What We Have Learned and What We Have Missed in Tuberculosis Pathophysiology for a New Vaccine Design: Searching for the "Pink Swan"

Abstract

This is a call to encourage the search for a new vaccine to stop the progression of Mycobacterium tuberculosis infection to tuberculosis (TB) disease. TB is a highly discreet and stigmatized disease, with a massive impact on human health. It has killed 1.2 billion people in the last 200 years and still kills 1.5 million people per year. Over the last 20 years, the TB vaccine field has experienced spectacular developments, and we have learned about (1) the importance of the Th1 response in controlling infection, mainly against RD1 and Ag85 antigens; (2) the stability of the antigenic repertoire; (3) the dynamics of M. tuberculosis granulomas; or (4) the link between typical and atypical pulmonary TB and the immune status of the host. However, we still do not (1) know how to avoid M. tuberculosis infection and reinfection; (2) understand the major role of the increase in lesion size in progression from infection to disease; (3) the role of interlobular septa in encapsulating pulmonary lesions; or (4) the role of neutrophilic infiltration and an exaggerated inflammatory response in the development of TB disease. These are strong reasons to pursue new, imaginative proposals involving both the antibody response and a balanced, tolerant immune response that averts progression toward TB. So far, the scientific mindset has been quite monolithic and has mainly focused on the stimulation of conventional T cells. But this approach has failed. For that reason, we are seeking unconventional perspectives to find a "pink swan," a more efficacious and safer vaccine candidate.

Keywords: Mycobacterium tuberculosis; Mycobacterium tuberculosis tolerance; bacillus Calmette–Guerin vaccine; damage theory; dynamic hypothesis; pink swan.

Figure 1

Dynamic hypothesis of Mycobacterium tuberculosis infection. Bacilli contained in an aerosol droplet of endogenous or exogenous origin (1) enter the alveolar space, infect it, and grow inside the alveolar macrophage (2). After necrotizing it, the bacilli infect neighboring alveolar macrophages and grow again, unleashing an inflammatory response that allows for the entry of monocytes and neutrophils in the lesions, and the drainage of bacilli via the lymphatic vessels (3). Once in the lymph node, the bacilli antigens are presented and a Th1 response is generated, resulting in the proliferation of specific effector lymphocytes that enter the systemic circulation toward the right heart. They reach the lung and are attracted to the infected lesions thanks to local chemokine production (4). The lymphocytes activate the infected macrophages, which kill most intracellular bacilli. A percentage of the bacilli become dormant and survive inside the necrotic tissue or the phagosomes of the macrophages (4a). Macrophages age and fill with lipid inclusions, turning into foamy macrophages, and are drained with the alveolar fluid toward the bronchial tree (6) entering the esophagus and reaching the gastrointestinal system where they are finally expelled from the body (7). Some of these foamy macrophages are destroyed on the way toward the pharynx, liberating the bacilli that become part of the aerosols and can reenter the lung again (1). This cycle is interrupted with the encapsulation and calcification of the granuloma, due to the action of the interlobular septa (5), or when neutrophils are attracted to the lesion, initially around the infected foamy macrophages, progressing toward a large degree of infiltration and cavitation (4b).

Figure 2

Encapsulation process of Mycobacterium tuberculosis lesions. (A–D) Interlobular septa are represented in green. Once the lesion is contacted, the encapsulation process starts surrounding it. The capsule completely envelops the lesion and aids the organization of miofibroblasts that stabilize the lesion. Non-drained necrotic tissue finally becomes calcified. Data are obtained from Gil et al. (51).

Figure 3

Size matters in progression toward tuberculosis (TB). (A) Disease development as it is usually represented in publications. The only difference shown is that, in the lesion corresponding to disease, there is a higher bacillary concentration. (B) A more realistic approach. The TB disease lesion is exudative, with a predominance of neutrophilic infiltration together with massive necrosis, and it is much larger than the infected lesion. It must be taken into account that lesions need to be at least 10 mm in diameter to be visible on a chest X-ray and that infection lesions measure between 0.5 and 2 mm.

Figure 4

Evolution toward active tuberculosis (TB). (A) The process toward a neutrophilic infiltrated lesion favors the induction of new lesions and their rapid growth; this leads to lesion coalescence and the induction of an active TB lesion. On the contrary, (B) shows a well-controlled lesion, without neutrophilic infiltration, which hardly induces new lesions and soon becomes encapsulated, blocking the induction of active TB.

Figure 5

Differences in local drainage determine the nature of the lesion. (A) The necrosis of an alveolar macrophage releases intracellular bacilli. The rate of bacilli drainage follows the breathing amplitude of the lobe, which is lower in the upper lobes, resulting in lower bacillary drainage (B). As a result, new incoming macrophages must face higher bacillary concentrations that, once the inflammatory response is triggered, cause a predominance of neutrophilic infiltration and the induction of neutrophilic extracellular traps that favor extracellular bacillary growth. This is the perfect scenario for the protective role of circulating antibodies, which can neutralize the bacilli and reduce the inflammatory response, controlling progression toward TB disease. (B1) The progression without antibodies. (B2) The control achieved by the presence of neutralizing antibodies. On the contrary, the larger breathing amplitude in the lower lobes causes significant bacillary dissemination, so macrophages face lower bacillary loads, favoring a less inflammatory lesion dominated by macrophages (C).

Figure 6

Relationship between the volume of a cavity and the whole-body mass of a host. Several laboratory animals plus humans are represented, comparing their mass with that of a cavitation. This is to illustrate the fact that in mice they would hardly develop, because they would disappear. Unable to eliminate the bacillary load, the majority of mouse strains (except C3Heb/FeJ) tolerate the presence of a constant, relatively high bacillary concentration in their lobes, controlling the induction of an excessive inflammatory response.

Figure 7

Damage theory of infectious diseases. This picture illustrates Arturo Casadevall’s “damage theory” (68). In the case of TB, a weak immune response leads to the proliferation of lesions and dissemination of the bacilli. However, the induction of an excessive inflammatory response also leads to exudative lesions characterized by massive tissue destruction. In this regard, we can consider that TB develops two kinds of diseases, and in between there is a wide range of situations where the immune response is balanced and allows the host to live with the bacilli without hampering its health status.