Preface

*Mycobacterium tuberculosis* has been the paradigm of genetic stability for years, compared to other bacterial families or viruses, which is mainly related to its lack of plasmid content. As recent investigations demonstrate, the bacillus has a complex signaling expression, which allows its close interaction with the environment and one of its most renowned properties: the ability to persist for long periods of time under a non-replicative status. Although this skill is well characterized in other bacteria, the intrinsically very slow growth rate of *Mycobium tuberculosis,* together with a very thick and complex cell wall, makes this pathogen specially adapted to the stress that could be generated by the host against them. In this book, different aspects of these properties are displayed by specialists in the field.

> **Dr. Pere-Joan Cardona**  Institut Germans Trias i Pujol (IGTP) Catalunya, Spain

**Part 1** 

**The "Quiet" Genome** 

**Part 1** 

**The "Quiet" Genome** 

**1** 

*UK* 

**Molecular Biomarkers for Ancient Tuberculosis** 

Tuberculosis is an ancient disease. It was recognised and described by Hippocratus (460–390 BCE) and Galen (2nd–3rd century CE) in the western Classical World (Xarchus & Bourandas, 2003), ancient Egypt, India and the Far East (Morse, 1961). The obvious symptoms that attracted attention were the late outcomes of skeletal tuberculosis, where collapsed vertebrae led to scoliosis and Pott's disease, plus the symptoms associated with pulmonary tuberculosis, such as fever, weight loss and haemoptysis (coughing up blood). In the UK, tubercular lesions of the lymph glands (cervical lymphadenitis) were formerly termed scrofula, or the King's evil, and tubercular skin lesions were described as Lupus vulgaris or tuberculous chancre. The palaeopathology of ancient skeletal remains, together with classical and historical reports, demonstrate that tuberculosis occurred in prehistory. However, tuberculosis is still the greatest cause of death from any single infectious disease in the world today, with over one third of the global population infected and an estimated 1.7 million deaths from the disease in 2009 (WHO, 2010). Therefore it is essential to understand the nature of tuberculosis in the past: its

The disease is caused by members of a group of very closely related bacteria, termed the *Mycobacterium tuberculosis* complex (MTBC). These are obligate parasites and have the ability to subvert the cell-mediated immune system of the host and to survive and multiply within macrophages. Most human infections are caused by *Mycobacterium tuberculosis* and are usually acquired via the aerosol route from an active case of pulmonary tuberculosis. Infectious aerosols lodge in the alveoli but, in the majority of cases, the bacilli are controlled by the host immune system to form a granuloma and the disease remains latent. Infection can also occur by ingestion – milk or meat from an infected animal can give rise to human zoonotic cases of tuberculosis caused by *Mycobacterium bovis* or other members of the MTBC. In endemic areas, infection takes place in early life and may remain latent throughout a lifetime or become re-activated due to lowered host resistance caused by physical or mental stress, immunosuppression or extreme age (Rustad et al., 2009). Active primary tuberculosis, estimated to occur in 2–5% of cases, normally causes lymphadenitis and subsequent spread via the blood stream can cause meningitis or miliary tuberculosis (Grange & Zumla, 2009). Post-primary tuberculosis is estimated to occur in a similar proportion of people and these

**1. Introduction** 

distribution, spread and relationship to human society.

David E. Minnikin1, Oona Y-C. Lee1, Houdini H.T. Wu1,

 *1School of Biosciences, University of Birmingham, Edgbaston, Birmingham, 2Research Department of Infection and The Centre for the History of Medicine,* 

Gurdyal S. Besra1 and Helen D. Donoghue2

*University College London,* 
