Immunobiology 217 (2012) 363–374 Contents lists available at ScienceDirect Immunobiology j ourna l homepage: www.elsevier.de/imbio Review Mycobacterium tuberculosis: Immune evasion, latency and reactivation Antima Gupta a,† , Akshay Kaul a,† , Anthony G. Tsolaki b , Uday Kishore b , Sanjib Bhakta a,∗ a Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, University of London, London WC1E 7HX, UK b Centre for Infection, Immunity and Disease Mechanisms, Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, London UB8 3PH, UK a r t i c l e i n f o Article history: Received 14 January 2011 Received in revised form 16 June 2011 Accepted 5 July 2011 Keywords: Immune evasion Immune response Latency Mycobacterium tuberculosis Reactivation a b s t r a c t One-third of the global human population harbours Mycobacterium tuberculosis in dormant form. This dormant or latent infection presents a major challenge for global efforts to eradicate tuberculosis, because it is a vast reservoir of potential reactivation and transmission. This article explains how the pathogen evades the host immune response to establish a latent infection, and how it emerges from a state of latency to cause reactivation disease. This review highlights the key factors responsible for immune evasion and reactivation. It concludes by identifying interesting candidates for drug or vaccine development, as well as identifying unresolved questions for the future research. © 2011 Elsevier GmbH. All rights reserved. Contents Introduction .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 Immunology of latent tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 Entry, recognition and phagocytosis .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364 Evasion of the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366 Arrest of phagosome–lysosome fusion ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 Resistance against reactive nitrogen intermediates and nitric oxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 Interference with antigen presentation .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 CD8 + T cells, NK cells and the complement membrane attack complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370 The granuloma .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370 Disease reactivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372 Abbreviations: Ab, antibody; Ag, antigen; Ahp, alkyl hydroperoxide; APC, anti- gen presenting cell; BCG, Bacillus Calmette-Guérin; CIITA, class II transactivator; CLIP, class II-associated invariant chain peptides; CR, complement receptors; DCs, dendritic cells; EEA, early endosome antigen; ER, endoplasmic reticulum; GTP, guanosine triphosphate; HIV, human immunodeficiency virus; HLA-DM, human leukocyte antigen-DM; IL, interleukin; IFN, interferon; Ig, immunoglobulin; LAM, lipoarabinomannan; ManLAM, mannosylated lipoarabinomannan; MAPK, mitogen- activated protein kinase; MR, mannose receptors; MHC, major histocompatibility complex; NET, neutrophil extracellular trap; NK, natural killer; NO, nitric oxide; NOS, nitric oxide synthase; PI-3P, phosphatydilinositol-3-phosphate; RNA, ribonu- cleic acid; RNI, reactive nitrogen intermediates; ROI, reactive oxygen intermediate; SNARE, soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein recep- tors; TACO, tryptophan-aspartate-rich coat protein; TB, tuberculosis; TLR, toll-like receptor; TNF, tumor necrosis factor; MBL, mannose-binding lectin; VPS, vaculor protein sorting; WHO, World Health Organization. ∗ Corresponding author. Tel.: +44 20 7631 6355. E-mail address: s.bhakta@bbk.ac.uk (S. Bhakta). † Both authors contributed equally to this work. Introduction Tuberculosis (TB) is once more an alarming disease. It claimed 1.8 million lives in 2009 (WHO 2010). Recent estimates sug- gest a third of the world’s population harbours Mycobacterium tuberculosis, the causative agent of TB in difficult-to-diagnose latent form and shows little or no clinical symptoms. A signif- icant risk of reactivation exists in immune-compromised host including HIV + individuals, for whom TB has become one of the leading causes of death (Tufariello et al. 2003). The bacteria have begun to show extensive resistance to most anti-TB drugs (Zvi et al. 2008). A comprehensive vaccine for TB remains elusive. The Bacillus Calmette-Guérin (BCG), the most common vaccine, protects children. However the efficacy of BCG is variable across the world and is generally ineffective against adult pulmonary 0171-2985/$ – see front matter © 2011 Elsevier GmbH. All rights reserved. doi:10.1016/j.imbio.2011.07.008