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Trained Immunity: a New Avenue for Tuberculosis Vaccine Development Trained immunity: a new avenue for tuberculosis vaccine development Maria Lerm and M. G. Netea Linköping University Post Print N.B.: When citing this work, cite the original article. Original Publication: Maria Lerm and M. G. Netea, Trained immunity: a new avenue for tuberculosis vaccine development, 2016, Journal of Internal Medicine, (279), 4, 337-346. http://dx.doi.org/10.1111/joim.12449 Copyright: 2015 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. This is an open access article under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs License. http://eu.wiley.com/WileyCDA/ Postprint available at: Linköping University Electronic Press http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-127425 Review doi: 10.1111/joim.12449 Trained immunity: a new avenue for tuberculosis vaccine development M. Lerm1 & M. G. Netea2 From the 1Division of Microbiology and Molecular Medicine, Faculty of Medicine and Health Sciences, Linkoping,€ Sweden; and 2Radboud Institute for Molecular Life Sciences, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands Abstract. Lerm M, Netea MG (Faculty of Medicine and of immunity is nonspecific. Evidence is now accu- Health Sciences, Linkoping,€ Sweden; and Radboud mulating that innate immunity can remember a University Medical Center, Nijmegen, the previous exposure to a microorganism and respond Netherlands). Trained immunity: a new avenue differently during a second exposure. Although the for tuberculosis vaccine development. (Review). specificity and memory of innate immunity cannot J Intern Med 2016; 279: 337–346. compete with the highly sophisticated adaptive immune response, its contribution to host defence Adaptive immunity towards tuberculosis (TB) has against infection and to vaccine-induced immunity been extensively studied for many years. In addi- should not be underestimated and needs to be tion, in recent years the profound contribution of explored. Here, we present the concept of trained innate immunity to host defence against this immunity and discuss how this may contribute to disease has become evident. The discovery of new avenues for control of TB. pattern recognition receptors, which allow innate immunity to tailor its response to different infec- Keywords: BCG, epigenetics, innate immunity, tious agents, has challenged the view that this arm trained immunity, tuberculosis. being at least 6 months with a combination of Introduction between two and four antibiotics. Mycobacteria belong to one of the largest and most ancient phyla of bacteria, the Actinobacteria [1], In the proposed checkpoint model for TB disease which occupies various habitats on Earth including progression [3], the innate immune system consti- soil and water. Most mycobacteria are free-living, tutes the first ‘checkpoint’ that M. tuberculosis has harmless saprophytes, but a few species have to pass to establish infection in a host (Fig. 1). Only evolved as pathogens that infect a variety of species. by passing the second ‘checkpoint’, which is rep- Although pathogenic mycobacteria are not strictly resented by adaptive immunity acting in concert species specific, Mycobacterium tuberculosis [which with innate immunity, is the bacterium able to causes tuberculosis (TB)], Mycobacterium leprae cause active disease and spread to other individ- (which causes leprosy), and Mycobacterium ulcer- uals. Though adaptive immunity undoubtedly ans (which causes painless skin lesions known as plays a central role in control of the infection in Buruli ulcers) are considered primarily human individuals in whom M. tuberculosis has estab- pathogens. M. tuberculosis was one of the first lished itself, the model suggests that there is a bacteria found to be the causative agent of a disease window of opportunity during which innate and is still among the most deadly human patho- immune mechanisms can eliminate M. tuberculo- gens, causing approximately 1.4 million deaths per sis. Indeed, there is substantial evidence that year. TB cannot be eliminated with the current tools many individuals who live under constant expo- of prevention, diagnosis, and treatment [2] and thus sure, e.g. household contacts of TB cases, can clear novel strategies to fight the disease are urgently the infection without the involvement of adaptive needed. During the last decade, many advances in immunity. This is referred to as ‘early clearance’ the understanding of the complex biology of TB have and can be explained by the presence of a highly been made. However, these efforts have not yet effective innate immunity in these individuals [4]. resulted in an improved regimen for TB control, such as a more effective vaccine or a shorter It has been suggested that the effectiveness of treatment duration, with the standard regimen