Fatal Disseminated BCG Infection in an 18-Year-Old Boy

Mackay, Alastair M.; Alcorn, M. J.; MacLeod, I.M.; STACK, B; Macleod, Torquil; M, Laidlaw; Millar, J. Donald; White, R. Alan

doi:10.1016/s0140-6736(80)92398-3

Cited by 34 publications

(14 citation statements)

References 16 publications

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“…tuberculosis in man remains to be established, there are several pointers. For example, there are indications that isoniazid-resistant tubercle bacilli may be of reduced virulence for man (Oestreicher et al, 1955) and that disseminated BCG infection might follow routine vaccination when macrophages are peroxide-deficient in patients with chronic granulomatous disease (Mackay et al, 1980;Urban et al, 1980). Human alveolar macrophages can probably use hydrogen peroxide to kill other phagocytosed bacteria and they release more peroxide after priming with lymphokines (Greening,Rees and Lowrie,198 l a and b).…”

Section: B Lowriementioning

confidence: 99%

How macrophages kill tubercle bacilli

Lowrie

1983

Journal of Medical Microbiology

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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,

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Section: B Lowriementioning

confidence: 99%

How macrophages kill tubercle bacilli

Lowrie

1983

Journal of Medical Microbiology

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“…The principal genetic difference between the two organisms is that BCG contains several well-defined deletions (4). M. bovis BCG mimics M. tuberculosis in its ability to persist in the body and is also able to cause reactivation disease in the immunocompromised host (1,33,41,43,45,56). Indeed, survival and persistence of the live BCG vaccine are necessary to elicit protective immunity.…”

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confidence: 99%

Compiling a Molecular Inventory for Mycobacterium bovis BCG at Two Growth Rates: Evidence for Growth Rate-Mediated Regulation of Ribosome Biosynthesis and Lipid Metabolism

et al. 2005

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An experimental system of Mycobacterium tuberculosis growth in a carbon-limited chemostat has been established by the use of Mycobacterium bovis BCG as a model organism. For this model, carbon-limited chemostats with low concentrations of glycerol were used to simulate possible growth rates during different stages of tuberculosis. A doubling time of 23 h (D ‫؍‬ 0.03 h ؊1 ) was adopted to represent cells during the acute phase of infection, whereas a lower dilution rate equivalent to a doubling time of 69 h (D ‫؍‬ 0.01 h ؊1 ) was used to model mycobacterial persistence. This chemostat model allowed the specific response of the mycobacterial cell to carbon limitation at different growth rates to be elucidated. The macromolecular (RNA, DNA, carbohydrate, and lipid) and elemental (C, H, and N) compositions of the biomass were determined for steady-state cultures, revealing that carbohydrates and lipids comprised more than half of the dry mass of the BCG cell, with only a quarter of the dry weight consisting of protein and RNA. Consistent with studies of other bacteria, the specific growth rate impacts on the macromolecular content of BCG and the proportions of lipid, RNA, and protein increased significantly with the growth rate. The correlation of RNA content with the growth rate indicates that ribosome production in carbon-limited M. bovis BCG cells is subject to growth rate-dependent control. The results also clearly show that the proportion of lipids in the mycobacterial cell is very sensitive to changes in the growth rate, probably reflecting changes in the amounts of storage lipids. Finally, this study demonstrates the utility of the chemostat model of mycobacterial growth for functional genomic, physiology, and systems biology studies.With three million people dying from tuberculosis (TB) annually, Mycobacterium tuberculosis remains a formidable pathogen. Tuberculosis ranks among the top 10 causes of global mortality and morbidity and is the leading cause of infectious disease (66). The ability of M. tuberculosis to adapt to and survive harsh environmental conditions in order to establish and maintain long-term infections within its human host is fundamental to this organism's success. Modification of the mycobacterial cell in response to changes in the environment is crucial to this adaptive process, but detailed information about how M. tuberculosis changes its macromolecular composition in response to its environment and growth rate is lacking.The genome sequence of M. tuberculosis has been available since 1998 (9). Although information obtained from the genome sequence provided new and valuable insights into the biology of the tubercle bacillus, the genome itself provides few clues regarding how the pathogen responds to its environment by changing its cellular composition. One of the principal tasks of postgenomic biological studies of M. tuberculosis is to understand how the genome orchestrates the structure and dynamics of the cell in response to changes in the environment. This task requires an integrat...

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“…It is associated with high mortality. [4][5][6][7][8][9] Although BCG dissemination has been reported in healthy children, such events are extremely rare. 10,11 In this paper, we report our experience with 11 patients with disseminated BCG infection from a tertiary care center in Saudi Arabia.…”

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confidence: 99%