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The vast majority of persons infected with Mycobacterium tuberculosis remain asymptomatic for life; at least 90% of infected adults never become ill. What is the basis for resistance to tuberculosis? The high rates of clinical tuberculosis among persons infected with the human immunodeficiency virus and also among persons receiving cytotoxic therapy point to a critical role of the intact adaptive immune system. However, the most important cellular player may be the macrophage, which has two mutually contradictory roles in tuberculosis. On the one hand, activated macrophages are capable of killing or at least controlling the growth of M. tuberculosis. Granulomas are present in persons with intact immunity but absent or poorly formed in persons with poor immune responses; this observation supports the hypothesis that they are critical for limiting bacterial growth. On the other hand, macrophages provide the primary growth niche for this intracellular organism; throughout infection, mycobacteria are largely intracellular.
The hypothesis that granulomas limit bacterial growth is based largely on animal models that do not permit the observation of infection continuously over time. Granulomas are located deep in tissues; most models require that infected animals be killed to permit observation of the interaction between bacteria and host structures. Thus, we have had to draw conclusions about a dynamic process from analyses at single time points.
Although the zebrafish cannot be infected with M. tuberculosis, it is a natural host for the fish (and occasionally human) pathogen M. marinum. More importantly, the zebrafish embryo (which is also a host for M. marinum) is transparent, allowing easy visualization of living bacteria in a living host. Davis and Ramakrishnan infected zebrafish with M. marinum that expressed fluorescent proteins. Phagocytic cells, the fish equivalent of human macrophages, then took up the labeled bacteria, allowing investigators to follow the fate of both infected and uninfected phagocytes over time by means of microscopy (Figure 1). Infected cells appear to recruit uninfected phagocytes. As infected cells die, apparently via apoptosis, they are taken up by previously uninfected cells that themselves become infected. These cells provide a new growth niche for the pathogen and permit renewed bacterial growth.
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How well does this model translate to human tuberculosis? There are important differences in both the pathogens and the hosts. For example, whereas M. tuberculosis resides largely within vacuoles in the infected cell, M. marinum can escape into the cytoplasm and probably takes advantage of efficient mechanisms of cell-to-cell spread.3 In addition, the embryo of the zebrafish lacks an adaptive immune system, and the human adaptive immune system is critical to containing M. tuberculosis infection at later stages. Remodeling of the granuloma in humans with contributions from immune cells and the cytokines they release might produce an environment that is less hospitable for the pathogen than for the fish granuloma.
Sand castles topple, however. For example, the long-held view that an initial encounter between M. tuberculosis and lung macrophages inevitably leads to chronic infection has been challenged. Newer and more specific tests indicate that the contacts of tuberculosis patients often mount an immune response that subsequently resolves,4 a finding that suggests that humans have innate mechanisms to eradicate early infection. The study by Davis and Ramakrishnan suggests that interfering with signaling between the host and pathogen might tip the scales in favor of clearance of infection.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Harvard School of Public Health, Harvard University, Boston.
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