Mycobacterium tuberculosis: Molecular Infection Biology, Pathogenesis, Diagnostics and New Interventions Seyed Ehtesham Hasnain • Nasreen Z. Ehtesham • Sonam Grover Editors Mycobacterium tuberculosis: Molecular Infection Biology, Pathogenesis, Diagnostics and New Interventions Editors Seyed Ehtesham Hasnain Nasreen Z. Ehtesham JH Institute of Molecular Medicine, Inflammation Biology and Cell Signaling Jamia Hamdard Laboratory New Delhi, Delhi, India ICMR-National Institute of Pathology, Safdarjung Hospital Campus Dr Reddy’s Institute of Life Sciences New Delhi, Delhi, India University of Hyderabad Campus Hyderabad, India Sonam Grover JH Institute of Molecular Medicine, Jamia Hamdard New Delhi, Delhi, India ISBN 978-981-32-9412-7 ISBN 978-981-32-9413-4 (eBook) https://doi.org/10.1007/978-981-32-9413-4 # Springer Nature Singapore Pte Ltd. 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Foreword I am delighted to write the foreword for Mycobacterium tuberculosis: Molecular Infection Biology, Pathogenesis, Diagnostics and New Interventions, edited by Prof. Seyed Hasnain and colleagues. Prof. Hasnain has brought together an impressive set of experts and authors to contribute to this seminal work. Tuberculosis (TB) remains the leading infectious killer disease of our times, with ten million new cases every year. A large portion of the burden is borne by countries in Asia and sub-Saharan Africa. Recent years have also seen growing numbers of drug and multidrug-resistant TB, leading to higher mortality and morbidity. While TB has been documented in Egyptian mummies, it has learnt to adapt and survive with mankind and continues to pose significant challenges for its control. The major risk factors include those associated with poverty like undernutrition, overcrowding, tobacco and alcohol use, low awareness, and lack of access to quality healthcare services. While HIV infection has been a major driver of TB in sub-Saharan Africa, the growing burden of diabetes and medication-induced immunosuppression are significant risk factors elsewhere. While the End TB targets of the WHO as well as the SDG global targets envision an end to this global epidemic, many gaps in understanding its pathogenesis, transmission, and factors that enhance or reduce the risk of virulence or the devel- opment of resistance mutations remain. Furthermore, there is presently no rapid diagnostic test that can diagnose all forms of TB simply and affordably, and as a consequence, millions of patients face delayed or wrong diagnoses. While a few new drugs have been developed in the last few years, patients with TB still face months or years of treatment with drugs, which could have potentially severe side effects, especially in the case of MDRTB treatment. Attempts have also been made to develop a vaccine that would be more effective than BCG, but the lack of surrogate markers of protection makes clinical trials of new vaccines time-consuming and expensive. This book addresses fundamental biology of tuberculosis as well as non-tubercu- lous mycobacteria, an increasingly recognized cause of chronic lung disease in many parts of the world. I am sure that this book will serve as a comprehensive knowledge base for M. tb, the pathogen that causes TB, as well as non-tuberculous mycobacteria (NTM). It highlights developments in understanding the disease at the molecular level, identification and validation of molecular drug targets, molecular v vi Foreword epidemiology, and novel diagnostics. A special chapter on TB vaccines describing present and future perspectives is also one of the highlights of this book. Posttrans- lational and epigenetic modifications in Mycobacterium with emphasis on methyltransferases are another key chapter. Functional biology of the unique group of proteins called PE/PPE, present exclusively in the genus Mycobacterium and nowhere else in the living kingdom, is also discussed in the book. The book has a total of 25 chapters written by eminent scientists drawn from abroad and India, such as from Robert Koch Institute, Berlin; Trinity College, Dublin; Harvard T.H. Chan School of Public Health, Boston, MA, USA; Yale School of Medicine, New Haven, USA; Emory University, Atlanta, USA; John Hopkins University, Baltimore, USA; Max Planck Institute for Infection Biology, Berlin, Germany; Indian Institute of Technology, Delhi; Indian Institute of Science, Bangalore; All India Institute of Medical Sciences (AIIMS), Delhi; National Institute of Pathology, New Delhi; National Institute of Immunology, New Delhi; Delhi University; University of Hyderabad; Jamia Hamdard; etc. A blend of basic scientists, drug discovery researchers, epidemiologists, clinicians, and vaccinologists has collectively focused on various facets of the disease and the causal organisms. With state-of-the-art contributions from experts in the respective domains, I am sure that this volume will be an informative resource for current practitioners as well as students and researchers. Chief Scientist, WHO Soumya Swaminathan, MD Geneva, Switzerland Preface Tuberculosis (TB), the disease, and Mycobacterium tuberculosis (M.tb), the causa- tive pathogen, need no introduction. This book on TB will serve as a comprehensive knowledge base for M.tb, as well as nontubercular bacteria (NTM). Presenting a wealth of information on the molecular infection biology of M.tb,as well as nontuberculous mycobacteria (NTM), this book provides an overview of the functional role of the PE/PPE group of proteins, which is exclusive to the genus Mycobacterium, of host-pathogen interactions, and of virulence. It also explores the pathogenesis of the infection, pathology, epidemiology, and diagnosis of NTM. Last but not least, it discusses current and novel approaches in vaccine development against tuberculosis, including the role of nanotechnology. This book highlights developments in understanding the disease at the molecular levels and identification and validation of molecular drug targets, molecular epidemiology, and novel diagnostic techniques. With state-of-the-art contributions from experts in the respective domains, this volume will be an informative resource for current practitioners as well as medical students, postgraduates, and researchers and is expected to be much in demand. The book is mainly divided into three sections covering all major aspects of TB. Pathogenesis and Epidemiology of Tuberculosis This section starts with a chapter on the history of tuberculosis with a description of fascinating events starting from the discovery of the elusive TB bacteria. A chapter on TB comorbidities describes the explicit involvement of TB in promoting other lung diseases such as bronchiectasis and chronic obstructive pulmonary disease during childhood. To reduce the global burden of chronic lung diseases, the management of TB in the early stages is imperative. A chapter on the role of host factors in susceptibility to TB serves as a primer to understand the efforts mounted by the host which can be useful in designing host-directed therapies and also reduce tissue damage due to chronic TB infections. A chapter on extrapulmonary tuber- culosis (EPTB) provides an in-depth overview of the clinical diagnosis and treatment of the different forms of EPTB. This section also covers nontubercular mycobacteria (NTM), a high priority due to its misdiagnosis and association with cystic fibrosis, COPD, and nosocomial infections. The last chapter in this section discusses the spread of M.tb strains circulating in New Zealand and emphasizes the need for early vii viii Preface detection and treatment of active cases together with contact tracing, if one has to minimize the emergence of epidemiological clusters of the disease. This chapter also illustrates the importance of a political will and decisive legislation in bringing down the incidence of disease from 150 cases per 100,000 to less than 10 cases per 100,000 and steps a country need to take to avoid new cases of TB. Molecular and Infection Biology of M.tb M.tb is highly adapted for survival in the extremely hostile intracellular environment in host macrophages. In order to cope up with stresses encountered by the bacterium