membrane, thereby altering its capacity to interact with immune or inflammatory cells (19). However, little progress has been made in identifying the genes and their corresponding products responsible for these properties.…”