Introduction
The pathogenesis of tuberculosis is the product of the interaction between bacterial virulence and host resistance, which are two distinct and independent variables; this has been appreciated for a long time (1). However, modern tools have allowed us to define the role of specific bacterial and host components to an unprecedented degree in recent years. The desired end point of efforts to define bacterial and host components of this devastating disease is to identify virulence factors and drug targets within the bacterium as well identify components of the host’s immune system which can be augmented and indeed altered by vaccination. In this review I will touch only lightly on the classic literature of the early modern period as this work has been eloquently reviewed in the two most recent Annual Review articles (2, 3). I will focus more on the relatively recent literature, which has benefited from the maturation of the tools available as a result of the publication of the mouse and bacterial genome (4, 5). These tools, along with the ability to genetically alter the bacterium (6, 7), have resulted in an increased ability to manipulate the disease model in a directed manner.
The detrimental impact of tuberculosis on public health worldwide is generally appreciated. Indeed with the number of exposed individuals being approximated at one third of the world’s population, the fact that only 5% of those exposed eventually develop disease is not comforting when the case rate is 8 million new cases per year (8). When the ability of HIV infection to reduce immunity to Mycobacterium tuberculosis (Mtb) infection is considered, the consequences for spread of both drug sensitive and drug resistant tuberculosis are daunting (9, 10). While the public health impact of the disease is enormous and warrants the high level of interest shown by scientists worldwide, the disease and the immunopathologic lesions it evokes have also fascinated immunologists since the birth of the discipline.
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Perhaps the key reason for the interest of immunologists is that both immunity and pathogenesis are mediated by the lymphocyte response to mycobacterial infection. Thus, while in the absence of an acquired cellular response there is limited to no immunity, the absence of this response also limits the generation of the classical caseation associated with transmission of the pathogen. This statement is perhaps best supported by considering the consequences of HIV infection on the development of tuberculosis. Tuberculosis is an index disease for HIV infected individuals and develops when CD4 numbers are still much higher than those predisposing to other opportunistic infections (11). However, when the immunopathologic consequences of Mtb infection in AIDS patients are assessed there is a much altered disease state (11) and an altered inflammatory response. Specifically, there is a dominant granulocytic infiltrate and necrosis but not the typical caseous necrosis seen in non-HIV infected tuberculosis granulomas (12). This strong tendency to granulocytic involvement is also see in the mouse model wherein the CD4 molecule is genetically disrupted (13). The acquired cellular response, as represented largely by CD4 T cells, provides therefore protective immunity while also promoting the development of mononuclear lesions and the caseous necrosis required for transmission. It is the duality of the role of the acquired cellular response that leads to the apparently contradictory presence of a strong cellular immune response at the site of unresolving disease.
The most important aspect of the acquired cellular response is the rapidity with which it is expressed. If the response is too slow, bacteria grow and reach a point where although a potentially protective response is being expressed, the environment is such that it is not effective. In this same vein it is clear that dose plays a role in the ability of the host to control bacteria. Specifically, if one is infected by too high a dose then the local bacterial burden may reach a level that interferes with the efficient expression of protective immunity. These ideas were brought together eloquently by Rich (1) using the lung histopathology from patients in the pre-drug era to describe the natural history of the disease. He suggested that the acquired cellular response was able to control bacterial growth but that it failed to do so in the face of high numbers of bacteria. To support this idea he observed that within the same patient, large lesions tend to progress while small ones are restrained in their growth. Further, the nature of metastatic lesions was different from the primary lesion in that they are generally circumscribed and bacterial growth is controlled. Finally, he reported that the large number of bacteria that arrive at a new site as a result of aspiration of large primary lesions usually results in a sizeable progressive lesion. This interpretation predates our understanding of much of the acquired cellular response but supports the importance of the kinetics of the response, the importance of the environment within which the response must occur and the potential for regulation of the response by either the bacteria or the acquired response itself.
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The importance of lymphocytes in controlling tuberculosis was under appreciated in early work, as although these cells were clearly present in lesions their function was unknown. It was early mouse model work that demonstrated that T cells were required for anti-tuberculous immunity in systemic (14, 15) and aerosol (16) challenge models. That CD4 T cells were the primary mediators of anti-tuberculous immunity was shown as a result of transfer models and then later by the use of gene-deficient mice (17, 18). It was also gene-deficient mice that demonstrated the importance of cytokine mediated macrophage activation in the control of bacterial growth (19, 20). The relevance of these studies to the human condition was demonstrated by the observation that HIV-mediated loss of CD4 T cell rendered patients susceptible to tuberculosis (11) and that people genetically deficient for the cytokine-mediated macrophage activation pathway were also susceptible to tuberculosis (21).
While significant progress has been made in our understanding of what lymphocytes do during both primary and recall responses to mycobacterial infection, the vaccine that is currently in use, a derivative of Mycobacterium bovis called bacille Calmette Guerin (BCG), was first developed in 1921 when we had no idea what lymphocytes were doing. While the efficacy of this early vaccine is clear for limiting disseminated childhood tuberculosis (22) its efficacy is less obvious for pulmonary disease (23) and we are still limited in the rational design of vaccines by our lack of understanding of both the primary and recall acquired cellular response to tuberculosis.
In order for significant progress to be made in the development of vaccines we need to understand the interaction between the acquired cellular response and the pathogen from the beginning of infection throughout the disease process. There are several important issues to be addressed. We need to know whether the acquired cellular response that is expressed upon infection is truly optimal and to what extent it is modulated by the pathogen. We also need to know what types of effector cell are activated by infection and whether each sub type is required for immunity or whether it acts to mediate pathologic or regulatory consequences. Further, we need to know the extent to which lymphocytes induced by infection, modulate the function of other cells and indeed the extent to which the pathogen modulates the function of host cells. Indeed, we need to know the extent to which the inflammatory site itself impacts the ability of effector cells to mediate their protective function. Finally, we need to identify anti-bacterial activities that are not induced during natural infection but which can be augmented by vaccination and which do not lead to adverse pathologic consequences. This list of objectives is somewhat daunting but the field has made dramatic progress recently and in light of new tools and approaches further progress should result in significant breakthroughs (24).
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