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Latent tuberculosis infection (LTBI) is established in over 90% of persons infected with Mycobacterium
tuberculosis (Mtb), from whom new active TB cases will arise. Understanding the spatio-temporal
dynamics of host immune responses in LTBI granulomas is essential to designing effective post-exposure
therapies that inhibit progression to TB. Information arising from cancer studies and other modalities –
where local chronic inflammation leads to immunopathology – can help provide insights into the
biological pathways at play in LTBI granulomas. Translational studies using patient material as well as
LTBI+ donor-derived tissue samples are instrumental in understanding the various components of
granuloma dynamics, immunological landscapes therein and how this could help to identify therapeutic
targets. Deep sequencing technologies may aid to decipher the genetic changes in lung granuloma and
blood samples from LTBI+ individuals associated with progression to active TB disease. This may lead to
advancement of development of targeted Host-Directed Therapies (HDTs) and their evaluation as adjunct
TB therapies for improving treatment outcomes for LTBI and pulmonary TB.

Tuberculosis (TB) has plagued humankind for centuries and has caused over one billion deaths. Today, an estimated 2 billion people worldwide have latent TB infection (LTBI). Humans are the main reservoir of Mycobacterium tuberculosis (Mtb) and human to human spread primarily occurs through inhalation of respira-tory aerosols and secretions containing Mtb exhaled from a patient with active pulmonary TB. Despite intense study over the past six
decades the sequence of human host-Mtb interactions and pathophysiological events following primary or secondary infection, remain a mystery (Zumla et al., 2011). The granuloma was thought to be a result of protective cell-mediated and has been central to the study of pathogenesis of TB and other intracellular pathogens (James and Zumla, 1999). A spectrum of granulomatous changes has been described from complete resolution, to continuing granuloma turnover with protective and deleterious inflammation, caseous necrosis, fibrosis and scarring of tissue leading to long-term functional disability (Drain et al., 2018). Technological advances over the years have enabled
more detailed studies at molecular and cellular level, several recent publications have questioned whether the granuloma or its individual immune components make the granuloma a ‘friend’ or a ‘foe’ (Rubin, 2009; Galizia and Marti, 2018). Thus, gaining a deeper understanding of the host-pathogen interactions in persons harbouring LTBI may hold quintessential clues to achieving the WHO’s goal of eliminating TB as a public health threat by 2050.


TB (PV)