Natural and trained innate immunity against Mycobacterium tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, remains a major global health emergency. It is estimated that one third of global population are affected, predominantly with latent granuloma form of the disease. Mtb co-evolved with humans, for its obligatory intra-macrophage phagosome habitat and slow replication, balanced against unique mycobacterial innate immunity, which appears to be highly complex. TB is transmitted via cough aerosol Mtb inhalation. Bovine TB attenuated Bacillus Calmette Guerin (BCG) live vaccine has been in practice for protection of young children from severe disseminated Mtb infection, but not sufficiently for their lungs, as obtained by trials in TB endemic community. To augment BCG vaccine-driven innate and adaptive immunity for neonates and better protection against adult pulmonary TB, a number of BCG pre-vaccination based, subset vaccine candidates have been tested via animal preclinical, followed by safe clinical trials. BCG also enhances innate macrophage trained immunity and memory, through primordial intracellular Toll-like receptors (TLRs) 7 and 9, which recognise distinct mycobacterial molecular pattern signature. This signature is transmitted by TLR signalling via nuclear factor-κB, for activating innate immune transcription and expression of gene profiling in a mycobacterial signature-specific manner. These are epigenetically imprinted in reprogramming of distinct chromatin areas for innate immune memory, to be recalled following lung reinfection. Unique TB innate immunity and its trained memory are considered independent from adaptive immune B and T cells. On the other hand, adaptive immunity is crucial in Mtb containment in granulomatous latency, supported by innate immune cell infiltration. In nearly 5–10 % of susceptible people, latent TB may be activated due to immune evasion by Mtb from intracellular phagosome within macrophage, perpetrating TB. However, BCG and new recombinant BCG vaccines have the capacity, as indicated in pre- and clinical trials, to overcome such Mtb evasion. Various strategies include pro-inflammatory-bactericidal type 1 polarisation (M1) phenotype of the infected macrophage, involving thrombospondin-TLR pathway. Saprophytic M. smegmatis-based recombinant vaccines are also promising candidates against TB. BCG vaccination of neonates/infants in TB endemic countries also reduced their pneumonia caused by various microbes independent of TB immunity. Here, we discuss host