Between 10 December 1929 and 30 April 1930, 251 infants born in the old Hanseatic town of Lubeck (Germany) received three doses of Bacillus Calmette–Guérin vaccine by the mouth during the first 10 days of life. Of these 251, 72 died of TB, most of them in 2 to 5 months and all but one before the end of the first year. Another 135 suffered from clinical TB but eventually recovered; and 44 became tuberculin-positive but remained well. The vaccine used was later found to have been contaminated with a Mtb strain being studied in the same lab (Wilson 1931). All children were equally infected by Mtb. Some of them died, some of them got sick with clinical TB, and 17.5 % remained healthy, because they had good innate resistance to TB. Although these children had no acquired immunity at all, as they all were new-born and had no time to train their immune system for Mtb, a rather big part of them won against dangerous infection owing to good innate immunity.

What kind of immunity is responsible for the outcome of the meeting with Mtb? Where were those 90 % of population, who were infected with Mtb but remained healthy, lucky due to acquired immune resistance to tuberculosis, or because they had strong innate resistance? Each stage of the host response to Mtb is under genetic control, including the initial encounter with Mtb by macrophages, epithelial cells and dendritic cells in the lung, provision of the inductive T-cell response, and killing Mtb by activated macrophages within granulomas (Yim and Selvaraj 2010). To switch on the acquired immunity to TB, meeting with a TB infection is necessary – either wild or vaccine. Yes, environmental factors, epidemic situation, co-morbidity etc. are important determinants of progression to tuberculosis; but there is a genetic component underlying susceptibility to TB, the basis of which may vary in different populations (Yim and Selvaraj 2010) – nobody can predict who will get sick with TB, and who will be resistant.

Humoral immunity plays only an auxiliary role. A humoral immune response is seen though not implicated in protection. Mtb are endowed with mechanisms through which they can evade the onslaught of host defense response: diminishing the ability of antigen presenting cells to present antigens to CD4(+) T cells; production of suppressive cytokines; escape from fused phagosomes and inducing T cell apoptosis (Boom et al. 2003; Raja 2004).

Polymorphonuclear neutrophils (PMN) are first in the infected organism to meet a infection aggressor. These are able to phagocytose and kill ingested Mtb, but are short-lived cells that constantly need to be removed from tissues to avoid tissue damage. Engulfment of Mtb-induced apoptotic PMN by macrophages initiates secretion of TNF-alpha from the macrophages, reflecting a pro-inflammatory response.

Moreover, Mtb-induced apoptotic PMN up-regulate heat shock proteins 60 and 72 (Hsp60, Hsp72) intracellularly and also release Hsp72 extracellularly. Both recombinant Hsp72 and released Hsp72 have enhanced the pro-inflammatory response to both Mtb-induced apoptotic PMN and Mtb. This stimulatory effect of the supernatant was abrogated by depleting the Hsp72 with immunoprecipitation (Persson et al. 2008).

In addition to direct bactericidal activities, such as phagocytosis and generation of reactive oxygen species (ROS), neutrophils can regulate the inflammatory response by undergoing apoptosis. Infection of human neutrophils with Mtb induces rapid cell death displaying the characteristic features of apoptosis such as morphologic changes, phosphatidylserine exposure, and DNA fragmentation (Perskvist et al. 2002).

Pretreatment of neutrophils with antioxidants markedly blocked Mtb-induced apoptosis but did not affect spontaneous apoptosis. The Mtb-induced apoptosis was associated with a speedy and transient increase in expression of Bax protein, a proapoptotic member of the Bcl-2 family, and a more prominent reduction in expression of the antiapoptotic protein Bcl-x(L). Phagocytosis of Mtb-induced apoptotic neutrophils markedly increases the production of proinflammatory cytokine TNF-alpha by human macrophages (Perskvist et al. 2002).

There are various aspects of macrophage-mycobacterium interactions. The role of macrophages in a host response is very important. Macrophages provide binding of Mtb to macrophages via surface receptors, phagosome-lysosome fusion, mycobacterial growth inhibition/killing through free radical based mechanisms such as reactive oxygen and nitrogen intermediates; cytokine-mediated mechanisms; recruitment of accessory immune cells for local inflammatory response and presentation of antigens to T cells for development of acquired immunity (Raja 2004).

Macrophages demonstrate tremendous phenotypic heterogeneity and functional plasticity which, depending on the site and stage of infection, facilitate the diverse outcomes. Moreover, host responses vary depending on the specific characteristics of the infecting Mtb strain (Guirado et al. 2013).

It was hypothesized that macrophages from individuals with different clinical manifestations of TB would have distinct gene expression profiles and that polymorphisms in these genes may also be associated with susceptibility to TB (Thuong et al. 2008).

A diverse T cell response allows the host to recognize a wider range of mycobacterial antigens presented by different families of antigen-presenting molecules, and thus greater ability to detect the pathogen (Boom et al., 2003).

Macrophages from subjects that are heterozygote, homozygote or compound heterozygote for these polymorphisms fail to undergo apoptosis and show partial or complete inhibition of mycobacterial killing. One of these non-functioning polymorphisms was significantly associated with increased susceptibility to TB disease, particularly extrapulmonary disease (Britton et al. 2007).

