Recent advances in our understanding of human host responses to tuberculosis

Respiratory Research 1465-9921 Recent advances in our understanding of human host responses to tuberculosis Neil W Schluger 0 Center , 630 West 168th Street, New York, NY 10032 , USA. Tel: 1 Associate Professor of Medicine and Public Health, Columbia University College of Physicians and Surgeons , New York , USA Tuberculosis remains one of the world's greatest public health challenges: 2 billion persons have latent infection, 8 million people develop active tuberculosis annually, and 2-3 million die. Recently, significant advances in our understanding of the human immune response against tuberculosis have occurred. The present review focuses on recent work in macrophage and T-cell biology that sheds light on the human immune response to tuberculosis. The role of key cytokines such as interferon- is discussed, as is the role of CD4+ and CD8+ T cells in immune regulation in tuberculosis, particularly with regard to implications for vaccine development and evaluation. CD4+ cell; CD8+ cell; immunity; interferon; tuberculosis - Introduction Tuberculosis remains one of the most important infectious diseases in the world [1]. It is estimated that 2 billion persons on the planet harbor latent tuberculosis infection. Eight to 12 million new cases of active tuberculosis occur each year, and at any given time there are approximately 16 million persons with active tuberculosis in the world. These cases result in 23 million deaths annually, making tuberculosis the single leading cause of death of any infectious disease. These figures are even more staggering when one realizes that the vast majority of cases of tuberculosis are curable with currently available medications. Although there have been some notable success stories in recent years in controlling tuberculosis and reducing case rates (mostly in wealthy countries such as the USA), there is little cause for optimism in parts of the world where poverty, political disorganization, and access to care remain major obstacles to global tuberculosis control. In fact, with the continued spread of the human immunodeficiency virus (HIV) epidemic, particularly in Africa and Asia, and the emergence of multidrug-resistant tuberculosis in many parts of the world, there will continue to be significant upwards pressure on the number of tuberculosis cases in the world for the next several years. This increasing pressure occurs in the context of what has been a long stagnant period in tuberculosis drug development. No new class of antituberculosis drugs has been introduced since the rifamycins came into use 30 years ago. The clinical manifestations of infectious disease are caused by the balance between virulence factors that are elaborated by the invading microbe, and the host immune response that the body mounts to defend itself. In many infectious syndromes, virulence factors are responsible for most of the disease manifestations. Examples include toxic shock syndrome and Gram-negative sepsis, in which lipopolysaccharide released by invading bacteria sets off a BCG = bacille CalmetteGurin; ESAT = early secreted antigen; HIV = human immunodeficiency virus; LACK = Leishmania homolog of receptors for activated C-kinase; MHC = major histocompatibility complex; Th = T-helper (cell); TLR = toll-like receptor; TNF = tumor necrosis factor. whole cascade of inflammatory events. On the other hand, in many infectious syndromes relatively avirulent organisms cause disease mainly by forcing the host to respond in one or more of a variety of ways that result in specific manifestations of disease. Such would seem to be the case in leprosy, for example. Mycobacterium leprae appears capable of eliciting two distinct host immune responses that result in the two different clinical manifestations of the disease [2,3]: tuberculoid leprosy and lepromatous leprosy. Little is known about virulence factors of Mycobacterium tuberculosis. Interesting studies have recently been reported that describe the mechanisms that underlie behaviors such as cording, and a body of work describing the relationship between sigma factors and mycobacterial latency has also been done [48]. During the next few years it is likely that significant advances will be made in our understanding of mycobacterial virulence as a result of projects such as the sequencing of the M tuberculosis genome (now already complete for several laboratory and clinical isolates), as well as advances in the field of mycobacterial genetics. Such advances in our understanding of the basic biology of M tuberculosis should aid in the design and evaluation of new therapeutic drugs. Understanding human host immunity to tuberculosis is important for several reasons. Paramount among these, however, must be that only through a thorough knowledge of how tuberculosis is recognized and controlled by the immune system will we be able to design and evaluate new vaccine candidates. In the long run, vaccination still represents an important goal in tuberculosis control, and is perhaps the best hope for ultimate eradication of this disease. The challenges in tuberculosis vaccine development are enormous. Two major features of clinical tuberculosis frame the challenge of vaccine development. The first is that, as noted above, 2 billion persons are already infected with M tuberculosis, so that a vaccine might need to protect against reactivation rather than infection. The second is that, unlike many other infections (particularly viral infections), the extent to which natural immunity to tuberculosis exists is not clear. Whereas patients who recover from chicken pox have lifelong immunity against reinfection, patients who have recovered from tuberculosis may be subject to reinfection. This has been demonstrated in patients with HIV who clearly are significantly immunocompromised, but recent data indicate that reinfection may also occur in patients without HIV infection or apparent immunosuppression [9,10]. This may be an infrequent occurrence, but it does raise the possibility (as recently pointed out by Kaufmann [11]) that we may be faced with the challenge of designing a vaccine that needs to provide better than natural immunity! In addition to aiding the effort to develop a novel vaccine for tuberculosis, understanding the human immune response might also point to novel immunotherapeutic approaches to treatment of tuberculosis, particularly in the setting of multidrug resistance, in which there are often no viable chemotherapy options. During the past several years much has been learned about the human immune response to tuberculosis. In fact, the conduct of direct experiments using human tissues, as well as in vivo studies of human immune responses to tuberculosis, represents a major advance in our understanding of the pathogenesis of this disease. Although animal models of tuberculosis have taught us (and will continue to teach us) a great deal about the pathogenesis of this disease, it remains the case that th (...truncated)