What can immunology contribute to control of the world's leading cause of death from bacterial infection?

For a brief couple of decades, roughly the 1950s-1980s, economically advantaged societies and their medical establishments indulged themselves in the illusion that bacterial infectious diseases had been brought under control. The interventions that got the most credit from the public—because they were provided after diagnosis and resulted in cure—were antibiotics, but three preventive interventions contributed at least as much if not more: immunization, nutrition, and sanitation (provision of potable water, uncontaminated food, adequate shelter and smoke-free air, together with the hygienic disposal of waste). In fact, an effective fort against bacterial pathogens requires all four of these walls. Now that the spread of antibiotic resistance and a markedly reduced rate of introduction of new antibiotics have allowed one of the walls to crumble, our control of bacterial infections has become increasingly tenuous (1-3). The loss of control over infections that are relatively common in economically advantaged areas is coming to resemble the lack of control over the same infections in areas where poverty blocks access to effective anti-infectives. Some infectious diseases are only prevalent in economically disadvantaged areas, and for most of these, rapidly acting, minimally toxic anti-infectives were never developed for lack of sufficient market incentives (4).

Tuberculosis (TB) provides a profoundly important illustration of each of these points. TB is the world's leading cause of death from a bacterial infection. TB is also the world's leading cause of death from a curable infection. That these two facts coexist constitutes a societal indictment (5). Among the 10 species of bacterial pathogens presenting the greatest threat today from drug resistance, Mycobacterium tuberculosis (Mtb) probably causes the largest number of cases. The incidence of TB plummeted in economically advantaged areas of the world when nutrition and sanitation were improved, and this occurred before the introduction of a TB vaccine or TB drugs, but the incidence remains high in many parts of the world where nutrition and sanitation are yet to become adequate. Bacillus Calmette-Guérin (BCG), which is used to immunize against TB, is the most widely administered vaccine in the world, and yet it faces the extraordinary challenge of trying to induce protection against a bacterial disease when having the disease and recovering from it does not reduce the likelihood of contracting the disease again.

TB holds a special claim on the attention of immunologists for reasons over and above the desperate need for a better vaccine and the special challenge to vaccinology that the disease presents (Fig. 1). These include the following.

Fig. 1. Immunology of tuberculosis: outstanding challenges.

First, Mtb is one of the most potent antigens and adjuvants known. TB activates all known types of cells and protective responses in the human immune system, as discussed herein by Flynn et al. (6), Cliff et al. (7), Majlessi et al. (8), Jasenosky et al. (9), Van Rhijn and Moody (10), Gold et al. (11), Achkar et al. (12), Stamm et al. (13), and Hmama et al. (14).

Second, despite the foregoing, Mtb infection is so infrequently eliminated by the host that an estimated one-third of humanity is latently infected for life. In those with latent TB infection (LTBI), waning immunity at any time predisposes to conversion of the infection from a latent to a clinically active state (‘reactivation’). Factors associated with reactivation of TB that reduce immune competence include malnutrition, age, treatment with corticosteroids or biologics that block the action of tumor necrosis factor (TNF), or exposure to agents like silica dust that induce immunosuppressive cytokines, such as transforming growth factor-β (TGF-β). However, in many people, it is unknown what predisposes to reactivation of TB, whether a change in immunity is to blame, and if so, what that change is. These issues are explored in this volume by Boisson-Dupui et al. (15) and Ronacher et al. (16).

Third, Mtb has no other major natural host but humans. Mtb co-evolved with Homo sapiens and perhaps predecessor hominids, as discussed herein by Brites and Gagneux (17). That we have not eliminated Mtb as a species and that Mtb has not eliminated us as a species defines a metastable equilibrium whose mechanism will teach us a great deal about the human immune system, provided we can answer the question, ‘What host-imposed pressures has Mtb evolved the ability to resist?’ Reviews in this volume from Weiss and Schaible (18), Hmama et al. (14), Niederweis et al. (19), Tan and Russel (20), Ehrt et al. (21), Hawn et al. (22), and Nathan and Barry (23) explore this relationship more fully.

Fourth, Mtb's life cycle depends on a timed exploitation of the balance between immunity and immunopathology. Understanding how this balance is maintained and then altered over time has the potential to teach us how we might manipulate it to our advantage. It has been reported that the most conserved sequences in the Mtb genome encode human T-cell epitopes (24). This implies that Mtb depends on the human adaptive immune response for its survival as a species. The pressures that human immunity brings to bear against Mtb usually stop its replication. This helps the infected individual, but it helps Mtb even more: Mtb avoids killing that host before transmission to multiple new hosts. Immunity contains Mtb indefinitely in most people, but in many hosts, immunity-driven inflammatory responses eventually destroy enough lung tissue to allow extensive bacterial replication, erosion into a space connected with an airway, provocation of cough and generation of infectious aerosol, allowing Mtb to complete its host-to-host cycle. When Mtb kills rapidly, as often seen in miliary (disseminated) disease that involves the central nervous system, particularly in young children, the infection is virulent but not contagious, and death of the host disadvantages the pathogen. The reader is referred to the reviews by Matty et al. (25), Robinson et al. (26), and Lenaerts et al. (27) that discuss these points in detail.

To restate, Mtb is best served when it provokes the host's immune system to produce the sort of immunopathology that expels infectious droplets, but this takes time. And a good thing it is for Mtb that the development of advanced immunopathology is usually slow: if a human-only pathogen is going to kill many of its hosts and it settles on this strategy in an era when its hosts are few, it better wait until they have had children. This constraint has been postulated to explain Mtb's evolution of the traits that result in host immunity being strong enough to suppress Mtb's replication for decades in most infected hosts, but not strong enough to eliminate all Mtb in every infected host, and strong enough to destroy lung tissue in a proportion of the hosts, but chiefly in adulthood (28).

Finally, TB offers immunologists an unparalleled opportunity to alter the course of an infectious scourge not only through vaccination, as discussed herein by Karp et al. (29), but through the development of drugs—small chemical compounds and biologics—that can alter the host-pathogen interaction in such a way as to upset the equilibrium in the host's favor, as reviewed by Lenaerts et al. (27), Mayer-Barber and Sher (30), Ehrt et al. (21), Baer et al. (31), and Nathan and Barry (23). Such drugs can be directed either at the host or at the pathogen. In both cases, their development will depend on the depth and accuracy of our understanding of the host-pathogen interaction.

Rarely have immunologists found such compelling reasons or cordial invitations to take a seat at the table of antibiotic development. This brings up another way in which TB's importance to global health is not fully described by TB's death toll, quality-adjusted life years lost, burden on developing economies or threats to security. The recent development of innovative academic-industrial partnerships for drug discovery, while not restricted to the development of TB drugs, has probably proceeded farthest in fundamentally new directions with TB, with what may be historic implications for the pharmaceutical industry in years to come (1-3). Such partnerships include the Tres Cantos Open Lab Foundation, the Lilly TB Drug Discovery Initiative, the Bill and Melinda Gates Foundation's TB Drug Accelerator, and a series of consortia funded by the European Commission.

The goal of this volume of Immunological Reviews is not to be complete or systematic. Instead, a few distinguished experts have taken this opportunity to share personal perspectives on the points introduced above. It is gratifying that the field of TB research has grown to such an extent and attained such a level of excellence that there was not space in this volume to include a large number of equally distinguished experts. The field of TB research is marked not only by the enormity of the stakes and the difficulty of the obstacles, but also by the collegiality of those struggling to understand the human immune system in action as it faces one of its greatest challenges.