these two immune barriers depends on genetic [5] ª 2015 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 337 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. M. Lerm & M. G. Netea Review: Trained immunity for TB prevention 1 2 Early clearance Latent tuberculosis Y N NK M B Mφ Th INFECTION DC CTL ACTIVE TUBERCULOSIS Mφ Disease progression Fig. 1 The checkpoint model for tuberculosis (TB) disease progression. Innate immunity poses the first ‘checkpoint’ (1) that Mycobacterium tuberculosis has to pass to cause disease. At the second ‘checkpoint’, M. tuberculosis also has to overcome the contribution of adaptive immunity (2). Here, control or elimination of the pathogen through innate immunity is referred to as early clearance. Latent TB represents the dynamic equilibrium between adaptive immunity and M. tuberculosis. NK, natural killer cell; DC, dendritic cell; Th, T helper cell; CTL, cytolytic T cell B, B cell; M, monocyte; N, neutrophil; Mφ, macrophage. and environmental factors, such as standard of mechanisms to counteract the microbicidal activ- living (nutritional state and housing), and comor- ities of these cells, which include phagosomal bidities [6, 7]. Another, not yet fully understood, acidification, activation of proteolytic enzymes in environmental factor in this context is the impact acidified phagolysosomes, and production of of previous exposure of innate immunity to micro- antimicrobial peptides as well as reactive oxygen bial agents or even vaccines, which could educate and nitrogen metabolites [9, 10]. Thus, if the the innate immune defence to pose a more effective macrophage defence fails, M. tuberculosis estab- response against related and sometimes even lishes itself in an intracellular niche, which is unrelated infections. This evolutionarily conserved initially the phagosome with impaired antimicro- phenomenon is known as trained immunity and bial capacity [11, 12] and later the cytosol [13] into has been demonstrated in plants, invertebrates, which it escapes by means of a membrane-dama- and animals [8]. ging toxin, early secreted antigenic target (ESAT)-6 [14]. The cytosolic mycobacteria replicate effi- Here, we will review the immunological mecha- ciently (step 2, Fig. 2) before the primary host cell nisms that are important for control of TB and is killed (step 3, Fig. 2), a process in which ESAT-6 discuss how trained immunity can contribute to plays an important role [15]. The inflammation control and elimination of mycobacterial infec- triggered by the dying cells induces recruitment to tions. the site of infection of further monocytes/macro- phages (step 4, Fig. 2), which then become infected (step 5, Fig. 2). Paradoxically, these cells can serve The life cycle of M. tuberculosis as vehicles for further dissemination of the infec- The primary target cells for M. tuberculosis infec- tion in the tissue [16]. The process of early gran- tion are the alveolar macrophages. These cells uloma formation is also dependent on ESAT-6 [16, encounter and engulf the pathogen when infected 17] and is probably linked to the inflammation aerosols are inhaled and enter the alveolar space generated through necrosis triggered by the toxin (step 1, Fig. 2). M. tuberculosis employs several [15]. As the inflammatory process proceeds, gran- 338 ª 2015 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. Journal of Internal Medicine, 2016, 279; 337–346 M. Lerm & M. G. Netea Review: Trained immunity for TB prevention 3 Mφ 2 Mφ LUNG TISSUE Th Mφ 1 CTL Mφ CTL Mφ 4 Mφ Th AIRWAYS 9 CTL M M 8 M M Th CTL 5 Mφ CTL Mφ Mφ Mφ Th Mφ Mφ Mφ CTL 6 7 Fig. 2 The life cycle of Mycobacterium tuberculosis. M. tuberculosis is taken up by alveolar macrophages (Mφ) (step 1) and replicates efficiently (step 2) until the host cells are killed (step 3). Recruitment of further monocytes (M)/macrophages to the site of infection (step 4) disseminates the infection (step 5) and as the inflammatory process proceeds, granuloma are formed (step 6). CD4+ T helper type 1 (Th1) cells and CD8+ cytolytic T cells (CTLs) are recruited to form a rim surrounding the infected macrophages (step 7). Eventually, the granuloma becomes necrotic (step 8) and the structure ruptures, draining viable bacilli into the alveolar space (step 9). ulomas (clusters of macrophages) are formed (step that a relatively large proportion (20–25%) of indi- 6, Fig. 2). As the granuloma further matures, viduals who are exposed to TB never develop any lymphocytes, including both CD4+ T helper type signs of an immunological memory against M. 1 (Th1) cells and CD8+ cytolytic T cells (CTLs) [18, tuberculosis, suggesting that the high efficacy of 19], are recruited to form a rim surrounding the the innate immune response in these individuals infected macrophages (step 7, Fig. 2). Eventually, precludes the need for adaptive immunity.
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