Pienaar and Lerm (2014) created the mathematical model of the initial interaction between Mtb and macrophages, which considers the interplay between bacterial killing and the pathogen’s interference with macrophage function. This model revealed an oscillating balance between host and pathogen, but the balance was transient and varies in length, indicating that stochasticity in the bacterial population or host response could contribute to the diverse incubation periods observed in exposed individuals.

The pathophysiology of Mtb infection is linked to the ability of a microorganism to grow within macrophages – it is an intracellular parasite. Apoptosis is a physiological programmed cell death process whose dysregulation plays an important role in some human infectious diseases. Apoptosis of the host macrophage is an important defense mechanism in mycobacterial infections, which prevents the spread of the infection. Unlike necrosis, apoptosis is a silent immunological event occurring without inflammation. Infection-induced target cell apoptosis may be a successful strategy to eliminate pathogens and assure host survival. Conversely, apoptosis inhibition could represent an adaptive mechanism for pathogen survival, while it may be beneficial for the host to initiate an effective immune response. Induction of early death of the infected cells may be one of the strategies of host defense against Mtb because macrophages go into apoptosis upon infection with Mtb, resulting in suppression of the intracellular replication (Danelishvili et al. 2003).

Apoptosis prevents the release of intracellular components and the spread of mycobacterial infection by sequestering the pathogens within apoptotic bodies (Fratazzi et al. 1999). Microarray analysis of infected human alveolar macrophages found serine protease inhibitor 9 (PI-9) to be the most prominently expressed of a cluster of apoptosis-associated genes induced by virulent Mtb. Inhibition of PI-9 by small inhibitory RNA decreased Mtb-induced expression of the antiapoptotic molecule Bcl-2 and resulted in a corresponding increase in production of caspase 3, a terminal effector molecule of apoptosis. Investigators concluded PI-9 induction within human mononuclear phagocytes by virulent Mtb serves to protect these primary targets of infection from elimination by apoptosis and thereby promotes intracellular survival of the organism (Toossi et al. 2012).

Danelishvili et al. (2003) has found, that both virulent (H37Rv) and attenuated (H37Ra) strains of Mtb were equally effective in inducing apoptosis macrophages; however, the attenuated strain – H37Ra resulted in significantly more apoptosis than the virulent strain H37Rv after 5 days of infection. In contrast, cytotoxicity of alveolar cells was the result of necrosis, but not apoptosis (Danelishvili et al. 2003). Although Mtb infection resulted in apoptosis of 14 % of the cells on the monolayer, cell death associated with necrosis was observed in 59 % of alveolar epithelial cells after no more than 5 days of infection. Fratazzi et al. (1999) also believed that the virulent Mtb strain H37Rv induces substantially less macrophage apoptosis than the attenuated strain H37Ra.

M. avium as well as Mtb replicate in human macrophages and induce apoptosis. Fratazzi et al. (1999) have shown that incubation of freshly added uninfected autologous macrophages with apoptotic M. avium-infected macrophages results in 90 % inhibition of bacterial growth. Apoptosis also prevents the release of intracellular components and the spread of mycobacterial infection by sequestering the pathogens within apoptotic bodies.

Weak macrophage activity and inefficient phagocytosis lead to uncontrolled replication of Mtb and death of phagocyte cells – and, so, dissemination of the infection on surrounding tissue. The apoptosis of the infected cells may result in self-recovery – it is one of the reasons for fragile balance between mycobacteria and humankind.

In TB-induced response several types of proteins participate: macrophage receptors, such as the mannose receptor, Toll-like receptors (TLRs), the vitamin D nuclear receptor; phagocyte cytokines, such as tumor necrosis factor (TNF), interleukin-1β (IL-1β), IL-6, IL-10, IL-12, and IL-18; chemokines, such as IL-8, and other important innate immune molecules. Polymorphisms in these genes have been variably associated with susceptibility to TB among different populations (Azad et al. 2012; Wu et al. 2012). In most of the clinical cases of TB, the production of IL-12, IL-18 and IFN-gamma is increased, however, the group of relatively lower cytokine production did not respond well to the treatment. In addition, the plasma level of one of the chemokines, IP-10, was shown to be an indicator for the severity of the disease (Mitsuyama et al. 2003; Volpe et al. 2006).

Granulysin is an important defensive molecule expressed by human T cells and NK cells and has a cytolytic activity against microbes including Mtb and tumors. Expression of granulysin protein and mRNA in CD8 positive T cells in the patients infected with drug sensitive or MDR M. tuberculosis were lower than that in the healthy volunteers, suggesting that granulysin treatment might improve the TB disease in human (Kita et al. 2011).

Chemokines (CK) are potent leukocyte activators and chemoattractants and participate in granuloma formation, functions critical for the immune response to Mtb. It was hypothesized by Saukkonen et al. (2002) that infection of alveolar macrophages with different strains of Mtb elicits distinct profiles of CK, which could be altered by human immunodeficiency virus (HIV) infection. Macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta were the major beta-CK produced in response to Mtb infection. Virulent Mtb (H37Rv) induced significantly less MIP-1 alpha than did the avirulent strain (H37Ra), while MIP-1 beta production was about equal for both strains. Mtb-induced CK secretion was partly dependent on tumor necrosis factor alpha (TNF-alpha). MIP-1 beta suppressed intracellular growth of Mtb twofold to threefold. Thus, beta-CK contribute to the innate immune response to Mtb infection (Saukkonen et al. 2002).